Biaryl-type heterocyclic compounds and Anti-bacterial uses thereof

Abstract

The invention relates to novel optically active heterodimeric 5,5'-linked biaryl-type heterocyclic compounds of Formula I, preferably bis-isochromans, as well as their isomers, pharmaceutically accepted salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic application, in particular anti-bacterial uses of the compounds having anti- bacterial activity. The optically active compound of the invention preferably contain a stereogenic ortho-trisubstituted biaryl axis and up to four chirality centers, and can be synthesized stereoselectively by using a Suzuki-Miyaura biaryl coupling reaction of optically active isochroman and 1-arylpropan-2-ol derivatives or alternative methods.

Description

[0001] Biaryl-type heterocyclic compounds and anti-bacterial uses thereof FIELD OF THE INVENTION The invention relates to new compounds of general formula (I), as well as their isomers, pharmaceutically accepted salts and solvates, to the pharmaceutical compositions containing them and to the therapeutic application thereof and in particular anti-bacterial uses of the compounds having anti-bacterial activity. The optically active compound of the invention preferably contain a stereogenic ortho-trisubstituted biaryl axis and up to four chirality centers, and can be synthesized stereoselectively by using a Suzuki-Miyaura biaryl coupling reaction of optically active isochroman and 1-arylpropan-2-ol derivatives or alternative methods. Further subjects of the invention are the methods of preparation of the compounds of general formula (I). TECHNICAL BACKGROUND The chiral 3-alkyl or 3-methylisochroman (3-metyl-3,4-dihydro-1H-isochromene) scaffold is a common subunit in optically active benzene-condensed O-heterocyclic secondary metabolites, in which the condensed benzene ring usually contains hydroxyl and methoxy substituents [He et al., 2004; Kock et al., 2009; Li, W. et al., 2017]. Optically active 1-aryl-3-methylisochromans containing phenolic hydroxyl groups were identified as natural components of olive with antioxidant, anti-inflammatory and neuroprotective activity [Bianco et al., 2002; Lorenz et al., 2005; Togna et al., 2013]. Benzene-condensed chiral O-heterocycles often form biaryl-type homo- or heterodimers with a stereogenic biaryl axis, the formation of which is aided by the presence of activating substituents of the benzene ring such as hydroxyl or alkoxy groups [Smyth et al., 2015]. Depending on the substitution pattern, the hindered rotation along the biaryl axis can result in atropisomers with axial chirality [Smyth et al., 2015] or interconverting conformers with different biaryl helicity [Rönsberg et al., 2013]. The axial chirality of biaryls is mainly governed by the number and size of the ortho-substituents, which impose strong steric repulsion in the periplanar transition state, and thus hinder the rotation about the biaryl axis. The axial chirality of biaryl natural products often plays a fundamental role in the bioactivity, since atropodiastereomers can possess markedly different activity [Clayden et al., 2009; Perreault et al., 2022; Yang et al., 2022; Patel et al., 2023; Sayed et al., 2023]. Although chiral isochroman natural products often contain activating hydroxyl or alkoxy groups on the condensed benzene ring, which would promote oxidative biaryl coupling reactions, there are only two reports on biaryl-type bis-isochroman natural products produced by oxidative biaryl coupling [Wu et al., 2009; Wu et al., 2021]. The homodimeric 7,7’-linked asperbiphenyl, the first axially chiral bis-isochroman, was isolated from the marine fungus Aspergillus sp. and it contains an ortho-tetrasubstituted stereogenic biaryl axis and four chirality centers [Wu et al., 2009]. The absolute configurations of the central and axial chirality elements were not determined. Penicisteckins A-D, two pairs of atropodiastereomeric biaryl-type hetero- and homodimeric bis-isochromans with 7,5’- and 7,7’-linkages, and a pair of atropodiastereomeric 2-(isochroman-5-yl)-1,4-benzoquinone derivatives [penicisteckin E and F] were reported as novel biaryl scaffolds containing both central and axial chirality elements from Penicillium steckii HNNU-5B18 [Wu et al., 2021]. The absolute configurations of penicisteckins A-D were determined by single crystal X-ray diffraction analysis, while those of penicisteckin E and F by TDDFT-ECD calculations of the atropodiastereomers [Wu et al., 2021]. The configurational assignment of both central and axial stereogenic elements in biaryl natural products is still a challenging task when single crystal X-ray analysis and chemical correlation is not applicable. In this case, the combination of electronic (ECD) and vibrational circular dichroism (VCD), and optical rotation (OR) calculations P139892 may offer a solution. Biaryl-type atropodiastereomers usually have near mirror-image ECD spectra when their biaryl chromophore is not symmetrical [Zhang et al., 2012], which can be used for the assignment of axial chirality with the aid of TDDFT-ECD calculations [Ola et al., 2014; Wu et al., 2015; Tang et al., 2020]. The sign and magnitude of the biaryl dihedral angle of the two aryl units in axially chiral biaryls are reflected in the interaction of the two aromatic chromophores, giving rise to exciton coupled ECD bands. The signs of the exciton coupled ECD couplets are usually characteristic of the axial chirality as exemplified by the mirror image ECD spectra of flavomannin A and B, atropodiastereomeric dihydroanthracenone dimers [Bara et al., 2013]. However, ECD data do not reflect the absolute configuration of the central chirality elements when they are also present in the condensed heterocyclic rings of biaryls. When the optically active monomeric units are also co-isolated with the dimers, they can be analysed independently by chiroptical methods to assign the central chirality [Zhang et al., 2012; Li, X.L. et al., 2017]. The central and axial chirality elements of cephalochromin, a homodimeric naphthpyranone natural product, could be determined simultaneously by VCD calculations [Polavarapu et al., 2009], but the same approach failed to determine the central chirality elements of flavomannin A [Bara et al., 2013]. Recently, the axial chirality of 9,10-phenanthrenequinone dimers has been determined by ECD calculations, while the central chirality of the side-chains were assigned by TDDFT-OR calculations [Csupor et al., 2020]. BRIEF DESCRIPTION OF THE INVENTION In an embodiment the invention relates to a chiral biaryl-type heterocyclic compound of general formula (I) Formula (I) wherein X is O, NH or N- PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group A is a heteroatom, preferably O, R1ais selected from H, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R1bis selected from H, (C1-6)alkyl-O-C(O), (C1-6)alkyl-O-C(O)-CH2-, preferably H, -CH2COOEt and -COOEt, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, more preferably (1-4)alkyl or (1- 4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H, R4ais H, OH, O-alkyl, O-PGAr or =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAror =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAris a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl, O-PGAr or =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPhor =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. In a preferred embodiment, the invention relates to a compound according to paragraph 1, said compound having general Formula (I), preferably Formula (Ia) wherein X is O, NH or NCbz, in particular O or NH, preferably O, A is a heteroatom, preferably O, R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H and CH2COOEt, wherein Y1is halogen, preferably F or Br, R2ais H or an alkyl, preferably methyl, R2bis H or an alkyl, preferably methyl, R3ais H, an alkyl or O-alkyl, preferably OCH3, R3bis H or alkyl, preferably H, R4ais H, OH, OCH3or =O, R4bis H, OH, OCH3or =O, R5ais H, OH, OCH3or =O, R5bis H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when R4band R5bis both =O, is a single bond. Preferably, the invention relates to a compound of general formula (I), according to any of the previous paragraphs, wherein X is O, NH or NCbz, is O or NH, preferably O, A is a heteroatom, preferably O, R1ais selected from H, , wherein Y1is halogen, preferably F or Br, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-, preferably H , wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, preferably methyl, R2bis (1-4)alkyl, preferably methyl, R3ais (1-4)alkoxy, preferably OCH3, R3bis H, R4ais (1-4)alkoxy, preferably OCH3, R4bis (1-4)alkoxy, preferably OCH3, R5ais (1-4)alkoxy, preferably OCH3, R5bis (1-4)alkoxy, preferably OCH3, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when R4band R5bis both =O, is a single bond. Preferably, the invention relates to a compound according to paragraph 1, said compound having general formula (I) wherein X is O, A is O, R1ais selected from H, , wherein Y1is F or Br, preferably F, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-, preferably H , wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, preferably methyl, R2bis (1-4)alkyl, preferably methyl, R3ais (1-4)alkoxy, preferably OCH3, R3bis H, R4ais (1-4)alkoxy, preferably OCH3, R4bis (1-4)alkoxy, preferably OCH3, R5ais (1-4)alkoxy, preferably OCH3, R5bis (1-4)alkoxy, preferably OCH3, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when R4band R5bis both =O, is a single bond. In a preferred embodiment in formula (I) X and A is O, R1ais selected from H, and , wherein Y1is F or Br, preferably F, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-, preferably H R2ais methyl, R2bis methyl, R3ais OH or OCH3, R3bis H, R4a, R4b, R5aand R5bis (1-4)alkoxy, preferably OCH3. According to a further preferred embodiment the invention relates to a compound of general formula (I) wherein X is O, NH or NCbz, preferably O or NH, in particular O, A is a heteroatom, preferably O, R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-,preferably H, -CH2COOEt and -COOEt, wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, in particular methyl, R2bis (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably H or OCH3, R3bis H, R4ais H, OH or (1-4)alkyloxy, preferably H, OH or OCH3, preferably OCH3, R4bis OH, (1-4)alkyloxy, OPGAr, preferably benzyloxy (BnO) or =O, preferably OH, OCH3, BnO or =O, in particular OH, OCH3or =O, R5ais H, OH, O-alkyl or =O, preferably OH, (1-4)alkyloxy or =O, in particular H, OH or OCH3, , R5bis H, OH, (1-4)alkyloxy, OPGAr, preferably BnO, or =O, preferably H, OH, OCH3, BnO or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. In a preferred embodiment in Formua (I) X and A is O R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, , wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, in particular methyl, R2bis (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably OCH3, R3bis H, R4ais H, R4bis (1-4)alkyloxy, BnO, preferably OH, R5ais H, or (1-4)alkyloxy, preferably H or OCH3, in particular OCH3, R5bis OH, or BzO, in particular OH. According to a further, particularly preferred embodiment the invention also relates to compounds according to formula (I.2), wherein said compounds have antimicrobial activity, and R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, wherein Y1is halogen, preferably F or Br, R2aand R2bare methyl, R3ais H or OH or OCH3, R3bis H R4ais H, OH, OCH3or =O, preferably H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, OCH3or =O, preferably H, OH or =O, R5ais OH or OCH3, preferably OH or =O, more preferably OH, R5bis OH, OCH3or =O, preferably OH or =O, more preferably OH, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. 1. The invention also relates to compounds according to formula (I.2) wherein said compounds have antimicrobial activity, and wherein said compound is:

[0002] Preferably, the invention also relates to compounds according to formula (I.2) wherein said compounds have antimicrobial activity, and wherein R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, wherein Y1is halogen, preferably F or Br, R2aand R2bare methyl, R3ais H or OH or OCH3, R3bis H R4ais H, OH, OCH3, preferably H or OH or OCH3, preferably OH or OCH3, R4bis H, OH, OCH3, preferably H or OH, R5ais OH or OCH3, preferably OH, R5bis OH, OCH3O, preferably OH. Preferably, the invention also relates to compounds according to formula (I.2) wherein said compounds have antimicrobial activity, and wherein said compound is selected from the group consisting of compounds 2, 4, 6, 9, 10, 18, 24, 25, 26, 27, 37, 41, 43,

[0003] In a preferred embodiment the compound of the invention is a compound of any of the previous paragraphs wherein the compound has axial chirality, preferably around the 5,5’ axis. The invention also relates to compounds of general formula (I), or a compound according to formula (I.1) or (I.2), or of any of the embodiments above, said compound being selected from the group consisting of the compounds defined above, for use as a medicine. Preferably, the compound is for use as an antimicrobial agent. Preferably, the compound is for use as an antibacterial agent. Preferably, the compound is for use as an antibacterial against Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii. In an embodiment, the compound is for use against a multidrug-resistant organism, preferably a multidrug- resistant bacterium. Preferably, the compound is for use in a method of treating or preventing a disease or infection caused by a microorganism. Preferably, the microorganism is a bacterium. Preferably, the bacterium is selected from Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii. Preferably, the microorganism is a multidrug-resistant organism, preferably a multidrug-resistant bacterium. The invention also relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. The invention also relates to a method of treating or preventing a disease or infection caused by a microorganism, said method comprising administering a compound of general formula (I), general formula (Ia) or general formula (II), or a compound selected from the group consisting of the compounds defined above, or a pharmaceutical composition as defined above to a subject. Preferably, the microorganism is a bacterium. Preferably, the bacterium is selected from Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii. Preferably, the microorganism is a multidrug-resistant organism, preferably a multidrug-resistant bacterium. Preferably, the compound is administered in an effective amount, preferably in a therapeutically effective amount. The invention also relates to a use of a compound of general formula (I), or a compound according to formula (I.1) or (I.2), or of any of the embodiments above as an antimicrobial agent, preferably an antibacterial agent, said compound being selected from the group consisting of the compounds defined above. Preferably the compound is used in vitro or ex vivo or out of the human or animal body. Preferably, the compound is used as an antibacterial against Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii. Preferably, the microorganism is a bacterium. Preferably, the bacterium is selected from Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii. Preferably, the microorganism is a multidrug-resistant organism, preferably a multidrug- resistant bacterium. The invention also relates to a compound of general formula (Ib) Formula (I.a) wherein X is O, NH or N-PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group R1is PGO is a hydroxyl-protecting group, preferably acetyl, R1ais selected from H, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, in particular (1-4)alkyl or (1-4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H, R4ais H, OH, O-alkyl or =O, preferably H, OH, (1-6)alkyloxy, preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAr or =O, preferably OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAr is a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl or =O, preferably OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPh or =O, preferably H, OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. Preferably, in the formula I.a X is O, NH or NCbz, R1ais selected from H, , wherein Y1is halogen, preferably Fl or Br, R2ais H or an alkyl, preferably methyl, R2bis H or an alkyl, preferably methyl, R3ais H, an alkyl or O-alkyl, preferably OCH3, R3bis H or alkyl, preferably H, R4ais H, OH, OCH3or =O, R4bis H, OH, OCH3or =O, R5ais H, OH, OCH3or =O, R5bis H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when R4band R5bis both =O, is a single bond. In a particular embodiment, the invention relates to a compound of any of formula (I) or (I.a), said compound being selected from the group consisting of: ,

[0004]

[0005] 61

[0006] . In a further major embodiment, the invention relates to the use of any of the compounds as defined in any of the previous paragraphs or embodiments as a reference compound, preferably in chiroptical spectroscopy and / or chiral chromatography. In a further major embodiment, the invention relates to a method for synthesis of 5,5’-linked biaryl-type heterocyclic compounds of general Formula I.1 (general synthesis method 1), said method comprising the steps of cross-coupling of a 5-halogen compound (preferably an isochroman) of general Formula (III) with the pinacolatoboronate ester derivative of general Formula (IV.1)

[0007] by a Suzuki-Miyaura biaryl cross-coupling reaction in the presence of a Pd catalysator and if desired in the presence of a phosphine ligand, to obtain a compound of general Formula (II.1), removal of the protecting groups, an oxa-Pictet-Spengler cyclization of said compound of general Formula (II.1) with an aldehyde having the formula R1b-CHOto produce general Formula (Ia), optionally as a mixture of stereoisomers, e.g. diastereoisomers or atropodiastereomers, wherein in the formulae X is O, NH or N-PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group PGOis a hydroxyl-protecting group, preferably acetyl, R1ais selected from H, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R1bis selected from H, (1-6)alkyl-O-C(O), (1-6)alkyl-O-C(O)-CH2-, preferably H, -CH2COOEt and -COOEt, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, more preferably (1-4)alkyl or (1- 4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H, R4ais H, OH, O-alkyl or =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAr or =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAris a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl or =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPh or =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. In a preferred embodiment the invention relates to a method wherein the pinacolatoboronate ester derivative of general Formula (IV) is a compound of Formula (IVH) whereas the compound of general Formula (III) is selected from the group of compounds consisting of: cis-(1R,3S)-J, trans-(1S,3S)-J cis-(1S,3R)-J and trans-(1R,3R)-J

[0008] (1S,3R)-(I.1) (1R,3R)-(I.1) the respective (1R,3S), (1S,3S), (1S,3R) and (1R,3R) derivatives of the biaryl compounds, whereas each may be present in the form of aR and / or aS stereomer(s), and wherein X is O, NH or NPGN, preferably O or NH, in particular O, R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-,preferably H, -CH2COOEt and -CH2COOEt, wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, in particular methyl, R2bis (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably H or OCH3, R3bis H, R4ais H, OH or (1-4)alkyloxy, preferably H, OH or OCH3, preferably OCH3, R4bis OH, (1-4)alkyloxy, O-PGAr(preferably BnO) or =O, preferably OH, OCH3, BnO or =O, in particular OH, OCH3or =O, R5ais H, OH, O-alkyl or =O, preferably OH, (1-4)alkyloxy or =O, in particular H, OH or OCH3, , R5bis H, OH, (1-4)alkyloxy, O-PGAr(preferably BnO) or =O, preferably H, OH, OCH3, BnO or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. In an alternative embodiment (general synthesis method 2), the invention relates to a method for synthesis of 5,5’- linked biaryl-type heterocyclic compounds of general Formula (I.2),

[0009] said method comprising the steps of coupling the pinacolatoboronate ester derivative of general Formula (IV.2) with a halogen compound of general formula (III.2) by a Suzuki-Miyaura biaryl cross-coupling reaction in the presence of a Pd catalyst and if desired in the presence of a phosphine ligand, to obtain a compound of general Formula (II.2) removal of the protecting groups, an oxa-Pictet-Spengler cyclization of said compound of general Formula (II.2) with an aldehyde having the formula R1b-CHO, preferably two equivalents of aldehydes, to produce general Formula (I.2), optionally as a mixture of stereoisomers, e.g. diastereoisomers or atropodiastereomers, wherein in the formulae X is O, NH or N-PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group PGOis a hydroxyl-protecting group, preferably acetyl, R1ais selected from H, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R1bis selected from H, (C1-6)alkyl-O-C(O), (C1-6)alkyl-O-C(O)-CH2-, preferably H, -CH2COOEt and -COOEt, wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, in particular (1-4)alkyl or (1-4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H, R4ais H, OH, O-alkyl or =O, preferably H, OH, (1-6)alkyloxy, preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAror =O, preferably OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAris a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl or =O, preferably OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPhor =O, preferably H, OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. Preferably, in this alternative embodiment, in the formulae X is O, NH or NPGN, preferably O or NH, in particular O, R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-,preferably H, -CH2COOEt and -COOEt, wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, in particular methyl, R2bis (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably H or OCH3, R3bis H, R4ais H, OH or (1-4)alkyloxy, preferably H, OH or OCH3, preferably OCH3, R4bis OH, (1-4)alkyloxy, O-PGAr (preferably BnO) or =O, preferably OH, OCH3, BnO or =O, in particular OH, OCH3or =O, R5ais H, OH, O-alkyl or =O, preferably OH, (1-4)alkyloxy or =O, in particular H, OH or OCH3, , R5bis H, OH, (1-4)alkyloxy, O-PGAr(preferably BnO) or =O, preferably H, OH, OCH3, BnO or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. In a preferred embodiment in the synthesis method claims X is O, , R1ais selected from H, wherein Y1is halogen, preferably F or Br, R1bis selected from H, wherein Y1is halogen, preferably F or Br, R2aand R2bare methyl, R3ais H or OH or OCH3, R3bis H R4ais H, OH, OCH3or =O, preferably H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, OCH3or =O, preferably H, OH or =O, R5ais OH or OCH3, preferably OH or =O, more preferably OH, R5bis OH, OCH3or =O, preferably OH or =O, more preferably OH, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond. It is to be understood that further parameters of the synthesis methods are usual parameters of the Suzuki-Miyaura biaryl cross-coupling and of the oxa-Pictet-Spengler cyclization and definition thereof is within the skills of a person skilled in the art based on the present teaching. In a preferred embodiment the substituents defined for the synthesis methods have any of the groups of substituents defined for the products or the product for uses or for the antimicrobial uses of the compounds. DEFINITIONS As used herein, the term “halo” or “halogen” means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. As used herein, the term “alkyl” alone or in combinations means a straight or branched-chain saturated hydrocarbon group containing from 1 to 6, preferably 1 to 5 carbon atom(s), preferably 1-4 carbon atoms (i.e. 1-6- alkyl or 1-5 alkyl or 1-4-alkyl groups), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and pentyl. In an embodiment, this phrase can relate to alkyl groups containing from 1 to 4, or 1 to 3, or 1 to 2 carbon atom(s), where the methyl or ethyl is a preferred embodiment. Alkoxy groups are defined analogously to alkyl groups. A “subject” as used herein is an individual of an animal species, preferably a vertebrate, more preferably a mammalian or avian species, in particular a mammalian species, highly preferably the individual is a primate, a hominid or a human. A “treatment” refers to any process, action, application, therapy, or the like, wherein the subject or patient is under aid, in particular medical or veterinarian aid with the object of improving the subject’s or patient’s condition, either directly or indirectly. Improving the subject’s condition may include improving an aesthetic condition (cosmetic treatment) and / or may include, in particular, restoring or maintaining normal function of an organ or tissue, preferably at least partly restoring or maintaining health (medical or veterinarian treatment). Treatment typically refers to the administration of an effective amount of a compound or composition described herein. Treatment may relate to or include medical or veterinarian treatment and cosmetic treatment, in particular medical or veterinarian treatment. “Preventing” or “prevention” of the development of a disease or condition refers to at least the reduction of likelihood of the risk of or susceptibility to acquiring a disease or disorder, or preferably causing at least one of the clinical symptoms of the disease or disorder not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease. A composition is a composition of matter which comprises an active agent and one or more other materials like carrier, excipient, buffer, salt etc. A pharmaceutically composition comprises, besides of the active agent, a pharmaceutically acceptable excipient. The terms “effective amount” or “therapeutically effective amount” are intended to qualify the amount of a therapeutic agent required to relieve to some extent one or more of the symptoms of a condition, disease or disorder. ABBREVIATIONS DFT Density Functional Theory DMF Dimethylformamide ECD Electronic Circular Dichroism ESI Electro-spray Ionization FTIR Fourier Transformed Infrared HPLC High-performance liquid chromatography HRMS High-resolution mass spectrometry MMFF Merck Molecular Force Field NBS N-Bromosuccinimide NMR Nuclear magnetic resonance NOE Nuclear Overhauser effect OR Optical Rotation TLC Thin layer chromatography TOF Time-of-Flight UV Ultraviolet VCD Vibrational Circular Dichroism DETAILED DESCRIPTION OF THE INVENTION Optically active heterodimeric 5,5’-linked biaryl-type heterocyclic compounds of Formula I, preferably bis- isochromans, containing a stereogenic ortho-trisubstituted biaryl axis and up to four chirality centers, were synthesized stereoselectively by using a Suzuki-Miyaura biaryl coupling reaction of optically active isochroman and 1-arylpropan-2-ol derivatives, providing the first access to synthetic biaryl-type isochroman dimers or biaryl-type isochroman-isoquinoline heterodimers, preferably isochroman dimers. As follow from the chirality centers and from the presence of axial chirality due to the stereogenic biaryl axis, a large variety of stereoisomers can be prepared for each compound having special chiroptical properties. By the inventors, in the exemplary embodiments enantiomeric pairs and stereoisomers up to seven derivatives were prepared with several, at least four different substitution patterns, which enabled to test how OR, ECD and VCD measurements and DFT calculations can be used to determine parallel central and axial chirality elements in three isolated blocks of chirality. In contrast to natural penicisteckins A-D and related biaryls, the ECD spectra and OR data of (aS) and (aR) atropodiastereomers did not reflect the opposite axial chirality but they were characteristic of the central chirality. The atropodiastereomers consistently resulted in near mirror image VCD curves, allowing the determination of axial chirality with the aid of DFT calculation or by comparison of characteristic VCD transitions. These particular chiral properties allow the use of present compounds as chiral chromatography standard as well as sets of reference compounds in spectroscopy, in particular chiroptical spectroscopy. In the recent work, the present inventors carried out the synthesis of optically active 5,5’-linked bis- isochromans with known absolute configuration and different substitution pattern at C-1 and C-1’, which contain an ortho-trisubstituted stereogenic biaryl axis and up to four chirality centers. This is the first synthesis of the bis- isochroman scaffold with central and axial chirality. The stereoselective synthesis enabled to change the absolute configurations of both axial and central chirality elements and to prepare up to seven stereoisomeric products including enantiomeric pairs and atropodiastereomers. The stereogenic elements constituted three isolated blocks of chirality, which consisted in the axial chirality and central chirality elements of the two isochroman subunits. The correlation of the configuration for these blocks of chirality is a very common and significant challenge in the stereochemical assignment of axially chiral biaryl-type homo- and heterodimers containing benzene-condensed heterocycles as monomeric units. The stereoisomeric bis- isochromans served as model compounds to test the combination of ECD, VCD and OR measurements and calculations to determine parallel the axial and central chirality elements. With the stereoisomeric bis-isochromans in hand, the present inventors could test how the different methods could distinguish the different stereoisomers, which may be extended to the stereochemical study of other related axially chiral biaryl natural products. Besides the chiroptical approach, the combination of NOE correlations and DFT conformational analysis was also tested to correlate the relative configuration of axial and central chirality elements. The planar structure and absolute configuration were confirmed independently by single crystal X-ray analysis for bis-isochroman derivatives. According to the present inventors’ synthetic plan, the target bis-isochromans P, R, U and V (Schemes 1.2 and 1.3) were obtained by oxa-Pictet-Spengler cyclization reactions of the axially chiral isochroman / 1-arylpropan-2-ol conjugate (N, O, S or T), which established diastereoselectively a new C-1’ chirality center and allowed varying the C-1 substituent. The key step of the preparation is the Suzuki-Miyaura biaryl cross-coupling reaction of cis- or trans- 5-iodoisochromans (cis-(1R,3S)-J or trans-(1S,3S)-J) with the pinacolatoboronate ester derivative H (Scheme 1,1), which produced the ortho-trisubstituted stereogenic biaryl axis [cis-(1R,3S)-J or trans-(1S,3S)-J + H → N, O, S or T ]. Chirality transfer from central to axial is expected to take place during formation of the biaryl axis. The boronate ester derivative H and the 5-iodoisochromans cis-(1R,3S)-J or trans-(1S,3S)-J could be traced back to (S)- propylenoxide [(S)-E] in two separate three- and four-step sequences. During the synthesis of the target bis-isochromans P, R, U and V, the present inventors could change the absolute configuration of the C-3 and C-3’ chirality centers by using (R)-propylene oxide instead of (S)-propylene oxide, which allowed preparing enantiomeric pairs. The formation of new axial and central chirality stereogenic elements during the biaryl cross-coupling and oxa-Pictet-Spengler reactions produced a series of stereoisomeric bis- isochromans, which were analyzed by ECD, VCD, OR, NOE measurements, X-ray analysis and DFT calculations. Stereoselective synthesis of heterodimeric 5,5’-linked bis-isochromans, containing a stereogenic ortho- trisubstituted biaryl axis and up to four chirality centers, was achieved using a Suzuki-Miyaura biaryl coupling reaction of optically active isochroman and 1-arylpropan-2-ol derivatives. Up to seven stereoisomers of the target compounds differing in the C-1 and C-1’ substitution were prepared, which were used as model compounds with three isolated blocks of chirality to determine axial and central chirality elements parallel by OR, ECD and VCD measurements and DFT calculations. The stereochemical analysis was also supported by single crystal X-ray analysis and NOE measurements. In contrast to related biaryl-type dimers such a penicisteckins A-D, the present inventors found that the ECD spectra and OR data of (aS) and (aR) atropodiastereomers were quite similar and did not reflect the opposite axial chirality. However, the atropodiastereomers showed consistently near mirror image VCD curves, allowing the determination of axial chirality with the aid of DFT calculation. The ECD spectra were dependent on the C-3 and C-3’ chirality centers, which also governed the helicity of the heteroring in the isochroman subunits. In some cases, weak VCD transitions were identified, which could serve to distinguish stereoisomers with different central chirality elements. In the chiroptical analysis of the present inventors’ bis-isochromans, the present inventors demonstrated the complimentary nature of ECD, OR and VCD methods to determine the AC of central and axial chirality elements in three isolated blocks of chirality. General procedure for synthesis of the compound according to the present invention It should be understood that the chemical reactions in Schemes 1.1-1.4 and 2 can be carried out with both (S)- propylene oxide and (R)-propylene oxide as a starting material. Scheme 1a-c shows the preparation of the biaryl coupling partners such as the boronate ester H, the diastereomeric haloisochromanes cis-(1R,3S)-J and trans-(1S,3S)- J and the halotetrahydroisoquinoline M. Scheme 1.1: Synthesis of the cross-coupling partners for the Suzuki reaction. Reagents and conditions: i) and v) n-BuLi, Ar / N2, anhydrous THF, -80°C, 20 min b) (S)-propylene oxide [(S)-E], Ar / N2, −80 °C, 20 min, c) BF3.Et2O, Ar / N2, −80 °C, 30 min; ii) AcCl, C5H5N, CH2Cl2, rt, 2.5-3 h; iii) and vii) N-halosuccinimide, MeCN, rt, 16h; iv) a) (Ph3P)2PdCl2, PPh3, NaOAc or KOAc, Ar / N2, DMF, rt, 15 min, b) B2pin2, Ar / N2, 150 °C, 1-3 h; vi) BF3.Et2O, CH2Cl2, 0 °C, 2 h → rt, 4 h; ix) TsCl, abs. C5H5N, DMAP, rt, 1 night; x) NaN3, abs. DMF, 80 °C, 4 h; xi) a) Ph3P, THF, rt, 2 h; b) H2O, 50 °C, 2 hours; xii) a) ArCHO, 3 Å MSz, abs. CH2Cl2, rt, 1 night; b) F3CCOOH, reflux 2-4 h; xiii) a) R6a-Cl, preferably CbzCl, Et3N, abs CH2Cl2, rt, 1 night a) N-halosuccinimide, F3CCOOH, MeCN, rt, 4 h.

[0010] The Suzuki cross-coupling reactions of trans-(1S,3S)-J with H afforded a mixture of atropodiastereomeric products (aR,1S,3S,2'S)-N and (aS,1S,3S,2'S)-N, which could be separated after the removal of the acetal protecting group. The subsequent oxa-Pictet-Spengler cyclizations with aldehydes produced the atropodiastereomric bis-isochroman products P and R. Scheme 1.2: Suzuki cross-coupling reactions of trans-(1S,3S)-J and subsequent mono-cyclization. Reagents and conditions: xiv) a) phosphine ligand, preferably PPh3, SPhos [Dicyclohexyl (2′,6′-dimethoxy[1,1′-biphenyl]-2- yl)phosphane (CAS No.: 657408-07-6)], (S)-BINAP or Xantphos [Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′- biphenyl]-2-yl]phosphane (CAS No.: 564483-18-7)], Pd(OAc)2, Ar / N2, DMF, rt, 1 h, b) CsF, Ar / N2, DMF, rt 30 min, c) a + b, Ar / N2, 150 °C, 1.5 h; xv) LiOH, MeOH:THF:H2O (5:2:3), rt, 4 h; xvi) a) MOMCl, ZnCl2, Et2O, 0 °C, 4-6 h, or b) (Et2O)2CHCOOEt, BF3.Et2O, toluene, or c) (Et2O)2CHCH2COOEt, BF3.Et2O, toluene, 0 °C → rt, 3 h or d) R1b- CHO BF3.Et2O, CH2Cl2, 0 °C, 2 h → rt, 4 h. Similarly, the Suzuki cross-coupling reactions of cis-(1R,3S)-J with H afforded a mixture of atrodiastereomeric products (aR,1R,3S,2'S)-S and (aS,1R,3S,2'S)-S, which could be separated after the removal of the acetal protecting group. The subsequent oxa-Pictet-Spengler cyclizations with aldehydes produced the atropodiastereomric bis- isochroman products U and V. Scheme 1.3: Suzuki cross-coupling reactions of cis-(1R,3S)-J and subsequent mono-cyclization. Reagents and conditions: xiv) a) phosphine ligand, preferably PPh3, SPhos [Dicyclohexyl (2′,6′-dimethoxy[1,1′-biphenyl]-2- yl)phosphane (CAS No.: 657408-07-6)], (S)-BINAP or Xantphos [Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′- biphenyl]-2-yl]phosphane (CAS No.: 564483-18-7)], Pd(OAc)2, Ar / N2, DMF, rt, 1 h, b) CsF, Ar / N2, DMF, rt 30 min, c) a + b, Ar / N2, 150 °C, 1.5 h; xv) LiOH, MeOH:THF:H2O (1:0.8:0.5) or (5:2:3), rt, 4 h; xvi) a) MOMCl, ZnCl2,

[0011] Et2O, 0 °C, 3-4 h, or b) (Et2O)2CHCOOEt, BF3.Et2O, toluene, or c) (Et2O)2CHCH2COOEt, BF3.Et2O, toluene, 0 °C → rt, 3 h or d) R1b-CHO BF3.Et2O, CH2Cl2, 0 °C, 2 h → rt, 4 h or R1b-CHO BF3.Et2O, CH2Cl2, 0 °C, 2 h → rt, 4 h. The protected halotetrahydroisoquinoline derivative M was also reacted with H in a Suzuki biaryl coupling reaction to produce atropodiastereomeric (aR,1R,3S,2'S)-W and (aS,1R,3S,2'S)-W, from which the acetyl group was removed and oxa-Pictet-Spengler cyclization afforded tetrahydroisoquinoline-isochroman hybrids X and Y after deprotection. Scheme 1.4: Suzuki cross-coupling reactions of M (on Schemes 1.1) and subsequent mono-cyclization. Reagents and conditions: xiv) a) Xantphos, Pd(OAc)2, Ar, abs DMF, rt, 1 h; b) CsF, Ar, abs. DMF, rt 30 min; c) a)

[0012] + b) 150 °C, 1,5 h; xv) LiOH, MeOH:THF:H2O, rt, 21 h; xvi) a) MeO-CH2-OMe, BF3.Et2O, abs. Et2O, 0 °C → rt, 18 h, or b) (Et2O)2CHCOOEt, BF3.Et2O, toluene, 0 °C → rt, 18 h; xvii) H2, Pd(C), THF, rt, 4-5 h. In a different sequence, the boronate ester H was coupled with the halo derivative G affording the biaryl product GH, which could be cyclized with two equivalents of aldehydes after the removal of the protecting groups to result in the bis-isochroman GL (Wuts, P. G. M. and Greene, T. W.2006.). Scheme 2: Suzuki cross-coupling reactions of M (on Schemes 1.1) and subsequent bis-cyclization. Reagents and conditions: xviii) a) phosphine ligand, Pd(OAc)2, Ar / N2, DMF, rt, 1 h, b) (S)-8, CsF, Ar / N2, DMF, rt 30 min, c) a + b, Ar / N2, 150 °C, 1.5 h; xix) LiOH, MeOH, rt, 1.5 h; xx) H2, Pd(C), THF, rt, 6 h; xxi) a) R1a-CHO = R1b-CHO,

[0013] (1S)-(+)-10-camphorsulfonic acid, toluene:MeOH (4:1), 80 °C, 8-16 h, or b) MOMCl, ZnCl2, THF, 0 °C → rt, 20 h, and c) H2, Pd(C), THF, rt, 1.5 h. EXAMPLES EXAMPLE 1: Material and Methods in Synthesys I The notation of the compounds (e.g. (S)-11) used in this section should be understood based on Schemes 3-6. Chemicals were purchased puriss p.a. from commercial suppliers. Thin layer chromatography (TLC) was performed on Silica gel 60 F254 (Merck) with visualization by UV-light (254 nm) and immersing into aqueous solution of sulfuric acidic ammonium molybdate or 5% ethanolic phosphomolybdic acid solution followed by heating. Flash column chromatography was performed on Silica gel 60 (Merck 0.040-0.063 mm). Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. Anhydrous solvents were used for all the reactions and distilled solvents were used as eluent for flash chromatography. HPLC-grade solvents were used for chiral HPLC separations. Preparative chiral HPLC was performed by Agilent 1260 Infinity II apparatus using Chiralpak IC column. The1H NMR (400 MHz) and13C NMR (100 MHz) spectra were recorded with Bruker Avance I 400 MHz spectrometer at 298 K. Chemical shifts are referenced to Me4Si (0.00 ppm for1H) and to the residual solvent signals (CDCl3: 77.16 ppm for13C). Chemical shifts were reported as δ in ppm and3JH,H coupling constants in Hz. IR spectra were recorded on a JASCO FT / IR-4100 spectrometer and absorption bands are presented as wavenumber in cm-1. Optical rotations were measured at room temperature with a Perkin-Elmer 241 automatic polarimeter (c [g / 100ml]). ECD spectra were recorded on a J-810 spectropolarimeter. VCD measurements were performed on a BioTools ChiralIR-2X spectrometer at a resolution of 4 cm-1under ambient temperature for 18 x 3000 scans, respectively. Sample were dissolved in CDCl3and the solutions were placed in a 100 μm BaF2cell. For spectroscopic measurements spectroscopic grade solvents were used. Diffraction intensity data were collected at room temperature and in case of (aS,1R,3R,1’R,3’R)-22 (Compound 13a) at low temperature (120K) using a Bruker-D8 Venture diffractometer (Bruker AXS GmbH, Karlsruhe, Germany) equipped with INCOATEC IμS 3.0 (Incoatec GmbH, Geesthacht, Germany) dual (Cu and Mo) sealed tube micro sources and a Photon II Charge-Integrating Pixel Array detector (Bruker AXS GmbH, Karlsruhe, Germany) using Mo Kα (λ = 0.71073 Å) radiation. Electrospay quadrupole time-of- flight HRMS measurements were performed with a MicroTOF-Q type QqTOF MS instrument equipped with an ESI source from Bruker (Bruker Daltoniks, Bremen, Germany). 1.1 Computational section Mixed torsional / low-frequency mode conformational searches were carried out by means of the Macromodel 10.8.011 software, using the Merck Molecular Force Field (MMFF) with an implicit solvent model for CHCl3[MacroModel, Schrödinger, LLC, 2015]. All quantum chemical calculations were carried out with the Gaussian 09 software package [Frisch et al., 2010 and 2013]. The B3LYP (VCD) and ωB97X [Chai & Head-Gordon, 2008] (ECD) functionals with the TZVP basis set and PCM solvent model for CHCl3(VCD) and MeCN (ECD) were used to re- optimize the initial MMFF geometries. TDDFT-ECD and -OR calculations were performed at the B3LYP / TZVP, BH&HLYP / TZVP, CAM-B3LYP / TZVP and the PBE0 / TZVP levels of theory with the PCM solvent model for MeCN. ECD spectra were generated as sums of Gaussians with 2100-3000 cm-1widths at half-height, using dipole- velocity-computed rotational strength values [Stephens & Harada, 2010]. VCD calculations were performed at the B3LYP / TZVP PCM / CHCl3level, while the spectra were gained by applying a 8 cm-1half-height width and scaled by a factor of 0.985. GBoltzmann distributions were estimated from the B3LYP and ωB97X energies. The MOLEKEL software package was used for visualization of the results [Varetto, 2009]. 1.2 Syntheses and characterization of the compounds 1.2.1 General procedure for synthesis of chiral non-racemic 1-arylpropan-2-ols The corresponding aryl bromide (1.3 or 1.5 equiv) was dissolved in anhydrous THF (~1 g aryl bromide / 10 ml anhydrous THF) under Ar or N2atmosphere and the solution was cooled to -80 °C. Then 2.5 M n-BuLi in hexane (1.3 or 1.5 equiv.) was added and after stirring for 20 minutes, (S)- or (R)-propylene oxide (1.0 equiv.) was added and the reaction mixture was stirred for 20 minutes at -80 °C. Next BF3·Et2O (1.1 equiv.) was added to the solution, which was stirred further for 30 minutes at -80 °C. Then the cooling was stopped and a saturated solution of NH4Cl was added to the reaction mixture. The mixture was stirred for 10 minutes and concentrated in vacuo. The suspension was diluted with EtOAc and the organic phase was washed twice with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the optically active 1-arylpropan-2-ol derivative. 1.2.1.1. - (S)-1-(3,4-dimethoxyphenyl)propan-2-ol [(S)-11] [Kerti et al., 2007] Starting from 4-bromoveratrole 9 (2.00 ml, 3.02 g, 13.90 mmol, 1.3 equiv.): anhydrous THF (30 ml), 2.5 M n-BuLi in hexane (5.56 ml, 13.90 mmol, 1.3 equiv.), (S)-propylene oxide (749 μl, 621 mg, 10.70 mmol, 1.0 equiv., ≥98.0 ee%), BF3·Et2O (1.45 ml, 1.67 g, 11.77 mmol, 1.1 equiv.). (S)-11: 1.38 g (yield: 66%) yellow syrup; (c = 0.50; CHCl3). Flash chromatography (hexane / EtOAc 7:3 → 6:4 → 4:6 → 3:7); Rf = 0.24 (hexane / EtOAc 6:4);1H NMR (400 MHz, CDCl3) δ = 6.85 – 6.79 (m, 1H, H-5 or H-8 or H-9), 6.78 – 6.72 (m, 2H, H- 5, H-8, or H-5, H- 9, or H-8, H-9), 4.02 – 3.93 (m, 1H, H-2), 3.87, 3.85 (2s, 2 x 3H, H-10, H- 11), 2.72 (dd, J = 13.6, 4.8 Hz, 1H, H-1- a), 2.62 (dd, J = 13.6, 8.0 Hz, 1H, H-1-b), 1.89 (bs, 1H, OH), 1.23 (d, J = 6.2 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 148.9, 147.7, 131.1 (3C, C-4, C-6, C-7), 121.3, 112.6, 111.4 (3C, C-5, C-8, C-9) 68.9 (1C, C-2), 55.9, 55.8 (2C, C- 10, C-11), 45.3 (1C, C-1), 22.7 (1C, C-3); IR (KBr) ν = 3398 (ν OH), 3061, 3000 (ν Ar =CH), 2963, 2933 (νas Me, νas CH2), 2858, 2841 (νs Me, νs CH2), 2007, 1905, 1830, 1789, 1716, 1682 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1604, 1588, 1519, 1464 (ν Ar C=C, δasMe, βsCH2), 1371, 1334 (δsMe, δ CH), 1261 (νasAr-O-Me), 1119, 1071 (ν C-OH), 1038, 1021 (νsAr-O-Me), 889, 829 (1,2,4-trisubstituated) cm-1; ESI-TOF- HRMS: m / z calculated for C11H16NaO3 [M+Na]+219.0992, found 219.0990. 1.2.1.2. - (R)-1-(3,4-dimethoxyphenyl)-propan-2-ol [(R)-11] [Inoue et al., 2005] Starting from 4-bromoveratrole 9 (4.31 ml, 6.51 g, 29.98 mmol, 1.5 equiv.): anhydrous THF (65 ml), 2.5 M n-BuLi in hexane (11.99 ml, 29.98 mmol, 1.5 equiv.), (R)-propylene oxide (1.40 ml, 1.16 g, 19.98 mmol, 1.0 equiv., ≥99.0 ee%), BF3·Et2O (2.71 ml, 3.12 g, 21.98 mmol, 1.1 equiv.). (R)-11: 2.90 g (yield: 74%) yellow syrup; [α]^^^−36 (c = 0.51; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of (S)- 11. 1.2.1.3. - (S)-1-(3,4,5-trimethoxyphenyl)propan-2-ol [(S)-16] [Ren et al., 2004] Starting from 5-bromo-1,2,3-trimethoxybenzene 15 (9.52 g, 38.54 mmol, 1.5 equiv.): anhydrous THF (95 ml), 2.5 M n-BuLi in hexane (15.42 ml, 38.54 mmol, 1.5 equiv.), (S)-propylene oxide (1.80 ml, 1.49 g, 25.69 mmol, 1.0 equiv., ≥98.0 ee%), BF3·Et2O (3.49 ml, 4.01 g, 28.26 mmol, 1.1 equiv.). (S)-16: 5.21 g (yield: 90%) yellow syrup; [α]^^^+25 (c = 0.52; CHCl3). Flash chromatography (hexane / EtOAc 7:3 → 6:4 → 4:6 → 3:7); Rf = 0.33 (hexane / EtOAc 1:1);1H NMR (400 MHz, CDCl3) δ = 6.43 (s, 2H, H-5, H-9), 4.06 – 3.97 (m, 1H, H-2), 3.85 (s, 6H, H-10, H-12), 3.83 (s, 3H, H-11), 2.73 (dd, J = 13.5, 4.6 Hz, 1H, H-1-a), 2.61 (dd, J = 13.5, 8.2 Hz, 1H, H-1-b), 1.96 (bs, 1H, OH), 1.26 (d, J = 6.2 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 153.2, 136.6, 134.4 (4C, C-4, C-6, C- 7, C-8), 106.3 (2C, C-5, C- 9), 68.8 (1C, C-2), 60.9 (1C, C-11), 56.1 (2C, C-10, C-12), 46.2 (1C, C-1), 22.9 (1C, C- 3); IR (KBr) ν = 3444 (ν OH), 2936 (νasCH2), 2837 (νsCH2), 2012, 1965 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1589, 1507, 1454 (ν Ar C=C, δas Me, βs CH2), 1371, 1333 (δs Me, δ CH), 1237(νas Ar-O-Me), 1126 (ν C-OH), 1054 (νs Ar-O-Me), 852 (1,2,3,5-tetrasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C12H18NaO4[M+Na]+249.1097, found 249.1096. 1.2.1.4. - (R)-1-(3,4,5-trimethoxy-phenyl)propan-2-ol [(R)-16] [Ren et al., 2004] Starting from 5-bromo-1,2,3-trimethoxybenzene 15 (6.35 g, 25.69 mmol, 1.5 equiv.): anhydrous THF (65 ml), 2.5 M n-BuLi in hexane (10.28 ml, 25.69 mmol, 1.5 equiv.), (R)-propylene oxide (1.20 ml, 1.00 g, 17.13 mmol, 1.0 equiv., ≥99.0 ee%), BF3·Et2O (2.33 ml, 2.67 g, 18.84 mmol, 1.1 equiv.). (R)-16: 3.41 g (yield: 88%) yellow syrup; [α]^^^−31 (c = 0.52; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of (S)-16. 1.2.2. General procedure for acetylation of chiral non-racemic 1-arylpropan-2-ols The corresponding 1-arylpropan-2-ol (1.0 equiv.) was dissolved in anhydrous CH2Cl2(20-70 ml) and anhydrous C5H5N (3.0 equiv.) and AcCl (2.0 equiv.) were added and the reaction mixture was stirred at room temperature. When the starting material was consumed (2.5-3 hours) on the basis of TLC monitoring, a saturated solution of NaHCO3was added to the reaction mixture and stirred for 10 minutes. The mixture was diluted with CH2Cl2and the phases were separated in a separatory funnel. The organic phase was washed twice with a 10% solution of NaHSO4, twice with a saturated solution of NaHCO3and twice with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the 1-arylpropan-2-yl acetate target derivative. 1.2.2.1. - (S)-1-(3,4-dimethoxyphenyl)propan-2-yl acetate [(S)-12] [González-Liste et al., 2016] Starting from (S)-11 (1.30 g, 6.63 mmol, 1.0 equiv.): anhydrous CH2Cl2(20 ml), anhydrous C5H5N (1.60 ml, 1.57 g, 19.89 mmol, 3.0 equiv.), AcCl (943 ml, 1.04 g, 13.26 mmol, 2.0 equiv.), reaction time: 2.5 hours. (S)-12: 1.32 g (yield: 84%) yellow syrup; [α]^^^+6 (c = 0.52; CHCl3). Flash chromatography (hexane / EtOAc 8:2 → 7:3); Rf= 0.60 (hexane / EtOAc 6:4);1H NMR (400 MHz, CDCl3) δ = 6.81 – 6.77 (m, 1H, H-5 or H-8 or H-9), 6.76 – 6.71 (m, 2H, H- 5, H-8, or H-5, H-9, or H-8, H-9), 5.14 – 5.03 (m, 1H, H-2), 3.87, 3.86 (2s, 2 x 3H, H-10, H- 11), 2.88 (dd, J = 13.7, 6.6 Hz, 1H, H-1-a), 2.68 (dd, J = 13.7, 6.6 Hz, 1H, H-1-b), 2.01 (s, 3H, H-13), 1.21 (d, J = 6.3 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 170.6 (1C, C-12), 148.8, 147.7, 130.3 (3C, C-4, C-6, C-7), 121.5, 112.6, 111.1 (3C, C-5, C-8, C-9), 71.7 (1C, C-2), 55.9 (2C, C-10, C-11), 41.9 (1C, C-1), 21.5 (1C, C-13), 19.5 (1C, C-3); IR (KBr) ν = 2935 (νas CH2), 2835 (νs CH2), 2061 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1731 (ν C=O), 1607, 1590, 1517, 1455 (ν Ar C=C, δasMe, βsCH2), 1372, 1331 (δsMe, δ CH), 1240 (νasC-O-C=O, νasAr-O-Me), 1029 (νsC-O-C=O, νsAr-O-Me), 856, 806 (1,2,4-trisubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C13H18NaO4 [M+Na]+261.1097, found 261.1096. 1.2.2.2. - (R)-1-(3,4-dimethoxyphenyl)propan-2-yl acetate [(R)-12] Starting from (R)-11 (3.74 g, 19.07 mmol, 1.0 equiv.): anhydrous CH2Cl2(70 ml), anhydrous C5H5N (4.61 ml, 4.53 g, 57.22 mmol, 3.0 equiv.), AcCl (2.71 ml, 2.99 g, 38.15 mmol, 2.0 equiv.), reaction time: 3 hours. (R)-12: 4.12 g (yield: 91%) yellow syrup; [α]^^^−16 (c = 0.54; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of (S)-12. 1.2.3. General procedure for the halogenation of 1-arylpropan-2-yl acetates or isochroman derivatives with N-halosuccinimides (NXS, X = I or Br) The corresponding 1-arylpropan-2-yl acetate (1.0 equiv.) was dissolved in anhydrous MeCN (5-30 ml), then NIS (1.1 or 1.3 equiv.) and F3CCOOH (0.3 equiv.) or NBS (1.2 equiv.) were added, and the solution was stirred at room temperature. When the starting material was consumed (1.5-16 hours) on the basis of TLC monitoring, the solvent was evaporated in vacuo and the residual solid was dissolved in EtOAc. The organic phase was washed with water, twice with a 10% aqueous solution of Na2S2O3and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the 1-(2-halo)arylpropan-2-yl acetate or isochroman target derivatives. 1.2.3.1. - (S)-1-(2-iodo-4,5-dimethoxyphenyl)propan-2-yl acetate [(S)-13] Starting from (S)-12 (1.28 g, 5.39 mmol, 1.0 equiv.): anhydrous MeCN (20 ml), NIS (1.58 g, 7.01 mmol, 1.3 equiv.) and F3CCOOH (124 μl, 184 mg, 1.62 mmol, 0.3 equiv.), reaction time: 16 hours. (S)-13: 1.88 g (yield: 96%) yellow syrup; [α]^^^+6 (c = 0.55; CHCl3). Flash chromatography (CH2Cl2 / EtOAc 10:0 → 10:0.05 → 10:0.1); Rf= 0.35 (CH2Cl2 / EtOAc 10:0.05);1H NMR (400 MHz, CDCl3) δ = 7.21, 6.74 (2s, 2 x 1H, H-6, H-9), 5.20 – 5.11 (m, 1H, H-2), 3.85 (s, 6H, H-10, H-11), 2.96 (dd, J = 14.0, 7.7 Hz, 1H, H-1-a), 2.89 (dd, J = 14.0, 5.7 Hz, 1H, H-1-b), 1.99 (s, 3H, H-13), 1.29 (d, J = 6.2 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 170.4 (1C, C-12), 149.2, 148.3, 133.1 (3C, C-4, C-7, C-8), 121.7, 113.2 (2C, C-6, C-9), 89.0 (1C, C-5), 71.0 (1C, C-2), 56.2, 56.0 (2C, C-10, C-11), 46.0 (1C, C-1), 21.4 (1C, C- 13), 19.8 (1C, C-3); IR (KBr) ν = 3078 (ν Ar =CH), 2976, 2933 (νas Me, νas CH2), 2840 (νsCH2), 2048, 1997 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1737 (ν C=O), 1596, 1567, 1507, 1441 (ν Ar C=C, δasMe, βsCH2), 1373, 1334 (δsMe, δ CH), 1257 (νasC-O-C=O, νasAr-O-Me), 1051 (ν Ar C-I), 1028 (νs C-O-C=O, νs Ar-O-Me), 858 (1,2,4,5-tetrasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C13H17INaO4 [M+Na]+387.0064, found 387.0064. 1.2.3.2. - (R)-1-(2-iodo-4,5-dimethoxyphenyl)propan-2-yl acetate[(R)-13] Starting from (R)-12 (1.75 g, 7.35 mmol, 1.0 equiv.): anhydrous MeCN (30 ml), NIS (2.15 g, 9.55 mmol, 1.3 equiv.), F3CCOOH (169 μl, 251 mg, 2.21 mmol, 0.3 equiv.), reaction time: 16 hours. (R)-13: 2.47 g (yield: 93%) yellow syrup; [α]^^^−17 (c = 0.53; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of (S)-13. 1.2.3.3. - (S)-1-(2-bromo-4,5-dimethoxyphenyl)propan-2-yl acetate [(S)-14] Starting from (S)-12 (1.36 g, 5.71 mmol, 1.0 equiv.): anhydrous MeCN (15 ml), NBS (1.22 g, 6.85 mmol, 1.2 equiv.), reaction time: 16 hours. (S)-14: 1.76 g (yield: 97%) pale yellow syrup; [α]^^^+8 (c = 0.52; CHCl3). Flash chromatography (CH2Cl2 / EtOAc 10:0.05 → 10:0.1); Rf= 0.40 (CH2Cl2 / EtOAc 10:0.05);1H NMR (400 MHz, CDCl3) δ = 7.00, 6.74 (2s, 2 x 1H, H-6, H- 9), 5.22 – 5.13 (m, 1H, H-2), 3.85 (s, 6H, H-10, H-11), 2.93 (d, J = 6.6 Hz, 2H, H-1), 1.99 (s, 3H, H-13), 1.27 (d, J = 6.3 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 170.5 (1C, C-12), 149.2, 148.3, 133.1 (3C, C-4, C-7, C-8), 115.5, 113.9 (2C, C-6, C-9), 114.9 (1C, C-5), 70.8 (1C, C-2), 56.2, 56.1 (2C, C-10, C-11), 41.6 (1C, C-1), 21.4 (1C, C-13), 19.8 (1C, C-3); IR (KBr) ν = 3081 (ν Ar =CH), 2978, 2934 (νasMe, νasCH2), 2842 (νsCH2), 2057 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1736 (ν C=O), 1604, 1573, 1509, 1461 (ν Ar C=C, δas Me, βs CH2), 1373, 1337 (δs Me, δ CH), 1244, 1207 (νas C-O-C=O, νas Ar-O-Me), 1051, 1031 (ν Ar C-Br, νs C-O-C=O, νs Ar-O-Me), 859 (1,2,4,5-tetrasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C13H17BrNaO4[M+Na]+339.0202, found 339.0201. 1.2.3.4. - (1R,3S)-1-(4-fluorophenyl)-5-iodo-6,7,8-trimethoxy-3-methylisochroman [cis-(1R,3S)-18] Starting from cis-(1R,3S)-17 (1.02 g, 3.06 mmol, 1.0 equiv.): anhydrous MeCN (30 ml), NIS (757 mg, 3.36 mmol, 1.1 equiv.), F3CCOOH (70 μl, 105 mg, 0.92 mmol, 0.3 equiv.), reaction time: 16 hours. cis-(1R,3S)-18: 968 mg (yield 69%) white powder; mp 168-172 °C −5 (c = 0.53; CHCl3). Flash chromatography (hexane / CH2Cl2 7:3 → 6:4 → 1:1 → 4:6 → 3:7 → 0:10); Rf= 0.22 (hexane / CH2Cl21:1);1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.20 (m, 2H, H- 14, H-18), 7.04 – 6.96 (m, 2H, H-15, H-17), 5.72 (s, 1H, H-1), 3.87 (s, 3H, H-9), 3.77 (s, 3H , H-10), 3.82 – 3.69 (m, 1H, H-3), 3.08 (s, 3H, H-11), 2.73 (dd, J = 16.4, 1.3 Hz, 1H, H-4eq), 2.60 (ddd, J = 16.4, 10.6, 1.4 Hz, 1H, H-4ax), 1.38 (d, J = 6.2 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F = 245.5 Hz, 1C, C-16), 152.8 (1C, C-6), 150.9 (1C, C-8), 144.7 (1C, C-7), 139.7 (d, JC-F= 3.0 Hz, 1C, C-13), 133.9 (1C, C-4a), 130.1 (d, JC-F= 8.1 Hz, 2C, C-14, C-18), 129.2 (1C, C-8a), 115.2 (d, JC-F = 21.4 Hz, 2C, C-15, C-17), 92.5 (1C, C-5), 77.5 (1C, C- 1), 71.0 (1C, C-3), 60.8, 60.7, 59.3 (3C, C-9, C-10, C-11), 42.8 (1C, C-4), 21.6 (1C, C-12); IR (KBr) ν = 3042 (ν Ar =CH), 2974, 2937 (νas Me, νas CH2), 2898, 2858 (νs Me, νs CH2, ν CH), 1902 (γ Ar C=C overtone and combination bands), 1604, 1579, 1552, 1513, 1505, 1462 (ν Ar C=C, βsCH2, δasMe), 1385, 1354, 1335, 1304 (δsMe, δ CH, γsCH2), 1290, 1274, 1262, 1225, 1153, 1120, 1100 (νas Ar-O-Me, ν Ar C-F), 1085, 1073, 1051, 1024 (νas C-O-C, ν Ar C-I, νs Ar-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C19H20FINaO4 [M+Na]+481.0283, found 481.0282. 1.2.3.5. - (1S,3R)-1-(4-fluorophenyl)-5-iodo-6,7,8-trimethoxy-3-methylisochroman [cis-(1S,3R)-18] Starting from cis-(1S,3R)-17 (1.45 g, 4.36 mmol, 1.0 equiv.): anhydrous MeCN (30 ml), NIS (1.08 g, 4.80 mmol, 1.1 equiv.), F3CCOOH (100 μl, 149 mg, 1.31 mmol, 0.3 equiv.), reaction time: 16 hours. cis-(1S,3R)-18: 1.40 g (yield 70%) white powder; mp 168-171 °C +48 (c = 0.52; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of cis-(1R,3S)-18. 1.2.3.6. - (1S,3S)-1-(4-fluorophenyl)-5-iodo-6,7,8-trimethoxy-3-methylisochroman [trans-(1S,3S)-18] Starting from trans-(1S,3S)-17 (1.21 g, 3.65 mmol, 1.0 equiv.): anhydrous MeCN (30 ml), NIS (902 mg, 4.01 mmol, 1.1 equiv.), F3CCOOH (84 μl, 125 mg, 1.09 mmol, 0.3 equiv.), reaction time: 16 hours. trans-(1S,3S)-18: 1.54 g (yield: 92%) white solid; mp 55-59 +5 (c = 0.53; CHCl3). Flash chromatography (hexane / EtOAc 97:3 → 95:5 → 93:7); Rf = 0.45 (hexane / EtOAc 9:1);1H NMR (400 MHz, CDCl3) δ = 7.21 – 7.14 (m, 2H, H-14, H-18), 7.03 – 6.95 (m, 2H, H-15, H-17), 5.94 (s, 1H, H-1), 3.91 (s, 3H, H-9), 3.86 (s, 3H, H-10), 3.75 – 3.63 (m, 1H, H-3), 3.55 (s, 3H, H-11), 2.69 (dd, J = 17.0, 3.7 Hz, 1H, H-4eq), 2.41 (dd, J = 17.0, 10.9 Hz, 1H, H-4ax), 1.23 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F = 246.4 Hz, 1C, C-16), 153.0 (1C, C-6), 150.4 (1C, C-8), 144.1 (1C, C-7), 137.6 (d, JC-F = 3.0 Hz, 1C, C-13), 132.9 (1C, C-4a), 130.3 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 126.7 (1C, C-8a), 114.8 (d, JC-F= 21.2 Hz, 2C, C-15, C-17), 92.8 (1C, C-5), 73.3 (1C, C-1), 63.8 (1C, C-3), 60.8, 60.7, 60.2 (3C, C-9, C-10, C-11), 41.7 (1C, C-4), 21.6 (1C, C-12); IR (KBr) ν = 3044 (ν Ar =CH), 2968, 2936 (νasMe, νasCH2), 2890, 2833 (νs Me, νs CH2, ν CH), 2021, 1914 (γ Ar C=C overtone and combination bands), 1603, 1557, 1507, 1462 (ν Ar C=C, βs CH2, δas Me), 1383, 1362, 1334 (δs Me, δ CH, γs CH2), 1283, 1263, 1225, 1197, 1160, 1141, 1122, 1110 (νasAr-O-Me, ν Ar C-F), 1089, 1068, 1047, 1022 (νasC-O-C, ν Ar C-I, νsAr-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C19H20FINaO4[M+Na]+481.0283, found 481.0282. 1.2.3.7. - (1R,3R)-1-(4-fluorophenyl)-5-iodo-6,7,8-trimethoxy-3-methylisochroman [trans-(1R,3R)-18] Starting from trans-(1R,3R)-17 (1.27 g, 3.82 mmol, 1.0 equiv.): anhydrous MeCN (30 ml), NIS (946 mg, 4.20 mmol, 1.1 equiv.), F3CCOOH (88 μl, 131 mg, 1.15 mmol, 0.3 equiv.), reaction time: 16 hours. trans-(1R,3R)-18: 1.63 g (yield: 93%) white solid; mp 57-59 °C; [α]^^^−11 (c = 0.53; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of trans-(1S,3S)-18. 1.2.3.8. - (S)-5-iodo-6,7,8-trimethoxy-3-methylisochroman [(S)-25] Starting from (S)-24 (556 mg, 2.33 mmol, 1.0 equiv.): anhydrous MeCN (10 ml), NIS (683 mg, 3.03 mmol, 1.3 equiv.), F3CCOOH (54 μl, 80 mg, 0.70 mmol, 0.3 equiv.) reaction time: 1.5 hours. (S)-25: 787 mg (yield: 93%) white solid; mp 33-36 °C; [α]^^^: +72 (c = 0.53; CHCl3). Flash chromatography (hexane / Et2O 95:5 → 9:1); Rf = 0.47 (hexane / Et2O 8:2);1H NMR (400 MHz, CDCl3) δ = 4.87 (d, J = 15.6 Hz, 1H, H-1-a), 4.57 (d, J = 15.6 Hz, 1H, H-1- b), 3.88, 3.86 (2s, 3 x 3H, H-9, H-10, H-11), 3.74 – 3.61 (m, 1H, H-3), 2.64 (dd, J = 16.7, 2.1 Hz, 1H, H-4- a), 2.39 (dd, J = 16.8, 10.7 Hz, 1H, H-4-b), 1.38 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 152.2, 149.7, 143.9, 132.4, 126.3 (5C, C-4a, C-8a, C-6, C-7, C-8), 92.8 (1C, C-5), 71.4 (1C, C-3), 64.6 (1C, C-1), 61.0, 60.7, 60.5 (3C, C-9, C-10, C-11), 41.6 (1C, C-4), 21.5 (1C, C-12); IR (KBr) ν = 2963, 2928 (νasMe, νasCH2), 2881, 2837 (νsMe, νs CH2), 2018, 1952, 1915, 1893, 1732 (γ Ar C=C overtone and combination bands), 1648, 1588, 1558, 1466, 1416 (ν Ar C=C, βs CH2, δas Me), 1387, 1367, 1350, 1334 (δs Me, δ CH, γs CH2), 1261, 1240, 1211 (νas Ar-O-Me), 1082, 1051, 1025 (νasC-O-C, ν Ar C-I, νsAr-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C13H17INaO4[M+Na]+387.0064; found 387.0063. 1.2.4. General procedure for Miyaura borylation of chiral non-racemic 1-(2-haloaryl)propan-2-yl acetates To the solution of 1-(2-haloaryl)propan-2-yl acetate (1.0 equiv.) in anhydrous DMF (18-37 ml), Ph3P (0.2 equiv.), (Ph3P)2PdCl2(0.1 equiv.) and anhydrous NaOAc (4.0 equiv.) or annealed KOAc (4.0 equiv.) were added under Ar or N2atmosphere, and the solution was stirred for 15 minutes with inert gas bubbling at room temperature. Then B2Pin2 (3.0 equiv.) was added to the reaction mixture and the temperature was raised to 150 °C. When the starting material was consumed (1 hour-3 hours) on the basis of TLC monitoring, the reaction mixture was poured on ice and diluted with Et2O and the mixture was filtered on a short pad of Celite. The Celite was washed with Et2O and the two layers were separated in a separatory funnel. The aqueous phase was extracted twice with Et2O and the combined organic layers were washed twice with brine and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to yield the 1-[2-(pinacolatoboryl)aryl]propan-2-yl acetate target derivative. 1.2.4.1. - (S)-1-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl acetate [(S)-8] Starting from (S)-13 (939 mg, 2.58 mmol, 1.0 equiv.): anhydrous DMF (20 ml), Ph3P (135 mg, 0.52 mmol, 0.2 equiv.), (Ph3P)2PdCl2(181 mg, 0.26 mmol, 0.1 equiv.), anhydrous NaOAc (846 mg, 10.31 mmol, 4.0 equiv.), B2Pin2 (1.96 g, 7.73 mmol, 3.0 equiv.), reaction time: 1 hour. (S)-8: 524 mg (yield: 56%) pale yellow syrup. Starting from (S)-14 (1.76 g, 5.54 mmol, 1.0 equiv.): anhydrous DMF (18 ml), Ph3P (291 mg, 1.11 mmol, 0.2 equiv.), (Ph3P)2PdCl2(389 mg, 0.55 mmol, 0.1 equiv.), annealed KOAc (2.18 g, 22.16 mmol, 4.0 equiv.), B2Pin2 (4.22 g, 16.62 mmol, 3.0 equiv), reaction time: 3 hours. (S)- 8: 1.92 g (yield: 95%) colorless syrup; [α]^^^+14 (c = 0.43; CHCl3). Flash chromatography (hexane / EtOAc 9:1 → 85:15 → 8:2 → 7:3); Rf = 0.43 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.27, 6.72 (2s, 2 x 1H, H-6, H-9), 5.13 – 5.00 (m, 1H, H- 2), 3.90, 3.88 (2s, 2 x 3H, H-10, H- 11), 3.21 (dd, J = 13.2, 5.7 Hz, 1H, H-1-a), 3.02 (dd, J = 13.2, 7.6 Hz, 1H, H-1-b), 1.96 (s, 3H, H-13), 1.33 (s, 12H, H-19, H-20, H-21, H-22), 1.22 (d, J = 6.2 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 170.5 (1C, C-12), 150.8, 146.8, 138.9 (3C, C-4, C-7, C-8), 118.2, 113.6 (2C, C-6, C-9), 83.5 (2C, C-17, C-18), 73.3 (1C, C-2), 56.0, 55.8 (2C, C-10, C-11), 41.2 (1C, C-1), 25.0 (4C, C-19, C-20, C-21, C-22), 21.4 (1C, C-13), 19.7 (1C, C-3); IR (KBr) ν = 2978, 2934 (νasMe, νasCH2), 1736 (ν C=O), 1600, 1571, 1519 (ν Ar C=C), 1371, 1349, 1320 (δsMe, δ CH, νasO-B-O), 1251, 1221, 1204 (νas C-O-C=O, νas Ar-O-Me), 1160, 1144 (νs O-B-O), 1054 (ν C-O-B, νs C-O-C=O, νs Ar-O-Me), 860 (1,2,4,5-tetrasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C19H29BNaO6 [M+Na]+387.1953, found 387.1957. 1.2.4.2. - (R)-1-[4,5-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl acetate [(R)-8] Starting from (R)-13 (2.50 g, 6.85 mmol, 1.0 equiv.): anhydrous DMF (37 ml), Ph3P (360 mg, 1.37 mmol, 0.2 equiv.), (Ph3P)2PdCl2(481 mg, 0.69 mmol, 0.1 equiv.), anhydrous NaOAc (2.25 g, 27.42 mmol, 4.0 equiv.), B2Pin2 (5.22 g, 20.56 mmol, 3.0 equiv), reaction time: 3 hours. (R)-8: 1.50 g (yield: 60%) pale yellow syrup; [α]^^^−23 (c = 0.44; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of (S)-8. 1.2.5. General procedure for oxa-Pictet-Spengler reactions of chiral non-racemic 1-arylpropan-2-ol derivatives Method A: The 1-arylpropan-2-ol derivative (1.0 equiv.) was dissolved in anhydrous Et2O (5- 20 ml), and the solution was cooled to 0 °C. The reagent MOMCl (5.0-10.0 equiv.) and annealed ZnCl2(0.3 equiv.) were added to the solution. When the starting material was consumed (2-4 hours) on the basis of TLC monitoring, the reaction was quenched with water and stirred for 15 minutes. Et2O was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the chiral non-racemic isochroman target derivative. Method B: The 1-arylpropan-2-ol derivative (1.0 equiv.) was dissolved in anhydrous CH2Cl2(30-55 ml), and 4-fluorobenzaldehyde (1.2 equiv.) was added to the solution. The solution was cooled to 0 °C and BF3·Et2O (0.3 equiv.) was added. The reaction mixture was allowed to warm up to room temperature. When the starting material was consumed (4 hours) on the basis of TLC monitoring, the reaction was quenched with water and stirred for 20 minutes. CH2Cl2was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the chiral non- racemic isochroman target derivatives. Method C: The 1-arylpropan-2-ol derivative (1.0 equiv.) was dissolved in anhydrous toluene (3 ml) and the solution was cooled to 0 °C. Then ethyl-3,3-diethoxypropionate (90%, technical grade, 2.0 equiv.) and BF3·Et2O (0.3 equiv.) were added to the solution and the reaction was allowed to warm up to room temperature. When the starting material was consumed (3-16 hours) on the basis of TLC monitoring, the reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture, and the layers were separated. The organic layers were extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the chiral non-racemic isochroman target derivatives. 1.2.5.1. - (1R,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman [cis-(1R,3S)-17] and (1S,3S)- 1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman [trans-(1S,3S)-17] Starting from (S)-16 (2.13 g, 9.39 mmol, 1.0 equiv.) using method B: anhydrous CH2Cl2(30 ml), 4- fluorobenzaldehyde (1.21 ml, 1.40 g, 11.27 mmol, 2.0 equiv.), BF3·Et2O (348 μl, 400 mg, 2.82 mmol, 0.3 equiv.), reaction time: 4 hours. cis-(1R,3S)-17: 1.12 g (yield: 36%) colorless syrup; +16 (c = 0.47; CHCl3); trans- (1S,3S)-17: 1.90g (yield: 61%) white solid; mp 49-51 °C −18 (c = 0.50; CHCl3); dr cis:trans = 1.0:1.7. Flash chromatography (hexane / CH2Cl27:3 → 65:35 → 6:4 → 55:45 → 1:1 → 4:6 → 3:7, then CH2Cl2 / EtOAc 1:1). cis-(1R,3S)-17: Rf = 0.38 (CH2Cl2);1H NMR (400 MHz, CDCl3) δ = 7.30 – 7.23 (m, 2H, H-14, H-18), 7.02 – 6.94 (m, 2H, H-15, H-17), 6.44 (s, 1H, H-5), 5.76 (s, 1H, H-1), 3.84 (s, 3H, H-9), 3.83 – 3.77 (m, 1H, H-3), 3.74 (s, 3H, H-10), 3.10 (s, 3H, H-11), 2.80 (dd, J = 15.8, 10.7 Hz, 1H, H-4ax), 2.61 (d, J = 15.6 Hz, 1H, H-4eq), 1.33 (d, J = 6.2 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.2 (d, JC-F= 245.1 Hz, 1C, C-16), 152.7 (1C, C-6), 150.3 (1C, C-8), 140.6 (1C, C-7), 140.2 (d, JC-F = 2.8 Hz, 1C, C-13), 130.6 (1C, C-4a), 130.0 (d, JC-F = 8.1 Hz, 2C, C-14, C-18), 123.4 (1C, C-8a), 115.0 (d, JC-F = 21.3 Hz, 2C, C-15, C-17) 106.7 (1C, C-5), 77.2 (1C, C-1), 70.4 (1C, C-3), 60.5 (1C, C-10), 59.2 (1C, C-11), 55.9 (1C, C-9), 36.9 (1C, C-4), 21.7 (1C, C-12); IR (KBr) ν = 3045 (ν Ar =CH), 2970, 2937 (νasMe, νasCH2), 2895, 2840 (νsMe, νsCH2), 1894, 1747 (γ Ar C=C overtone and combination bands), 1602, 1583, 1509, 1492, 1457 (ν Ar C=C, βs CH2, δas Me), 1383, 1342, 1305 (δs Me, δ CH, γs CH2), 1258, 1240, 1221, 1148, 1114 (νas Ar-O-Me, ν Ar C-F), 1083, 1055, 1024 (νas C-O-C, νs Ar-O-Me), 859 (1,2,3,4,5- pentasubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C19H21FNaO4[M+Na]+355.1316, found 355.1315. trans-(1S,3S)-17: Rf = 0.24 (CH2Cl2);1H NMR (400 MHz, CDCl3) δ = 7.24 – 7.15 (m, 2H, H-14, H-18), 7.01 – 6.94 (m, 2H, H-15, H-17), 6.48 (s, 1H, H-5), 5.95 (s, 1H, H-1), 3.87 (s, 3H, H-9), 3.82 (s, 3H, H-10), 3.79 – 3.68 (m, 1H, H-3), 3.53 (s, 3H, H-11), 2.71 – 2.58 (m, 2H, H-4), 1.18 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.1 (d, JC-F= 245.7 Hz, 1C, C-16), 152.9 (1C, C-6), 149.8 (1C, C-8), 140.0 (1C, C-7), 138.3 (d, JC-F= 2.9 Hz, 1C, C-13), 130.2 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 129.8 (1C, C-4a), 121.0 (1C, C-8a), 114.7 (d, JC-F = 21.3 Hz, 2C, C-15, C-17), 106.9 (1C, C-5), 73.2 (1C, C-1), 63.0 (1C, C-3), 60.7 (1C, C-10), 60.0 (1C, C-11), 55.9 (1C, C- 9), 35.4 (1C, C-4), 21.5 (1C, C-12); IR (KBr) ν = 3047, 3011 (ν Ar =CH), 2969, 2943 (νasMe, νasCH2), 2882, 2846 (νsMe, νsCH2), 1904 (γ Ar C=C overtone and combination bands), 1602, 1584, 1505, 1492, 1460 (ν Ar C=C, βsCH2, δas Me), 1385, 1365, 1344, 1329 (δs Me, δ CH, γs CH2), 1265, 1241, 1223, 1201, 1172, 1161, 1145, 1120 (νas Ar-O- Me, ν Ar C-F), 1097, 1069, 1051, 1023 (νas C-O-C, νs Ar-O-Me), 882 (1,2,3,4,5-pentasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C19H21FNaO4[M+Na]+355.1316, found 355.1315. 1.2.5.2. - (1S,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman [cis-(1S,3R)-17] and (1R,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman [trans-(1R,3R)-17] Starting from (R)-16 (3.95 g, 17.48 mmol, 1.0 equiv.) using method B: anhydrous CH2Cl2(55 ml), 4- fluorobenzaldehyde (2.25 ml, 2.60 g, 20.97 mmol, 1.2 equiv.), BF3·Et2O (647 μl, 744 mg, 5.24 mmol, 0.3 equiv.), reaction time: 4 hours. cis-(1S,3R)-17: 2.03 g (yield: 35%) colorless syrup; −16 (c = 0.50; CHCl3); trans- (1R,3R)-17: 3.45 g (yield: 59%) white solid; mp 47-50 °C; +14 (c = 0.49; CHCl3); dr cis:trans = 1.0:1.7. Chromatographic and spectral data except for the chiroptical ones were identical with those of cis-(1R,3S)-17 and trans-(1S,3S)-17. 1.2.5.3. - (aS,1S,3S,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis-isochroman [(aS,1S,3S,3’S)-21] (Compound 1a) Starting from (aS,1S,3S,2’S)-20 (Compound 22a) (70 mg, 0.13 mmol, 1.0 equiv.) using method A: anhydrous Et2O (5 ml), MOMCl (100 μl, 106 mg, 1.32 mmol, 10.0 equiv.), annealed ZnCl2(5 mg, 0.04 mmol, 0.3 equiv.), reaction time: 4 hours. (aS,1S,3S,3’S)-21 (Compound 1a): 68 mg (yield: 96%) white amorphous solid foam; [α]^^^+203 (c = 0.51; MeCN); ECD: (c = 1.94×10−4M; MeCN) λ [nm], (Δε) = 287sh (−0.35), 271 (−0.96), 263sh (−1.57), 243 (−5.99), 221 (1.12), 215 (−1.23), 198sh (34.62). Flash chromatography (hexane / EtOAc 9:1 → 85:15 → 8:2 → 7:3); Rf = 0.29 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.22 – 7.17 (m, 2H, H-14, H-18), 7.06 – 6.99 (m, 2H, H-15, H-17), 6.61 (s, 1H, H-6’), 6.04 (s, 1H, H-1), 5.07 (d, J = 15.8 Hz, 1H, H-1’eq), 4.77 (d, J = 15.8 Hz, 1H, H- 1’ax), 3.89 (s, 3H, H-10), 3.89 (s, 3H, H-10’), 3.83 (s, 3H, H-9’), 3.71 – 3.66 (m, 1H, H-3’), 3.66 (s, 3H, H-9), 3.64 – 3.58 (m, 1H, H-3), 3.57 (s, 3H, H-11), 2.41 (dd, J = 16.4, 10.6 Hz, 1H, H-4’ax), 2.25 (dd, J = 17.1, 11.0 Hz, 1H, H-4ax), 2.08 (dd, J = 16.4, 2.5 Hz, 1H, H-4’eq), 1.97 (dd, J = 17.1, 3.5 Hz, 1H, H-4eq), 1.30 (d, J = 6.1 Hz, 1H, H-11’), 1.08 (d, J = 6.1 Hz, 1H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F= 246.1 Hz, 1C, C-16), 151.2 (1C, C-6), 150.0 (1C, C-7’), 149.4 (1C, C-8), 144.1 (1C, C- 7), 143.7 (1C, C-8’), 138.3 (d, JC-F = 2.9 Hz, 1C, C-13), 131.3 (1C, C-5’), 130.3 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 128.8 (2C, C-5, C-8a’), 128.3 (1C, C-4a), 125.1 (1C, C-4a’), 124.3 (1C, C-8a), 114.9 (d, JC-F= 21.1 Hz, 2C, C-15, C- 17), 112.6 (1C, C-6’), 73.4 (1C, C-1), 70.8 (1C, C-3’), 64.9 (1C, C-1’), 63.3 (1C, C-3), 61.2 (1C, C-9), 60.8 (1C, C-10), 60.3 (1C, C-10’), 60.1 (1C, C-11), 55.9 (1C, C-9’), 34.4 (1C, C-4), 33.7 (1C, C-4’), 21.8 (2C, C-11’, C-12); IR (KBr) ν = 2967, 2935 (νas Me, νas CH2), 2838 (νs CH2), 1603, 1578, 1507, 1491, 1464, 1420, 1408 (ν Ar C=C, βs CH2, δasMe), 1383, 1363, 1316, (δsMe, δ CH, γsCH2), 1254, 1223, 1199, 1157, 1114 (νasAr-O-Me, ν Ar C-F), 1085, 1064, 1028 (νasC-O-C, νsAr-O-Me), 864 (1,2,3,4,5-pentasubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C31H35FNaO7 [M+Na]+561.2259, found 561.2257. 1.2.5.4. - (aR,1R,3R,3’R)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis- isochr und 2a Compound 2a Starting from (aR,1R,3R,2’R)-20 (Compound 24a) (310 mg, 0.59 mmol, 1.0 equiv.) using method A: anhydrous Et2O (20 ml), MOMCl (447 μl, 474 mg, 5.89 mmol, 10.0 equiv.), annealed ZnCl2(24 mg, 0.18 mmol, 0.3 equiv.), reaction time: 4 hours. (aR,1R,3R,3’R)-21 (Compound 2a): 272 mg (yield: 86%) white amorphous solid foam; −158 (c = 0.52; MeCN); ECD: (c = 1.71×10−4M; MeCN) λ [nm], (Δε) = 287sh (0.45), 271 (0.98), 263sh (1.56), 242 (5.56), 220 (-0.67), 214 (0.77), 198 (−31.91). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aS,1S,3S,3’S)-21 (Compound 1a). 1.2.5.5. - (aR,1S,3S,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis-isochroman [(aR,1S,3S,3’S)-21] (Compound 3a)

[0014] Compound 3a Starting from (aR,1S,3S,2’S)-20 (Compound 23a) (93 mg, 0.18 mmol, 1.0 equiv.) using method A: anhydrous Et2O (5 ml), MOMCl (100 μl, 106 mg, 1.32 mmol, 7.5 equiv.), annealed ZnCl2(7 mg, 0.05 mmol, 0.3 equiv.), reaction time: 4 hours. (aR,1S,3S,3’S)-21 (Compound 3a): 94 mg (yield: 99%) off-white solid; mp 147-150 °C; +301 (c = 0.49; MeCN); ECD: (c−4 = 2.24×10 M; MeCN) λ [nm], (Δε) = 286 (0.09), 271 (−0.43), 264 (−0.51), 259sh (−0.20), 255 (0.12), 243 (−0.73), 234sh (1.68), 219sh (5.73), 206 (20.54). Purification was not required for the crude product. Rf= 0.27 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.29 – 7.22 (m, 2H, H-14, H-18), 7.08 – 6.97 (m, 2H, H-15, H-17), 6.61 (s, 1H, H- 6’), 6.01 (s, 1H, H-1), 5.06 (d, J = 15.8 Hz, 1H, H-1’eq), 4.78 (d, J = 15.8 Hz, 1H, H-1’ax), 3.89 (s, 3H, H-10), 3.88 (s, 3H, H-10’), 3.86 (s, 3H, H-9’), 3.76 – 3.67 (m, 1H, H-3’), 3.67 (s, 3H, H-9), 3.66 – 3.62 (m, 1H, H-3), 3.57 (s, 3H, H-11), 2.27 (dd, J = 16.3, 3.3 Hz, 1H, H-4’eq), 2.26 (dd, J = 17.0, 3.7 Hz, 1H, H-4eq), 2.14 (dd, J = 16.3, 10.4 Hz, 1H, H-4’ax), 2.05 (dd, J = 17.0, 10.7 Hz, 1H, H-4ax), 1.26 (d, J = 6.1 Hz, 3H, H-11’), 1.08 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F = 245.8 Hz, 1C, C-16), 150.3 (1C, C-6), 149.9 (1C, C-7’), 149.4 (1C, C-8), 143.9 (1C, C- 7), 143.8 (1C, C-8’), 138.3 (d, J = 2.9 Hz, 1C, C-13), 131.5 (1C, C-5’), 130.4 (d, JC-F= 8.0 Hz, 2C, C-14, C-18), 129.3 (1C, C-5), 129.0 (1C, C-4a), 128.9 (1C, C-8a’), 125.8 (1C, C-4a’), 124.5 (1C, C-8a), 114.8 (d, JC-F= 21.2 Hz, 2C, C-15, C-17), 112.4 (1C, C-6’), 73.4 (1C, C-1), 70.8 (1C, C-3’), 65.0 (1C, C-1’), 63.4 (1C, C-3), 61.0 (1C, C-9), 60.8 (1C, C-10), 60.2 (1C, C-10’), 60.1 (1C, C-11), 56.1 (1C, C-9’), 33.5 (1C, C-4’), 33.3 (1C, C-4), 21.7 (1C, C- 11’), 21.6 (1C, C-12); IR (KBr) ν = 2963, 2934 (νasMe, νasCH2), 2837 (νsCH2), 1907, 1729 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1602, 1579, 1506, 1489, 1465, 1421, 1408 (ν Ar C=C, βsCH2, δasMe), 1383, 1361, 1315, (δs Me, δ CH, γs CH2), 1267, 1253, 1233, 1218, 1198, 1159, 1129, 1117 (νas Ar-O-Me, ν Ar C-F), 1096, 1086, 1066, 1052, 1027 (νas C-O-C, νs Ar-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C31H35FNaO7 [M+Na]+561.2259, found 561.2257. 1.2.5.6. - (aS,1R,3R,3’R)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis- isochroman [(aS,1R,3R,3’R)-21] (Compound 4a)

[0015] Compound 4a Starting from (aS,1R,3R,2’R)-20 (Compound 25a) (300 mg, 0.57 mmol, 1.0 equiv.) using method A: anhydrous Et2O (20 ml), MOMCl (325 μl, 344 mg, 4.27 mmol, 7.5 equiv.), annealed ZnCl2(23 mg, 0.17 mmol, 0.3 equiv.), reaction time: 4 hours. (aS,1R,3R,3’R)-21 (Compound 4a): 304 mg (yield: 99%) off-white solid; mp 150-151 −298 (c = 0−4 .50; MeCN); ECD (c = 1.44×10 M; MeCN) λ [nm], (Δε) = 286 (−0.15), 271 (0.40), 264 (0.48), 259sh (0.16), 253 (−0.06), 243 (0.70), 232sh (−1.62), 219sh (−6.00), 206 (−20.88). Purification was not required for the crude product. Chromatographic and spectral data except for the chiroptical ones were identical with those of (aR,1S,3S,3’S)-21 (Compound 3a). 1.2.5.7. - (aS,1R,3S,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis-isochroman [(aS,1R,3S,3’S)-21] (Compound 5a) Compound 5a Starting from (aS,1R,3S,2’S)-20 (Compound 26a) (63 mg, 0.12 mmol, 1.0 equiv.) using method A: anhydrous Et2O (5 ml), MOMCl (91 μl, 97 mg, 1.20 mmol, 10.0 equiv.), annealed ZnCl2(5 mg, 0.04 mmol, 0.3 equiv.), reaction time: 4 hours. (aS,1R,3S,3’S)-21 (Compound 5a): 63 mg (yield: 97%) off-white amorphous solid foam; [ −279 (c = 0.49; MeCN); ECD (c = 1.65×10−4M; MeCN) λ [nm], (Δε) = 287 (−1.45), 270sh (−1.14), 249sh (−5.90), 224 (−28.53), 201 (31.60). Flash chromatography (hexane / EtOAc 9:1 → 85:15); Rf = 0.28 (hexane / EtOAc 85:15);1H NMR (400 MHz, CDCl3) δ = 7.39 – 7.31 (m, 2H, H-14, H-18), 7.08 – 6.99 (m, 2H, H-15, H-17), 6.65 (s, 1H, H-6’), 5.82 (s, 1H, H-1), 5.07 (d, J = 15.8 Hz, 1H, H-1’ax), 4.77 (d, J = 15.8 Hz, 1H, H-1’eq), 3.90 (s, 3H, H-10’), 3.87 (s, 3H, H-9’), 3.80 (s, 3H, H-10), 3.76 – 3.59 (m, 2H, H-3, H-3’), 3.57 (s, 3H, H-9), 3.15 (s, 3H, H-11), 2.41 (dd, J = 16.4, 10.9 Hz, 1H, H-4’ax), 2.41 (dd, J = 16.4, 10.9 Hz, 1H, H-4ax), 1.99 (ddd, J = 16.4, 2.3, 1.2 Hz, 1H, H-4’eq), 1.97 (ddd, J = 16.4, 3.2, 1.0 Hz, 1H, H-4eq), 1.26 (d, J = 6.1 Hz, 3H, H-11’), 1.23 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F = 245.0 Hz, 1C, C-16), 150.9 (1C, C- 6), 149.8 (1C, C-7’), 149.8 (1C, C-8), 144.6 (1C, C-7), 143.8 (1C, C-8’), 140.2 (d, J = 2.7 Hz, 1C, C-13), 131.3 (1C, C-5’), 130.2 (d, JC-F= 8.1 Hz, 2C, C-14, C-18), 129.2 (1C, C-4a), 128.7 (1C, C-8a’), 128.4 (1C, C-5), 126.7 (1C, C- 8a), 125.8 (1C, C-4a’), 115.1 = 21.3 Hz, 2C, C-15, C-17), 113.0 (1C, C-6’), 77.6 (1C, C-1), 70.8, 70.6 (2C, C- 3, C-3’), 65.0 (1C, C-1’), 61.0 (1C, C-9), 60.7 (1C, C-10), 60.3 (1C, C-10’), 59.4 (1C, C-11), 56.1 (1C, C-9’), 35.6 (1C, C-4), 33.5 (1C, C-4’), 21.8 (1C, C-12), 21.7 (1C, C-11’); IR (KBr) ν = 2970, 2936 (νas Me, νas CH2), 2843 (νs CH2), 1604, 1575, 1510, 1490, 1463, 1420 (ν Ar C=C, βsCH2, δasMe), 1383, 1361, 1317, (δsMe, δ CH, γsCH2), 1279, 1255, 1232, 1200, 1148, 1118 (νasAr-O-Me, ν Ar C-F), 1102, 1085, 1029 (νasC-O-C, νsAr-O-Me) cm-1; ESI- TOF-HRMS: m / z calculated for C31H35FNaO7 [M+Na]+561.2259, found 561.2256. 1.2.5.8. - (aR,1S,3R,3’R)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis- isochr Starting from (aR,1S,3R,2’R)-20 (Compound 27a) (100 mg, 0.19 mmol, 1.0 equiv.) using method A: anhydrous Et2O (5 ml), MOMCl (144 μl, 153 mg, 1.90 mmol, 10.0 equiv.), annealed ZnCl2(8 mg, 0.06 mmol, 0.3 equiv.), reaction time: 4 hours. (aR,1S,3R,3’R)-21 (Compound 6a): 90 mg (yield: 88%) off-white amorphous solid foam; +269 (c = 0.49; MeCN); ECD (c = 1.94×10−4M; MeCN) λ [nm], (Δε) = 287 (1.13), 270sh (1.00), 248sh (5.02), 223 (24.51), 201 (−28.82). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aS,1R,3S,3’S)-21 (Compound 5a). 1.2.5.9. - (aR,1R,3S,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis- isochroman [(aR,1R,3S,3’S)-21] (Compound 7a)

[0016] Starting from (aR,1R,3S,2’S)-20 (Compound 28a) (41 mg, 0.08 mmol, 1.0 equiv.) using method A: anhydrous Et2O (7 ml), MOMCl (30 μl, 31 mg, 0.39 mmol, 5.0 equiv.), annealed ZnCl2(3 mg, 0.02 mmol, 0.3 equiv.), reaction time: 3 hours. (aR,1R,3S,3’S)-21 (Compound 7a): 37 mg (yield: 89%) off-white amorphous solid foam −35; −147 (c = 0.46; MeCN); ECD (c = 1.98×10−4M; MeCN) λ [nm], (Δε) = 287 (−0.49), 271sh (−0.66), 226 (−14.37), 205 (13.86), 202sh (12.76). Flash chromatography (hexane / EtOAc 9:1 → 85:15); Rf= 0.42 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.31 – 7.22 (m, 2H, H-14, H-18), 7.07 – 6.99 (m, 2H, H- 15, H-17), 6.61 (s, 1H, H-6’), 5.83 (s, 1H, H-1), 5.08 (d, J = 15.8 Hz, 1H, H-1’ax), 4.79 (d, J = 15.8 Hz, 3.89 (s, 3H, H-10’), 3.84 (s, 3H, H-9’), 3.82 (s, 3H, H-10), 3.78 – 3.68 (m, 2H, H-3, H-3’), 3.61 (s, 3H, H-9), 3.17 (s, 3H, H-11), 2.35 – 2.18 (m, 4H, H-4’, H-4), 1.32 (d, J = 6.1 Hz, 3H, H-11’), 1.22 (d, J = 6.1 Hz, 3H, H- 12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F= 245.3 Hz, 1C, C-16), 150.3 (1C, C-6), 150.0 (1C, C-7’), 149.7 (1C, C-8), 144.6 (1C, C-7), 143.8 (1C, C-8’), 140.2 (d, JC-F = 3.0 Hz, 1C, C-13), 131.3 (1C, C-5’), 130.1, (1C, C-4a), 130.0 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 128.9 (1C, C-8a’), 128.7 (1C, C-5), 126.9 (1C, C-8a), 125.6 (1C, C-4a’), 115.2 (d, JC-F= 21.4 Hz, 2C, C-15, C-17), 112.6 (1C, C-6’), 77.3 (1C, C-1), 70.7 (1C, C-3’), 70.5 (1C, C-3), 65.1 (1C, C-1’), 60.9 (1C, C-9), 60.7 (1C, C-10), 60.3 (1C, C-10’), 59.3 (1C, C-11), 56.0 (1C, C-9’), 34.4 (1C, C-4), 33.6 (1C, C-4’), 21.8 (2C, C-11’, C-12); IR (KBr) ν = 2970, 2935 (νas Me, νas CH2), 2847 (νs CH2), 1730 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1604, 1577, 1509, 1490, 1463, 1421, 1407 (ν Ar C=C, βs CH2, δas Me), 1384, 1359, 1317, (δsMe, δ CH, γsCH2), 1279, 1255, 1223, 1201, 1152, 1116 (νasAr-O-Me, ν Ar C-F), 1074, 1054, 1029 (νasC-O-C, νsAr-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C31H35FNaO7[M+Na]+561.2259, found 561.2251. 1.2.5.10. - (aS,1R,3S,1’S,3’S)-ethyl 1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-1’-carboxylate [(aS,1R,3S,1’S,3’S)-22] (Compound 8a) and (aS,1S,3S,1’S,3’S)-ethyl 1-(4- fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-1’-carboxylate [(aS,1S,3S,1’S,3’S)-22] (Compound 9a)

[0017] Compound 8a Compound 9a (aS,1R,3S,2’S)-20 (Compound 26a) (141 mg, 0.27 mmol, 1 equiv.) was dissolved in anhydrous toluene (3 ml), and the solution was cooled to 0 °C. Then ethyl-diethoxyacetate (96 μl, 94 mg, 0.54 mmol, 2 equiv.) and BF3·Et2O (10 μl, 11 mg, 0.08 mmol, 0.3 equiv.) were added to the solution, and the reaction was allowed to warm up to room temperature. After stirring overnight, another portion of BF3·Et2O (10 μl, 11 mg, 0.08 mmol, 0.3 equiv.) was added to the solution and stirred for overnight. The reaction was stirred for 4 hours at 60 °C and allowed to cool down to room temperature. After another day, the reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 85:15 → 6:4). (aS,1R,3S,1’S,3’S)-22 (Compound 8a): 37 mg (yield: 23%) white amorphous solid foam; − −2614 (c = 0.49; MeCN); ECD (c = 1.93×10 M; MeCN) λ [nm], (Δε) = 288 (−1.69), 271sh (−1.44), 252sh (−6.17), 225 (−27.82), 201 (33.46). (aS,1R,3S,1’S,3’S)-22 (Compound 8a): Rf= 0.21 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.40 – 7.29 (m, 2H, H-14, H-18), 7.09 – 6.98 (m, 2H, H-15, H-17), 6.72 (s, 1H, H-6’), 5.82 (s, 1H, H-1), 5.47 (s, 1H, H- 1’), 4.36 – 4.18 (m, 2H, H-13’), 3.88 (s, 3H, H-10’), 3.87 (s, 3H, H-9’), 3.80 (s, 3H, H-10), 3.73 – 3.61 (m, 2H, H-3, H-3’), 3.54 (s, 3H, H-9), 3.15 (s, 3H, H-11), 2.56 (ddd, J = 16.2, 11.3, 0.9 Hz, 1H, H-4’ax), 2.43 (ddd, J = 16.3, 10.9, 1.4 Hz, 1H, H-4ax), 1.99 (dd, J = 16.0, 2.5 Hz, 1H, H-4’eq), 1.97 (d, J = 16.2 Hz, 1H, H-4eq), 1.32 (t, J = 7.2 Hz, 3H, H-14’), 1.29 (d, J = 6.1 Hz, 3H, H-11’), 1.23 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 171.0 (1C, C-12’), 162.3 (d, JC-F = 245.3 Hz, 1C, C-16), 151.2 (1C, C-6), 149.9 (2C, C-7’, C-8), 144.6 (1C, C-7), 144.5 (1C, C- 8’), 140.2 (d, JC-F = 2.9 Hz, 1C, C-13), 130.5 (1C, C-5’), 130.2 (d, JC-F = 8.1 Hz, 2C, C-14, C-18), 129.2 (1C, C-4a), 128.0 (1C, C-5), 127.0 (1C, C-4a’), 126.7 (1C, C-8a), 126.6 (1C, C-8a’), 115.1 (d, JC-F= 21.4 Hz, 2C, C-15, C-17), 114.3 (1C, C-6’), 77.6 (1C, C-1), 75.6 (1C, C-1’), 71.2 (1C, C-3’), 70.6 (1C, C-3), 61.4 (1C, C-13’), 60.9 (1C, C-9), 60.8 (1C, C-10), 60.1 (1C, C-10’), 59.4 (1C, C-11), 56.2 (1C, C-9’), 35.8 (1C, C-4), 33.4 (1C, C-4’), 21.9 (1C, C- 12), 21.7 (1C, C-11’), 14.3 (1C, C-14’); IR (KBr) ν = 2973, 2936 (νas Me, νas CH2), 2849 (νs CH2), 1746 (ν C=O), 1604, 1576, 1509, 1492, 1463, 1420 (ν Ar C=C, βsCH2, δasMe), 1384, 1361, 1318 (δsMe, δ CH, γsCH2), 1257, 1232, 1183, 1150, 1116 (νasAr-O-Me, ν Ar C-F, νasC-O-C=O), 1068, 1029 (νasC-O-C, νsAr-O-Me, νsC-O-C=O) cm-1; ESI-TOF-HRMS: m / z calculated for C34H39FNaO9 [M+Na]+633.2470, found 633.2470. Epimerization of C-1 caused by BF3·Et2O also resulted in (aS,1S,3S,1’S,3’S)-22 (Compound 9a) (52 mg, yield 32%) as pale yellow amorphous solid foam. 1.2.5.11. - (aR,1S,3R,1’R,3’R)-ethyl 1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’- bis-isochroman]-1’-carboxylate [(aR,1S,3R,1’R,3’R)-22] (Compound 10a) and (aR,1R,3R,1’R,3’R)-ethyl 1-(4- fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-1’-carboxylate [(aR,1R,3R,1’R,3’R)-22] (Compound 11a) Compound 10a Compound 11a (aR,1S,3R,2’R)-20 (Compound 27a) (323 mg, 0.61 mmol, 1 equiv.) was dissolved in anhydrous toluene (7 ml), and the solution was cooled to 0 °C. Then ethyl-diethoxyacetate (220 μl, 216 mg, 1.22 mmol, 2 equiv.) and BF3·Et2O (23 μl, 26 mg, 0.18 mmol, 0.3 equiv.) were added to the solution, and the reaction were allowed to warm up to room temperature. After stirring overnight, another portion of BF3·Et2O (11 μl, 13 mg, 0.09 mmol, 0.15 equiv.) was added to the solution and the reaction was stirred for 8 hours at 60 °C. Then it was allowed to cool down to room temperature. After stirring overnight, the mixture was quenched with a saturated solution of NaHCO3 and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography. (aR,1S,3R,1’R,3’R)-22 (Compound 10a): 62 mg (yield: 17%) white amorphous solid foam; −4 +276 (c = 0.48; MeCN); ECD (c = 1.59×10 M; MeCN) λ [nm], (Δε) = 288 (1.55), 271sh (1.41), 251sh (6.08), 224 (26.63), 201 (−35.87). Epimerization of C-1 caused by BF3·Et2O also resulted in (aR,1R,3R,1’R,3’R)-22 (Compound 11a) (126 mg, yield 34%) as pale yellow amorphous solid foam. Chromatographic and spectral data except for the chiroptical ones were identical with those of the corresponding enantiomers (aS,1R,3S,1’S,3’S)- 22 and (aS,1S,3S,1’S,3’S)-22 (Compound 9a). 1.2.5.12. - (aS,1S,3S,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis- isochroman [(aS,1S,3S,3’S)-21] (Compound 1a) and (aS,1S,3S,1’S,3’S)-ethyl 1-(4-fluorophenyl)-6,7,7’,8,8’- pentamethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-1’-carboxylate [(aS,1S,3S,1’S,3’S)-22] (Compound 9a)

[0018] Compound 1a Compound 9a (aS,1S,3S,2’S)-20 (Compound 22a) (141 mg, 0.27 mmol, 1.0 equiv.) was dissolved in anhydrous toluene (3 ml), and the solution was cooled to 0 °C. Then ethyl-diethoxyacetate (96 μl, 94 mg, 0.53 mmol, 2.0 equiv.) and BF3·Et2O (10 μl, 11 mg, 0.08 mmol, 0.3 equiv.) were added to the solution, and the reaction was allowed to warm up to room temperature. After four days, another portion of ethyl-diethoxyacetate (96 μl, 94 mg, 0.53 mmol, 2.0 equiv.) was added to the reaction mixture. The temperature was raised to 60 °C. After stirring overnight, the reaction was allowed to cool down to room temperature and stirred for another day. The reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (hexane / EtOAc 95:5 → 9:1 → 85:15→ 75:25 → 7:3) to yield (aS,1S,3S,1’S,3’S)-22 (Compound 9a) (62 mg, 38%) as white amorphous solid foam; +119 (c = 0.50; MeCN); ECD (c = 1.3977.10−4M; MeCN) λ [nm], (Δε) = 291 (−0.44), 270 (−1.19), 264sh (−2.05), 239sh (−7.35), 231 (−7.84), 217 (−4.58), 197 (36.15). (aS,1S,3S,1’S,3’S)-22 (Compound 9a): Rf = 0.35 (hexane / EtOAc 75:25);1H NMR (400 MHz, CDCl3) δ = 7.22 – 7.16 (m, 2H, H-14, H-18), 7.06 – 6.99 (m, 2H, H-15, H-17), 6.67 (s, 1H, H-6’), 6.03 (s, 1H, H-1), 5.46 (s, 1H, H- 1’), 4.36 – 4.19 (m, 2H, H-13’), 3.89 (s, 3H, H-10), 3.87 (s, 3H, H-10’), 3.82 (s, 3H, H-9’), 3.73 – 3.65 (m, 1H, H- 3’), 3.63 (s, 3H, H-9), 3.62 – 3.58 (m, 1H, H-3), 3.57 (s, 3 , 2.54 (ddd, J = 16.1, 11.1 Hz, 1.3 Hz, 1H, H-4’ax), 2.26 (dd, J = 17.0, 11.0 Hz, 1H, H-4ax), 2.08 (dd, J = 16.1, 2.1 Hz, 1H, H-4’eq), 1.93 (dd, J = 17.1, 3.5 Hz, 1H, H-4eq), 1.33 (t, J = 7.1 Hz, 3H, H-14’), 1.33 (d, J = 6.1 Hz, 3H, H-11’), 1.08 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 170.9 (1C, C-12’), 162.3 (d, JC-F= 246.1 Hz, 1C, C-16), 151.5 (1C, C-6), 150.1 (1C, C-7’), 149.5 (1C, C-8), 144.4 (1C, C-8’), 144.2 (1C, C-7), 138.3 (d, JC-F = 3.0 Hz, 1C, C-13), 130.5 (1C, C-5’), 130.3 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 128.4 (1C, C- 5), 128.3 (1C, C-4a), 126.6 (1C, C-8a’), 126.2 (1C, C-4a’), 124.2 (1C, C-8a), 114.9 (d, JC-F= 21.3 Hz, 2C, C-15, C-17), 113.9 (1C, C-6’), 75.6 (1C, C-1’), 73.4 (1C, C-1), 71.2 (1C, C-3’), 63.2 (1C, C- 3), 61.4 (1C, C-13’), 61.1 (1C, C-9), 60.9 (1C, C-10), 60.2 (1C, C-11), 60.1 (1C, C-10’), 56.0 (1C, C-9’), 34.5 (1C, C-4), 33.6 (1C, C-4’), 21.8 (2C, C-11’, C-12), 14.2 (1C, C- 14’); IR (KBr) ν = 2974, 2935 (νas Me, νas CH2), 2867 (νs Me), 1746 (ν C=O), 1603, 1579, 1507, 1492, 1464, 1420, 1407 (ν Ar C=C, βs CH2, δas Me), 1384, 1363, 1317 (δs Me, δ CH, γsCH2), 1282, 1255, 1223, 1182, 1158, 1112 (νasAr-O-Me, ν Ar C-F, νasC-O-C=O), 1066, 1028 (νasC-O-C, νsAr-O-Me, νsC-O-C=O) cm-1; ESI-TOF-HRMS: m / z calculated for C34H39FNaO9[M+Na]+633.2470, found 633.2472. Hydrolysis of ethyl ester and subsequent decarboxylation of C-1’ caused by BF3·Et2O also resulted in (aS,1S,3S,3’S)-21 (Compound 1a) (42 mg, 29%) as white amorphous solid foam. 1.2.5.13. - (aR,1R,3R,1’R,3’R)-ethyl 1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’- bis-isochroman]-1’-carboxylate [(aR,1R,3R,1’R,3’R)-22] (Compound 11a) Compound 11a (aR,1R,3R,2’R)-20 (Compound 24a) (100 mg, 0.19 mmol, 1 equiv.) was dissolved in anhydrous toluene (2 ml), and the solution was cooled to 0 °C. Then ethyl-diethoxyacetate (68 μl, 67 mg, 0.38 mmol, 2 equiv.) and BF3·Et2O (7 μl, 8 mg, 0.06 mmol, 0.3 equiv.) were added to the solution, and the reaction were allowed to warm up to room temperature. After stirring overnight, another portion of BF3·Et2O (4 μl, 4 mg, 0.03 mmol, 0.15 equiv.) was added to the solution and the reaction was stirred for 8 hours at 60 °C. Then it was allowed to cool down to room temperature. After stirring overnight, the reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layers were extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield (aR,1R,3R,1’R,3’R)-22 (Compound 11a) (45 mg, 39%) as a white amorphous solid foam; −72 (c = 0.44; MeCN); ECD (c = 1.7170.10−4M; MeCN) λ [nm], (Δε) = 288 (0.50), 270 (1.04), 263sh (1.85), 239sh (6.54), 230 (7.19), 215 (3.56), 195 (−29.62). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aS,1S,3S,1’S,3’S)-22 (Compound 9a). 1.2.5.14. - (aR,1S,3S,1’S,3’S)-ethyl 1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-1’-carboxylate [(aR,1S,3S,1’S,3’S)-22] (Compound 12a)

[0019] Compound 12a (aR,1S,3S,2’S)-20 (Compound 23a) (143 mg, 0.27 mmol, 1 equiv.) was dissolved in anhydrous toluene (3 ml), and the solution was cooled to 0 °C. Then ethyl-diethoxyacetate (97 μl, 95 mg, 0.54 mmol, 2 equiv.) and BF3·Et2O (10 μl, 12 mg, 0.08 mmol, 0.3 equiv.) were added to the solution. After stirring for three days at room temperature, the reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layers were extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield (aR,1S,3S,1’S,3’S)-22 (Compound 12a) (118 mg, 71%) as white solid; mp 70-72 °C 74 (c = 0.48; MeCN); ECD (c = 1.67×10−4M; MeCN) λ [nm], (Δε) = 287 (0.44), 279sh (0.18), 270 (−0.48), 264 (−0.69), 257sh (−0.65), 242sh (−3.31), 231 (−4.71), 205 (25.83). Flash chromatography (hexane / EtOAc 9:1 → 85:15); Rf = 0.32 (hexane / EtOAc 75:25);1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.22 (m, 2H, H-14, H-18), 7.06 – 6.99 (m, 2H, H-15, H-17), 6.68 (s, 1H, H-6’), 6.02 (s, 1H, H-1), 5.45 (s, 1H, H-1’), 4.34 – 4.20 (m, 2H, H- 13’), 3.89 (s, 3H, H-10), 3.87 (s, 3H, H-10’), 3.85 (s, 3H, H-9’), 3.78 – 3.72 (m, 1H, H-3’), 3.71 – 3.60 (m, 1H, H-3), 3.64 (s, 3H, H-9), 3.57 (s, 3H, H-11), 2.32 (dd, J = 15.9, 11.3 Hz, 1H, H- 4’ax), 2.29 (dd, J = 17.1, 3.3 Hz, 1H, H-4eq), 2.23 (dd, J = 16.0, 2.7 Hz, 1H, H-4’eq), 2.11 (dd, J = 17.0, 10.8 Hz, 1H, H-4ax), 1.33 (t, J = 7.1 Hz, 3H, H-14’), 1.30 (d, J = 6.0 Hz, 3H, H- 11’), 1.09 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 171.0 (1C, C-12’), 162.3 (d, JC-F= 245.9 Hz, 1C, C-16), 150.4 (1C, C-6), 150.0 (1C, C-7’), 149.5 (1C, C-8), 144.4 (1C, C- 8’), 143.8 (1C, C-7), 138.3 (d, JC-F= 2.9 Hz, 1C, C-13), 130.8 (1C, C-5’), 130.3 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 129.3 (1C, C-4a), 128.9 (1C, C-5), 126.7 (2C, C-8a’, C-4a’), 124.5 (1C, C-8a), 114.8 (d, JC-F = 21.2 Hz, 2C, C-15, C-17), 113.7 (1C, C-6’), 75.6 (1C, C-1’), 73.4 (1C, C-1), 71.3 (1C, C-3’), 63.4 (1C, C-3), 61.3 (1C, C-13’), 60.9 (1C, C-9), 60.8 (1C, C-10), 60.1 (1C, C-10’); 60.0 (1C, C-11), 56.1 (1C, C-9’), 33.3 (2C, C-4’, C-4), 21.6 (2C, C-11’, C-12), 14.2 (1C, C-14’); IR (KBr) ν = 2974, 2936 (νas Me, νas CH2), 2898 (νs Me), 1747 (ν C=O), 1602, 1579, 1507, 1492, 1464, 1421, 1407 (ν Ar C=C, βs CH2, δas Me), 1385, 1362, 1315 (δs Me, δ CH, γs CH2), 1282, 1266, 1233, 1183, 1159, 1127, 1113 (νas Ar-O-Me, ν Ar C-F, νasC-O-C=O), 1095, 1066, 1053, 1029 (νasC-O-C, νsAr-O-Me, νsC-O-C=O), 872 (1,2,3,4,5- pentasubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C34H39FNaO9[M+Na]+633.2470, found 633.2461. 1.2.5.15. - (aS,1R,3R,1’R,3’R)-ethyl 1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’- bis-isochroman]-1’-carboxylate [(aS,1R,3R,1’R,3’R)-22] (Compound 13a)

[0020] Compond 13a (aS,1R,3R,2’R)-20 (Compound 25a) (100 mg, 0.19 mmol, 1 equiv.) was dissolved in anhydrous toluene (2 ml), and the solution was cooled to 0 °C. Then ethyl-diethoxyacetate (68 μl, 67 mg, 0.38 mmol, 2 equiv.) and BF3·Et2O (7 μl, 8 mg, 0.06 mmol, 0.3 equiv.) were added to the solution. After stirring for 24 hours at room temperature, the reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layers were extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash to yield (aS,1R,3R,1’R,3’R)-22 (Compound 13a) (40 mg, 34%) as white solid; mp 72-73 °C −147 (c = 0.32; MeCN); ECD (c = 1.59×10−4M; MeCN) λ [nm], (Δε) = 287 (−0.34), 279sh (−0.14), 271 (0.45), 264 (0.66), 257sh (0.69), 239sh (3.48), 227 (4.95), 204 (−25.22). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aR,1S,3S,1’S,3’S)- 22. 1.2.5.16. - Ethyl 1’-{(aS,1S,3S,1’R,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl- [5,5’-b (Compound 14a) o pou d 14a Starting from (aS,1S,3S,2’S)-20 (Compound 22a) (132 mg, 0.25 mmol, 1.0 equiv.) using method C: anhydrous toluene (3 ml), ethyl-3,3-diethoxypropionate (90%, technical grade, 108 μl = 98 μl, 95 mg, 0.50 mmol, 2.0 equiv.), BF3·Et2O (9 μl, 11 mg, 0.08 mmol, 0.3 equiv.), reaction time: 4 hours. (aS,1S,3S,1’R,3’S)-23 (Compound 14a): 141 mg (yield: 90%), white amorphous solid foam = 0.51; MeCN); ECD (c = 1.82×10−4M; MeCN) λ [nm], (Δε) = 292 (−0.47), 270 (−1.26), 264sh (−2.30), 242 (−7.40), 220 (3.33), 199 (28.46). Flash chromatography (hexane / EtOAc 9:1 → 85:15 → 8:2 → 75:25 → 7:3); Rf= 0.40 (hexane / EtOAc 75:25);1H NMR (400 MHz, CDCl3) δ = 7.23 – 7.16 (m, 2H, H-14, H-18), 7.06 – 6.99 (m, 2H, H-15, H-17), 6.64 (s, 1H, H-6’), 6.04 (s, 1H, H-1), 5.44 (dd, J = 8.2, 2.9 Hz, 1H, H-1’), 4.20 (q, J = 7.1 Hz, 2H, H-14’), 3.91 (s, 3H, H-10’), 3.89 (s, 3H, H-10), 3.84 (s, 3H, H- 9’), 3.66 (s, 3H, H-9), 3.64 – 3.58 (m, 2H, H-3, H-3’), 3.57 (s, 3H, H-11), 3.31 (dd, J = 15.2, 3.2 Hz, 1H, H-12’-a), 2.66 (dd, J = 15.2, 8.3 Hz, 1H, H-12’-b), 2.42 (dd, J = 15.5, 10.9 Hz, 1H, H-4’ax), 2.27 (dd, J = 17.1, 11.1 Hz, 1H, H-4ax), 2.03 (d, J = 15.5 Hz, 1H, H-4’eq), 1.90 (dd, J = 17.1, 3.4 Hz, 1H, H-4eq), 1.28 (t, J = 7.1 Hz, 3H, H-15’), 1.24 (d, J = 6.1 Hz, 3H, H-11’), 1.09 (d, J = 6.1 Hz, 3H, H-12); 13C NMR (100 MHz, CDCl3) δ = 171.9 (1C, C-13’), 162.2 (d, JC-F= 246.0 Hz, 1C, C-16), 151.3 (1C, C-6), 150.3 (1C, C-7’), 149.3 (1C, C-8), 144.5 (1C, C-8’), 144.1 (1C, C-7), 138.2 (d, JC-F= 2.8 Hz, 1C, C-13), 130.6 (1C, C-5’), 130.4 (1C, C-8a’), 130.2 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 128.7 (1C, C-5), 128.2 (1C, C-4a), 126.8 (1C, C-4a’), 124.1 (1C, C-8a), 114.8 (d, JC-F = 8.0 Hz, 2C, C-15, C-17), 112.8 (1C, C-6’), 73.3 (1C, C-1), 71.6 (1C, C-1’), 69.9 (1C, C-3’), 63.1 (1C, C-3), 61.0 (1C, C-9), 60.7 (1C, C-10), 60.3 (1C, C-10’), 60.2 (1C, C-14’), 60.0 (1C, C-11), 55.9 (1C, C-9’), 41.9 (1C, C-12’), 34.6 (1C, C-4’), 34.4 (1C, C-4), 21.7 (2C, C-11’, C-12), 14.3 (1C, C-15’); IR (KBr) ν = 2973, 2936 (νas Me, νas CH2), 2841 (νs CH2), 1737 (ν C=O), 1602, 1579, 1507, 1486, 1464, 1420 (ν Ar C=C, βs CH2, δas Me), 1383, 1363, 1314 (δs Me, δ CH, γs CH2), 1280, 1254, 1223, 1174, 1159, 1112 (νas Ar-O-Me, ν Ar C-F, νasC-O-C=O), 1093, 1067, 1027 (νasC-O-C, νsAr-O-Me, νsC-O-C=O) cm-1; ESI-TOF-HRMS: m / z calculated for C35H41FNaO9[M+Na]+647.2627, found 647.2626. 1.2.5.17. - Ethyl 1’-{(aR,1R,3R,1’S,3’R)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl- [5,5’- (Compound 15a) Compound 15a Starting from (aR,1R,3R,2’R)-20 (Compound 24a) (170 mg, 0.32 mmol, 1.0 equiv.) using method C: anhydrous toluene (4 ml), ethyl-3,3-diethoxypropionate (90%, technical grade, 140 μl = 126 μl, 123 mg, 0.65 mmol, 2.0 equiv.), BF3·Et2O (14 μl, 12 mg, 0.10 mmol, 0.3 equiv.), reaction time: 4 hours. (aR,1R,3R,1’S,3’R)-23 (Compound 15a): 140 mg (yield: 69%), white amorphous solid foam; −202 (c = 0.51; MeCN); ECD (c = 1.83×10−4M; MeCN) λ [nm], (Δε) = 291 (0.45), 270 (1.12), 264sh (2.30), 244 (6.93), 220 (−2.65), 200 (−26.80). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aS,1S,3S,1’R,3’S)-23 (Compound 14a). 1.2.5.18. - Ethyl 1’-{(aR,1S,3S,1’R,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl- (Compound 16a) Compound 16a Starting from (aR,1S,3S,2’S)-20 (Compound 23a) (140 mg, 0.27 mmol, 1.0 equiv.) using method C: anhydrous toluene (3 ml), ethyl-3,3-diethoxypropionate (90%, technical grade, 115 μl = 103 μl, 101 mg, 0.53 mmol, 2.0 equiv.), BF3·Et2O (10 μl, 11 mg, 0.08 mmol, 0.3 equiv.), reaction time: 3 hours. (aR,1S,3S,1’R,3’S)-23 (Compound 16a): 156 mg (yield: 94%), white amorphous solid foam; +233 (c = 0.50; MeCN); ECD (c = 1.66×10−4M; MeCN) λ [nm], (Δε) = 287 (0.18), 270 (−0.61), 264 (−0.97), 257sh (−1.29), 242sh (−4.07), 233 (−4.18), 206 (27.41). Flash chromatography (hexane / EtOAc 9:1 → 85:15 → 8:2 → 7:3 → 6:4); Rf= 0.49 (hexane / EtOAc 75:25);1H NMR (400 MHz, CDCl3) δ = 7.28 – 7.22 (m, 2H, H-14, H-18), 7.06 – 6.98 (m, 2H, H-15, H-17), 6.65 (s, 1H, H-6’), 6.02 (s, 1H, H-1), 5.43 (dd, J = 8.0, 3.1 Hz, 1H, H-1’), 4.18 (q, J = 7.1, 2H, H-14’), 3.90 (s, 3H, H-10’), 3.89 (s, 3H, H-10), 3.87 (s, 3H, H-9’), 3.73 – 3.60 (m, 2H, H-3’, H- 3), 3.66 (s, 3H, H-9), 3.57 (s, 3H, H-11), 3.32 (dd, J = 15.1, 3.4 Hz, 1H, H-12’-a), 2.66 (dd, J = 15.1, 8.1 Hz, 1H, H- 12’-b), 2.24 (dd, J = 17.0, 3.6 Hz, 1H, H-4eq), 2.22 – 2.15 (m, 2H, H-4’), 2.11 (dd, J = 17.0, 10.7 Hz, 1H, H-4ax), 1.27 (t, J = 7.1 Hz, 3H, H-15’), 1.21 (d, J = 6.1 Hz, 3H, H-11’), 1.09 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 171.8 (1C, C-13’), 162.2 (d, JC-F = 245.9 Hz, 1C, C-16), 150.3 (1C, C-6), 150.2 (1C, C-7’), 149.3 (1C, C-8), 144.6 (1C, C-8’), 143.8 (1C, C-7), 138.2 (d, JC-F = 2.9 Hz, 1C, C-13), 130.9 (1C, C-5’), 130.5 (1C, C-8a’), 130.3 (d, JC-F= 8.0 Hz, 2C, C-14, C-18), 129.2 (2C, C-4a, C-5), 127.4 (1C, C-4a’), 124.4 (1C, C-8a), 114.7 (d, JC-F= 21.2 Hz, 2C, C-15, C-17), 112.7 (1C, C-6’), 73.4 (1C, C-1), 71.7 (1C, C-1’), 69.9 (1C, C-3’), 63.3 (1C, C-3), 60.8 (1C, C- 9), 60.7 (1C, C-10), 60.3 (1C, C-10’), 60.2 (1C, C-14’), 60.0 (1C, C-11), 55.9 (1C, C-9’), 41.8 (1C, C-12’), 34.4 (1C, C-4’), 32.2 (1C, C-4), 21.5 (2C, C-11’, C-12), 14.3 (1C, C-15’); IR (KBr) ν = 2973, 2935 (νas Me, νas CH2), 1738 (ν C=O), 1602, 1507, 1486, 1464, 1421, 1407 (ν Ar C=C, βsCH2, δasMe), 1384, 1360, 1315 (δsMe, δ CH, γsCH2), 1267, 1254, 1222, 1174, 1159, 1122 (νasAr-O-Me, ν Ar C-F, νasC-O-C=O), 1093, 1066, 1029 (νasC-O-C, νsAr-O-Me, νs C-O-C=O), 871 (1,2,3,4,5-pentasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C35H41FNaO9 [M+Na]+647.2627, found 647.2628. 1.2.5.19. - Ethyl 1’-{(aS,1R,3R,1’S,3’R)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl- [5,5’-bis-isochroman]-1’-yl}acetate [(aS,1R,3R,1’S,3’R)-23] (Compound 17a)

[0021] Compound 17a Starting from (aS,1R,3R,2’R)-20 (Compound 25a) (100 mg, 0.19 mmol, 1.0 equiv.) using method C: anhydrous toluene (2 ml), ethyl-3,3-diethoxypropionate (90%, technical grade, 82 μl = 74 μl, 72 mg, 0.38 mmol, 2.0 equiv.), BF3·Et2O (7 μl, 8 mg, 0.06 mmol, 0.3 equiv.), reaction time: 3 hours. (aS,1R,3R,1’S,3’R)-23 (Compound 17a): 98 mg (yield: 83%), white amorphous solid foam (c = 0.50; MeCN); ECD (c = 1.87×10−4M; MeCN) λ [nm], (Δε) = 287 (−0.14), 270 (0.55), 263 (0.89), 257sh (1.28), 241 (4.08), 232sh (3.89), 205 (−24.28). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aR,1S,3S,1’R,3’S)-23 (Compound 16a). 1.2.5.20. - Ethyl 1’-{(aS,1R,3S,1’R,3’S)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl- [5,5’-bis-isochroman]-1’-yl}acetate [(aS,1R,3S,1’R,3’S)-23] (Compound 18a) Compound 18a Starting from (aS,1R,3S,2’S)-20 (Compound 26a) (140 mg, 0.27 mmol, 1.0 equiv.) using method C: anhydrous toluene (3 ml), ethyl-3,3-diethoxypropionate (90%, technical grade, 115 μl = 103 μl, 101 mg, 0.53 mmol, 2.0 equiv.), BF3·Et2O (10 μl, 11 mg, 0.08 mmol, 0.3 equiv.), reaction time: 16 hours. (aS,1R,3S,1’R,3’S)-23 (Compound 18a): 150 mg (yield: 91%), white amorphous solid foam; −253 (c = 0.48; MeCN); ECD (c = 1.41×10−4M; MeCN) λ [nm], (Δε) = 289 (−2.02), 250sh (−7.82), 225 (−30.99), 201 (30.75). Flash chromatography (hexane / EtOAc 95:5 → 9:1 → 85:15 → 8:2); Rf= 0.55 (hexane / EtOAc 75:25);1H NMR (400 MHz, CDCl3) δ = 7.38 – 7.32 (m, 2H, H-14, H-18), 7.07 – 7.00 (m, 2H, H-15, H-17), 6.69 (s, 1H, H-6’), 5.82 (s, 1H, H-1), 5.44 (dd, J = 8.4, 3.2 Hz, 1H, H-1’), 4.20 (qd, J = 7.1, 1.2 Hz, 2H, H- 14’), 3.92 (s, 3H, H-10’), 3.88 (s, 3H, H-9’), 3.80 (s, 3H, H-10), 3.73 – 3.64 (m, 1H, H-3), 3.63 – 3.56 (m, 1H, H-3’), 3.55 (s, 3H, H-9), 3.29 (dd, J = 15.1, 3.3 Hz, 1H, H-12’-a), 3.15 (s, 3H, H-11), 2.64 (dd, J = 15.1, 8.3 Hz, 1H, H-12’- b), 2.49 – 2.38 (m, 2H, H-4ax, H-4’ax), 1.99 – 1.91 (m, 1H, H-4eq), 1.95 – 1.89 (m, 1H, H-4’eq), 1.28 (t, J = 7.1 Hz, 3H, H-15’), 1.23 (d, J = 6.1 Hz, 3H, H-12), 1.20 (d, J = 6.1 Hz, 3H, H-11’);13C NMR (100 MHz, CDCl3) δ = 172.0 (1C, C-13’), 162.2 (d, JC-F= 245.3 Hz, 1C, C-16), 151.1 (1C, C-6), 150.1 (1C, C-7’), 149.7 (1C, C-8), 144.6 (1C, C- 8’), 144.5 (1C, C-7), 140.1 (d, JC-F = 2.8 Hz, 1C, C-13), 130.6 (1C, C- 5’), 130.3 (1C, C-8a’), 130.1 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 129.1 (1C, C-4a), 128.4 (1C, C-5), 127.6 (1C, C-4a’), 126.6 (1C, C-8a), 115.0 (d, JC-F = 21.4 Hz, 2C, C-15, C-17), 113.3 (1C, C-6’), 77.5 (1C, C-1), 71.6 (1C, C-1’), 70.5 (1C, C-3), 69.9 (1C, C-3’), 60.9 (1C, C-9), 60.6 (1C, C-10), 60.4 (1C, C-10’), 60.2 (1C, C-14’), 59.3 (1C, C-11), 56.0 (1C, C-9’), 42.0 (1C, C-12’), 35.6 (1C, C- 4), 34.5 (1C, C-4’), 21.8 (1C, C-12), 21.6 (1C, C-11’), 14.3 (1C, C-15’); IR (KBr) ν = 2974, 2936 (νas Me, νas CH2), 2847 (νs CH2), 1737 (ν C=O), 1605, 1576, 1510, 1486, 1462, 1420 (ν Ar C=C, βs CH2, δas Me), 1383, 1359, 1315 (δs Me, δ CH, γsCH2), 1279, 1256, 1224, 1154, 1117 (νasAr-O-Me, ν Ar C-F, νasC-O-C=O), 1072, 1029 (νasC-O-C, νsAr- O-Me, νsC-O-C=O) cm-1; ESI-TOF-HRMS: m / z calculated for C35H41FNaO9[M+Na]+647.2627, found 647.2619. 1.2.5.21. - Ethyl 1’-{(aR,1S,3R,1’S,3’R)-1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl- [5,5’-bis-isochroman]-1’-yl}acetate [(aR,1S,3R,1’S,3’R)-23] (Compound 19a) and ethyl 1’-{(aR,1R,3R,1’S,3’R)- 1-(4-fluorophenyl)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-1’-yl}acetate [(aR,1R Compound 15a (aS,1S,3S,2’S)-20 (Compound 22a) (100 mg, 0.19 mmol, 1.0 equiv.) was dissolved in anhydrous toluene (2 ml), and the solution was cooled to 0 °C. Then ethyl-3,3-diethoxypropionate (90%, technical grade, 82 μl = 74 μl, 72 mg, 0.38 mmol, 2.0 equiv.) and BF3·Et2O (7 μl, 8 mg, 0.06 mmol, 0.3 equiv.) were added to the solution, and the reaction was allowed to warm up to room temperature. After two days, another portion of BF3·Et2O (4 μl, 4 mg, 0.03 mmol, 0.15 equiv.) was added to the reaction mixture. The temperature was raised to 60 °C. After stirring 4.5 hours, the reaction was allowed to cool down to room temperature. The reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the chiral non-racemic isochroman target derivative. (aR,1S,3R,1’S,3’R)-23 (Compound 19a): 34 mg (yield: 30%), white amorphous solid foam; (c = 0.39; MeCN); ECD (c = 1.81×10−4M; MeCN) λ [nm], (Δε) = 289 (1.57), 250sh (6.47), 225 (25.77), 202 (−28.36). Epimerization of C-1 caused by BF3·Et2O also resulted in (aR,1R,3R,1’S,3’R)-23 (Compound 15a): (38 mg, yield: 33%) as white amorphous solid foam. Chromatographic and spectral data except for the chiroptical ones were identical with those of the corresponding enantiomers (aS,1R,3S,1’R,3’S)-23 and (aS,1S,3S,1’R,3’S)-23 (Compound 14a). 1.2.5.22. - (S)-6,7,8-trimethoxy-3-methylisochroman [(S)-24] Starting from (S)-16 (600 mg, 2.65 mmol, 1.0 equiv.) using method A: anhydrous Et2O (20 ml), MOMCl (1.01 ml, 1.07 g, 13.26 mmol, 5.0 equiv.), annealed ZnCl2(109 mg, 0.80 mmol, 0.3 equiv.), reaction time: 2 hours. (S)-24: 575 mg (yield: 91%), colorless syrup; [α]^^^+112 (c = 0.33; CHCl3). Flash chromatography (hexane / EtOAc 95:5 → 93:7 → 9:1); Rf= 0.74 (hexane / EtOAc 6:4);1H NMR (400 MHz, CDCl3) δ = 6.39 (s, 1H, H-5), 4.88 (d, J = 15.3 Hz, 1H, H-1-a), 4.62 (d, J = 15.3 Hz, 1H, H-1-b), 3.86, 3.83, 3.82 (3s, 3x 3H, H-9, H-10, H-11), 3.78 – 3.65 (m, 1H, H-3), 2.59 (d, J = 6.8 Hz, 2H, H-4), 1.33 (d, J = 6.2 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 152.2, 149.2, 139.9, 129.1, 120.4 (5C, C-4a, C-8a, C-6, C-7, C- 8), 107.2 (1C, C-5), 70.5 (1C, C-3), 64.4 (1C, C-1), 60.8, 60.4, 55.9 (3C, C-10, C-11, C-12), 35.5 (1C, C-4), 21.5 (1C, C-9); IR (KBr) ν = 2969, 2936 (νasMe, νasCH2), 2837 (νs CH2), 2017, 1725 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1605, 1589, 1495, 1463 (ν Ar C=C, βs CH2, δas Me), 1383, 1365, 1336 (δs Me, δ CH), 1263, 1244, 1223 (νas Ar-O-Me), 1091 (νas C-O-C), 1050, 1031 (νs Ar-O-Me), 866 (1,2,3,4,5-pentasubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C13H18NaO4[M+Na]+261.1097, found 261.1096. 1.2.5.23. - (aR,3S,3’S)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis-isochroman [(aR,3S,3’S)-28] (Compound 20a) and (aS,3S,3’S)-6,7,7’,8,8’-pentamethoxy-3,3’-dimethyl-5,5’-bis-isochroman [(aS,3S,3’S)- 28] (Compound 21a) Compound 20a Compound 21a Starting from the mixture of (aR,3S,2’S)-27 (Compound 29a) and (aS,3S,2’S)-27 (Compound 30a) (136 mg, 0.32 mmol, 1.0 equiv.) using method A: anhydrous Et2O (5 ml), MOMCl (185 μl, 196 mg, 2.44 mmol, 7.7 equiv.), annealed ZnCl2(13 mg, 0.10 mmol, 0.3 equiv.), reaction time: 4 hours. The mixture of (aR,3S,2’S)-28 and (aS,3S,3’S)- 28 (Compound 21a): 120 mg, (yield: 86%), yellow syrup. Flash chromatography (hexane / EtOAc 85:15 → 8:2 → 7:3); Rf = 0.24 (hexane / EtOAc 8:2); ESI-TOF-HRMS: m / z calculated for C25H32NaO7 [M+Na]+467.2040, found 467.2040. The atropdiastereomers were separated by preparative chiral HPLC using Chiralpak IC column with isocratic elution (hexane / i-PrOH 85:15). (aR,3S,3’S)-28 (Compound 20a): tR= 12.29 min; (c = 0.45; MeCN); ECD (c = 2.66×10−4M; MeCN) λ [nm], (Δε) = 289 (−0.07), 268 (0.09), 239 (−1.45), 228sh (−1.36), 204 (34.79);1H NMR (400 MHz, CDCl3) δ = 6.56 (s, 1H, H-6’), 5.05 (d, J = 15.8 Hz, 1H, H-1’eq), 4.98 (d, J = 15.6 Hz, 1H, H-1eq), 4.77 (d, J = 15.8 Hz, 1H, H-1’ax), 4.68 (d, J = 15.6 Hz, 1H, H-1ax), 3.93 (s, 3H, H-11), 3.92 (s, 3H, H-10), 3.87 (s, 3H, H-10’), 3.82 (s, 3H, H-9’), 3.74 – 3.63 (m, 2H, H-3, H-3’), 3.62 (s, 3H, H-9), 2.27 – 2.01 (m, 3H, H- 4eq, H-4’), 2.06 (dd, J = 17.1, 10.4 Hz, 1H, H-4ax) 1.25 (d, J = 6.2 Hz, 3H, H-11’), 1.22 (d, J = 6.3 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 149.9 (1C, C-7’), 149.7 (1C, C-6), 148.7 (1C, C-8), 143.9 (1C, C-7), 143.7 (1C, C-8’), 131.4 (1C, C-5’), 129.4 (1C, C-5), 128.8 (1C, C- 8a’), 128.5 (1C, C-4a), 125.7 (1C, C-4a’), 124.0 (1C, C-8a), 112.4 (1C, C-6’), 70.8 (2C, C-3, C-3’), 65.0 (1C, C-1’), 64.7 (1C, C-1), 61.1 (1C, C-9), 61.0 (1C, C-10), 60.6 (1C, C-11), 60.3 (1C, C-10’), 56.0 (1C, C-9’), 33.6 (1C, C-4’), 33.4 (1C, C-4), 21.7 (2C, C-11’, C-12); IR (KBr) ν = 3051 (ν Ar =CH), 2967, 2934 (νas Me, νas CH2), 2893, 2839 (νs Me, νs CH2, ν CH), 1958, 1733 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1598, 1579, 1489, 1466, 1422, 1408 (ν Ar C=C, βsCH2, δasMe), 1384, 1362, 1314 (δsMe, δ CH, γsCH2), 1280, 1258, 1233, 1215 (νasAr-O-Me), 1131, 1114, 1083 (νasC-O-C, νsAr-O-Me), 869 (1,2,3,4,5- pentasubstituated γs Ar =CH) cm-1. (aS,3S,3’S)-28 (Compound 21a): tR= 14.33 min; (c = 0.44; MeCN); ECD (c = 2.87×10−4M; MeCN) λ [nm], (Δε) = 287 (−0.81), 242sh (−4.11), 227 (−6.99), 201 (35.19);1H NMR (400 MHz, CDCl3) δ = 6.57 (s, 1H, H-6’), 5.05 (d, J = 15.8 Hz, 1H, H-1’eq), 4.97 (d, J = 15.5 Hz, 1H, H-1eq), 4.76 (d, J = 15.8 Hz, 1H, H-1’ax), 4.69 (d, J = 15.5 Hz, 1H, H-1ax), 3.93 (s, 3H, H-11), 3.91 (s, 3H, H-10), 3.88 (s, 3H, H-10’), 3.81 (s, 3H, H-9’), 3.72 – 3.57 (m, 2H, H-3’, H-3), 3.58 (s, 3H, H-9), 2.37 (dd, J = 16.4, 10.7 Hz, 1H, H-4’ax), 2.25 (dd, J = 16.8, 10.6 Hz, 1H, H-4ax), 2.03 (dd, J = 16.5, 2.3 Hz, 1H, H-4’eq), 1.94 (dd, J = 16.9, 2.0 Hz, 1H, H-4eq), 1.25 (d, J = 5.9 Hz, 3H, H-11’), 1.24 (d, J = 5.9 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 150.4 (1C, C-6), 149.9 (1C, C-7’), 148.7 (1C, C-8), 143.9 (1C, C-7), 143.7 (1C, C-8’), 131.2 (1C, C-5’), 129.1 (1C, C-5), 128.6 (1C, C-8a’), 127.7 (1C, C-4a), 125.5 (1C, C-4a’), 123.8 (1C, C-8a), 112.7 (1C, C-6’), 70.9 (1C, C-3), 70.8 (1C, C-3’), 64.9 (2C, C-1’, C-1), 61.1 (1C, C-9), 61.0 (1C, C-10), 60.6 (1C, C-11), 60.3 (1C, C-10’), 56.0 (1C, C-9’), 34.6 (1C, C-4), 33.6 (1C, C-4’), 21.8 (1C, C-12), 21.7 (1C, C-11’); IR (KBr) ν = 3051 (ν Ar =CH), 2967, 2934 (νasMe, νasCH2), 2839 (νsCH2), 1956, 1731 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1598, 1579, 1489, 1465, 1421 (ν Ar C=C, βs CH2, δas Me), 1383, 1362, 1314 (δs Me, δ CH, γs CH2), 1280, 1258, 1233 (νas Ar-O- Me), 1131, 1113, 1084, 1062, 1035 (νas C-O-C, νs Ar-O-Me), 865 (1,2,3,4,5-pentasubstituated γs Ar =CH) cm-1. 1.2.6. General procedure for the Suzuki coupling reaction of chiral non-racemic 1-[(2- pinacolatoboryl)aryl]propan-2-yl acetate and 5-iodoisochroman derivatives To the solution of the 5-iodoisochroman derivative (1.0 equiv.) in anhydrous DMF (2-22 ml), phosphine ligand (method D: SPhos, 0.2 equiv.; method E: (S)-BINAP, 0.1 equiv.; method F: Xantphos, 0.1 equiv.) and Pd(OAc)2 (0.1 equiv.) were added under Ar or N2 atmosphere, and the solution was stirred for 1 hour with inert gas bubbling at room temperature. To the solution of the 1-[(2-pinacolatoboryl)aryl]propan-2-yl acetate (1.2 equiv.) in anhydrous DMF (2-14 ml), CsF (4.0 equiv.) was added under Ar or N2 atmosphere, and the solution was stirred for 0.5 hour with inert gas bubbling at room temperature. The first solution was merged with the second, and the mixture was stirred at 150 °C. When the 5-iodoisochroman derivative was consumed (1.5-3 hours) on the basis of TLC monitoring, the reaction mixture was poured on ice and diluted with Et2O and the mixture was filtered on a short pad of Celite. The Celite was washed with Et2O. The two layers were separated in a separatory funnel. The aqueous phase was extracted twice with Et2O. The combined organic layers were washed twice with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the 1-[2-(6,7,8-trimethoxy-3-methylisochroman-5-yl)-4,5-dimethoxyphenyl]propan-2-yl acetate target derivative. 1.2.6.1. - (2S)-1-{2-[(aS,1S,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-yl acetate and (2S)-1-{2-[(aR,1S,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3- methylisochroman-5-yl]-4,5-dimethoxyphenyl}propan-2-yl acetate [the mixture of (aR,1S,3S,2’S)-19 and (aS,1S,3S,2’S)-19] Starting from trans-(1S,3S)-18 (255 mg, 0.56 mmol, 1.0 equiv.) using method D: anhydrous DMF (2.5 ml), SPhos (46 mg, 0.11 mmol, 0.2 equiv.), Pd(OAc)2(13 mg, 0.06 mmol, 0.1 equiv.), (S)-8 (243 mg, 0.67 mmol, 1.2 equiv.), anhydrous DMF (2 ml), CsF (338 mg, 2.23 mmol, 4.0 equiv.), reaction time: 2 hours. The mixture of (aR,1S,3S,2’S)-19 and (aS,1S,3S,2’S)-19: 209 mg (yield: 66%, dr 1.0:1.2) pale brown amorphous solid foam. Starting from trans-(1S,3S)-18 (152 mg, 0.33 mmol, 1.0 equiv.) with method E: anhydrous DMF (2 ml), (S)- BINAP (21 mg, 0.03 mmol, 0.1 equiv.), Pd(OAc)2(7 mg, 0.03 mmol, 0.1 equiv.), (S)-8 (145 mg, 0.40 mmol, 1.2 equiv.), anhydrous DMF (2.5 ml), CsF (201 mg, 1.32 mmol, 4.0 equiv.), reaction time: 2 hours. The mixture of (aR,1S,3S,2’S)-19 and (aS,1S,3S,2’S)-19: 102 mg (yield: 54%, dr 1.0:1.7) pale brown amorphous solid foam. Starting from trans-(1S,3S)-18 (815 mg, 1.78 mmol, 1.0 equiv.) with method F: anhydrous DMF (5 ml), Xantphos (103 mg, 0.18 mmol, 0.1 equiv.), Pd(OAc)2(40 mg, 0.18 mmol, 0.1 equiv.), (S)-8 (778 mg, 2.14 mmol, 1.2 equiv.), anhydrous DMF (3 ml), CsF (1.08 g, 7.12 mmol, 4.0 equiv.), reaction time: 1.5 hours. The mixture of (aR,1S,3S,2’S)-19 and (aS,1S,3S,2’S)-19: 797 mg (yield: 79%, dr 1.0:1.4) pale brown amorphous solid foam. Flash chromatography (hexane / EtOAc 85:15 → 8:2 → 75:25 → 7:3); Rf= 0.27 (hexane / EtOAc 75:25);1H NMR (400 MHz, CDCl3) δ = 7.30 – 7.14 [2m, 2 x 2H, (aR), (aS) H-14, H-18], 7.08 – 6.96 [2m, 2 x 2H, (aR), (aS) H- 15, H-17], 6.91, 6.85 [2s, 2 x 1H, (aR), (aS) H-9’], 6.65, 6.62 [2s, 2 x 1H, (aR), (aS) H-6’], 6.04, 6.03 [2s, 2 x 1H, (aR), (aS) H-1], 5.21 – 5.08 [m, 1H, (aR) or (aS) H-2’], 4.89 – 4.76 [m, 1H, (aR) or (aS) H-2’], 3.94, 3.93, 3.89, 3.86, 3.71, 3.65, 3.57, 3.55 [10s, 10 x 3H, (aR), (aS) H-11, H-10’, H-10, H-11’, H-9], 3.69 – 3.62 [2m, 2 x 1H, (aR), (aS) H-3], 2.67, 2.55, 2.32, 2.24, 2.21, 2.05, 2.02 [dd, J = 14.1, 7.4 Hz, 1H, dd, J = 13.8, 8.0 Hz, 1H, dd, J = 13.8, 5.8 Hz, 1H, dd, J = 14.1, 6.4 Hz, 1H, dd, J = 17.8, 10.2 Hz, 1H, dd, J = 17.8, 2.5 Hz, 1H, dd, J = 17.9, 4.3 Hz, 1H, dd, J = 17.9, 9.8 Hz, 1H, (aR), (aS) H-1’-a,b, H-4- a,b], 1.99, 1.95 [2s, 2 x 3H, (aR), (aS) H-13’], 1.10 [d, J = 6.2 Hz, 3H, (aR) or (aS) H-12], 1.08 [d, J = 6.1 Hz, 3H, (aR) or (aS) H-12], 1.06 [d, J = 5.8 Hz, 2 x 3H, (aR), (aS) H-3’];13C NMR (100 MHz, CDCl3) δ = 170.5, 170.0 [2C, (aR), (aS) C-12’], 162.3 [d, JC-F= 245.8 Hz, 2C, (aR), (aS), C-16], 151.1, 150.8 [2C, (aR), (aS) C-6], 149.4 [2C, (aR), (aS) C-8], 148.2, 147.9 [2C, (aR), (aS) C-7’], 147.4, 147.2 [2C, (aR), (aS) C-8’], 144.2, 143.9 [2C, (aR), (aS) C-7], 138.3 [2C, (aR), (aS) C-13], 130.4, 130.3 [2d, JC-F = 7.8 Hz, 4C, (aR), (aS) C-14, C-18], 129.6, 129.3, 129.1, 128.6, 128.3, 128.2 [8C, (aR), (aS) C-5’, C-4’, C-4a, C-5], 124.5, 124.1 [2C, (aR), (aS) C-8a], 114.8 [d, J = 21.1 Hz, 4C, (aR), (aS) C-15, C-17], 113.5, 113.1, 112.8, 112.1 [4C, (aR), (aS) C-6’, C-9’], 73.5, 73.3, 71.4, 70.6 [4C, (aR), (aS) C-2’, C-3], 63.3, 63.1 [2C, (aR), (aS) C- 1], 61.1, 61.0, 60.8, 60.7, 60.1 [6C, (aR), (aS) C-9, C-10, C-11], 56.1, 56.0, 55.9, 55.8 [4C, (aR), (aS) C-11’, C-10’], 40.1, 38.7 [2C, (aR), (aS) C-1’], 34.4, 33.7 [2C, (aR), (aS) C-4], 21.7, 21.6, 21.5, 21.3 [4C, (aR), (aS) C-12, C-13’], 20.1, 19.8 [2C, (aR), (aS) C-3’]; IR (KBr) ν = 2930 (νasCH2), 2850 (νsCH2), 1735 (ν C=O), 1604, 1508, 1463, 1422, 1409 (ν Ar C=C, βsCH2, δasMe), 1364, 1329 (δ CH, γsCH2, δsMe), 1249, 1158, 1113 (νasC-O-C=O, νasAr-O-Me, ν Ar C-F), 1069, 1025 (νasC-O-C, νs C-O-C=O, νs Ar-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C32H37FNaO8 [M+Na]+591.2365, found 591.2364. 1.2.6.2. - (2R)-1-{2-[(aR,1R,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-yl acetate and (2R)-1-{2-[(aS,1R,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3- methylisochroman-5-yl]-4,5-dimethoxyphenyl}propan-2-yl acetate [the mixture of (aR,1R,3R,2’R)-19 and (aS,1R,3R,2’R)-19] Starting from trans-(1R,3R)-18 (1.00 g, 2.18 mmol, 1.0 equiv.) using method G: anhydrous DMF (6 ml), Xantphos (126 mg, 0.22 mmol, 0.1 equiv.), Pd(OAc)2 (49 mg, 0.22 mmol, 0.1 equiv.), (R)-8 (954 mg, 2.62 mmol, 1.2 equiv.), anhydrous DMF (4 ml), CsF (1.33 g, 8.73 mmol, 4.0 equiv.), reaction time: 3 hours. The mixture of (aR,1R,3R,2’R)-19 and (aS,1R,3R,2’R)-19: 899 mg (yield: 73%, dr 1.0:1.4) pale brown amorphous solid foam. Chromatographic and spectral data except for the chiroptical ones were identical with those of the mixture of (aR,1S,3S,2’S)-19 and (aS,1S,3S,2’S)-19. 1.2.6.3. - (2S)-1-{2-[(aS,1R,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-yl acetate [(aS,1R,3S,2’S)-19] and (2S)-1-{2-[(aR,1R,3S)-1-(4-fluorophenyl)-6,7,8- trimethoxy-3-methylisochroman-5-yl]-4,5-dimethoxyphenyl}propan-2-yl acetate [(aR,1R,3S,2’S)-19] Starting from cis-(1R,3S)-18 (500 mg, 1.09 mmol, 1.0 equiv.) using method G: anhydrous DMF (8 ml) Xantphos (63 mg, 0.11 mmol, 0.1 equiv.), Pd(OAc)2(25 mg, 0.11 mmol, 0.1 equiv.), (S)-8 (477 mg, 1.31 mmol, 1.2 equiv.), anhydrous DMF (5 ml), CsF (663 mg, 4.36 mmol, 4.0 equiv.), reaction time: 1.5 hours. (aS,1R,3S,2’S)-19: 423 mg (yield: 68%) off-white amorphous solid foam −110 (c = 0.48; CHCl3). (aR,1R,3S,2’S)-19: 69 mg (yield: 11%) yellow amorphous solid foam; [α]^^^−45 (c = 0.14; CHCl3). Flash chromatography (hexane / EtOAc 9:1 → 85:15 → 8:2 → 75:25 → 7:3 → 65:35); ESI-TOF-HRMS: m / z calculated for C32H37FNaO8 [M+Na]+591.2365, found 561.2360. (aS,1R,3S,2’S)-19: Rf= 0.31 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.40 – 7.31 (m, 2H, H-14, H-18), 7.08 – 6.98 (m, 2H, H-15, H-17), 6.84 (s, 1H, H-9’), 6.67 (s, 1H, H-6’), 5.85 (s, 1H, H-1), 4.78 – 4.65 (m, 1H, H-2’), 3.94 (s, 3H, H-11’), 3.90 (s, 3H, H-10’), 3.79 (s, 3H, H-10), 3.76 – 3.66 (m, 1H, H-3), 3.55 (s, 3H, H-9), 3.14 (s, 3H, H-11), 2.67 – 2.53 (m, 2H, H-1’), 2.39 (ddd, J = 16.2, 10.7, 1.3 Hz, 1H, H-4ax), 2.05 (d, J = 16.2 Hz, 1H, H- 4eq), 1.93 (s, 3H, H-13’), 1.21 (d, J = 6.2 Hz, 3H, H-12), 1.02 (d, J = 6.2 Hz, 3H, H-3’);13C NMR (100 MHz, CDCl3) δ = 170.2 (1C, C-12’), 162.3 (d, JC-F= 245.1 Hz, 1C, C-16), 150.3 (1C, C-6), 149.8 (1C, C-8), 148.0 (1C, C-8’), 147.4 (1C, C-7’), 144.6 (1C, C-7), 140.3 (d, JC-F = 3.0 Hz, 1C, C-13), 130.3 (d, JC-F = 7.9 Hz, 2C, C-14, C-18), 130.2 (1C, C-4a), 129.2 (1C, C-4’), 128.8 (1C, C-5), 128.2 (1C, C-5’), 127.0 (1C, C-8a), 115.1 (d, JC-F = 21.4 Hz, 2C, C-15, C- 17), 113.7 (1C, C-6’), 113.4 (1C, C-9’), 77.5 (1C, C-1), 70.8 (1C, C-3), 70.7 (1C, C-2’), 61.0 (1C, C-9), 60.7 (1C, C- 10), 59.4 (1C, C-11), 56.2 (1C, C-10’), 56.0 (1C, C-11’), 39.9 (1C, C-1’), 35.8 (1C, C-4), 21.7 (1C, C-12), 21.4 (1C, C-13’), 20.3 (1C, C-3’); IR (KBr) ν = 2974, 2936 (νas Me, νas CH2), 2845 (νs CH2), 1735 (ν C=O), 1606, 1573, 1513, 1462, 1421, 1410 (ν Ar C=C, βs CH2, δas Me), 1371, 1351, 1328 (δ CH, γs CH2, δs Me), 1251, 1225, 1171, 1154, 1119, 1102 (νasC-O-C=O, νasAr-O-Me, ν Ar C-F), 1075, 1051, 1027, 1001 (νasC-O-C, νsC-O-C=O, νsAr-O-Me), 861 (1,2,4,5-tetrasubstituated γsAr =CH) cm-1. (aR,1R,3S,2’S)-19: Rf = 0.21 (hexane / EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ = 7.32 – 7.24 (m, 2H, H-14, H-18), 7.06 – 6.99 (m, 2H, H-15, H-17), 6.90, 6.62 (2s, 2 x 1H, H-6’, H-9’), 5.84 (s, 1H, H-1), 5.18 – 5.08 (m, 1H, H-2’), 3.94, 3.86, 3.81, 3.67, 3.20 (5s, 5 x 3H, H-9, H-10, H-11, H-10’, H-11’), 3.78 – 3.71 (m, 1H, H-3), 2.39 (dd, J = 14.2, 7.7, 1H, H-4-a or H-1’-a), 2.50 (dd, J = 14.2, 6.3 Hz, 1H, H-4-b or H-1’-b), 2.30 – 2.18 (m, 2H, H-4 or H- 1’), 2.00 (s, 3H, H-13’), 1.20, 1.14 (2d, J = 6.1 Hz, J = 6.2 Hz, 2 x 3H, H-12, H-3’);13C NMR (100 MHz, CDCl3) δ = 170.5 (1C, C-12’), 162.3 (d, JC-F = 245.4 Hz, 1C, C-16), 150.9, 149.7, 148.2, 147.3, 144.6, 130.1, 129.1, 128.9, 128.3, 126.5 (10C, C-4a, C-5, C-6, C-7, C-8, C-8a, C-4’, C-5’, C-7’, C-8’), 140.3 (d, JC-F= 3.0 Hz, 1C, C-13), 130.0 (d, JC-F= 8.1 Hz, 2C, C-14, C-18), 115.4 (d, JC-F= 21.4 Hz, 2C, C-15, C-17), 113.3, 112.3 (2C, C-6’, C-9’), 77.3 (1C, C-1), 71.0, 70.4 (2C, C-3, C-2’), 61.0, 60.5, 59.4, 56.1, 55.9 (5C, C-9, C-10, C-11, C-10’, C-11’), 39.0, 34.8 (3C, C- 4, C-1’), 21.7, 21.5, 20.1 (3C, C-12, C-3’, C-13’); IR (KBr) ν = 2973, 2936 (νas Me, νas CH2), 2846 (νs CH2), 1735 (ν C=O), 1604, 1575, 1512, 1463, 1421, 1408 (ν Ar C=C, βsCH2, δasMe), 1371, 1352, 1329 (δ CH, γsCH2, δsMe), 1249, 1172, 1154, 1115 (νasC-O-C=O, νasAr-O-Me, ν Ar C-F), 1074, 1050, 1027 (νasC-O-C, νsC-O-C=O, νsAr-O- Me), 863 (1,2,4,5-tetrasubstituated γs Ar =CH) cm-1. 1.2.6.4. - (2R)-1-{2-[(aR,1S,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-yl acetate [(aR,1S,3R,2’R)-19] Starting from cis-(1S,3R)-18 (1.40 g, 3.06 mmol, 1.0 equiv.) using method G: anhydrous DMF (22 ml) Xantphos (177 mg, 0.31 mmol, 0.1 equiv.), Pd(OAc)2 (69 mg, 0.31 mmol, 0.1 equiv.), (R)-8 (1.34 g, 3.67 mmol, 1.2 equiv.), anhydrous DMF (14 ml), CsF (1.86 g, 12.22 mmol, 4.0 equiv.), reaction time: 3 hours. (aR,1S,3R,2’R)-19: 983 mg (yield: 57%) off-white amorphous solid foam; +90 (c = 0.47; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of (aS,1R,3S,2’S)-19. 1.2.6.5. - (2S)-1-{2-[(aR,3S)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5-dimethoxyphenyl}-propan- 2-yl acetate and (2S)-1-{2-[(aS,3S)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5-dimethoxyphenyl}propan- 2-yl acetate [the mixture of (aR,3S,2’S)-26 and (aS,3S,2’S)-26] Starting from (S)-25 (415 mg, 1.14 mmol, 1.0 equiv.) using method D: anhydrous DMF (4 ml), SPhos (94 mg, 0.23 mmol, 0.2 equiv.), Pd(OAc)2(26 mg, 0.11 mmol, 0.1 equiv.), (S)-8 (498 mg, 1.37 mmol, 1.2 equiv.), anhydrous DMF (4 ml), CsF (692 mg, 4.55 mmol, 4.0 equiv.), reaction time: 1.5 hours. The mixture of (aR,3S,2’S)- 26 and (aS,3S,2’S)-26: 359 mg (yield: 66%), yellow syrup. Flash chromatography (hexane / acetone 95: 5 → 9:1 → 85:15 → 8:2); Rf = 0.46 (hexane / acetone 7:3);1H NMR (400 MHz, CDCl3) δ = 6.90, 6.84 [2s, 2 x 1H, (aR), (aS) H- 9’], 6.60, 6.59 [2s, 2 x 1H, (aR), (aS) H-6’], 5.16 – 5.07 [m, 1H, (aR) or (aS) H-2’], 5.00, 4.96 [2d, J = 15.4 Hz, 2 x 1H, (aR), (aS) H-1-a], 4.86 – 4.75 [m, 1H, (aR) or (aS) H-2’], 4.76 – 4.65 [m, 2 x 1H, (aR), (aS) H-1-b], 3.94 [s, 3 x 3H, (aR), (aS) H-11, (aR) or (aS) H-10’], 3.93 [s, 3H, (aR) or (aS) H-10’], 3.91, 3.90 [2s, 2 x 3H, (aR), (aS) H-10], 3.85, 3.84 [2s, 2 x 3H, (aR), (aS) H-11’], 3.68 [s, 3H, (aR) or (aS) H-9], 3.67 – 3.59 [m, 3H, (aR), (aS) H-3], 3.56 [s, 3H, (aR), (aS) H-9], 2.67 [dd, J = 14.1, 7.4 Hz, 1H, (aR) or (aS) H-1’-a], 2.59 [qd, J = 14.1, 7.0 Hz, 2H, (aR) or (aS) H-1’-a,b], 2.33 [dd, J = 14.1, 6.4 Hz, 1H, (aR) or (aS) H-1’-b], 2.35 – 2.14 [m, 2 x 1H, (aR), (aS) H-4-a], 2.08 – 2.01 [m, 2 x 1H, (aR), (aS) H-4-b], 1.98, 1.94 [2s, 2 x 3H, (aR), (aS) H-13’], 1.22 [2d, J = 6.1 Hz, 2 x 3H, (aR), (aS) H- 12], 1.08, 1.03 [2d, J = 6.2 Hz, 2 x 3H, (aR), (aS) H-3’];13C NMR (100 MHz, CDCl3) δ = 170.5, 170.2 [2C, (aR), (aS) C-12’], 150.3, 149.8 [2C, (aR), (aS) C-6], 148.6 [2C, (aR), (aS) C-8], 148.0, 147.8 [2C, (aR), (aS) C-7’], 147.2, 147.1 [2C, (aR), (aS) C-8’], 143.8 [2C, (aR), (aS) C-7], 129.7, 129.3 [2C, (aR), (aS) C-5’], 129.1, 128.8 [2C, (aR), (aS) C-4’], 128.5, 128.4 [2C, (aR), (aS) C-4a], 128.2, 128.1 [2C, (aR), (aS) C-5], 123.9, 123.5 [2C, (aR), (aS) C-8a], 113.2, 113.1 [2C, (aR), (aS) C-6’], 112.7, 111.9 [2C, (aR), (aS) C-9’], 71.3 [1C, (aR) or (aS) C-2’], 70.8 [1C, (aR) or (aS) C-3], 70.6 [2C, (aR) or (aS) C-3, (aR) or (aS) C-2’], 64.8, 64.6 [2C, (aR), (aS) C-1], 61.0 [2C, (aR), (aS) C-9], 60.9, 60.7, 60.5 [4C, (aR), (aS) C-10, C-11], 55.9 [2C, (aR), (aS) C-11’], 55.8 [2C, (aR), (aS) C-10’], 39.6, 38.6 [2C, (aR), (aS) C-1’], 34.7, 33.7 [2C, (aR), (aS) C-4], 21.6, 21.5 [2C, (aR), (aS) C-12], 21.4, 21.3 [2C, (aR), (aS) C-13’], 20.1, 19.7 [2C, (aR), (aS) C-3’]; IR (KBr) ν = 2970, 2935 (νas Me, νas CH2), 2844 (νs CH2), 1735 (ν C=O), 1606, 1578, 1516, 1465, 1423, 1410 (ν Ar C=C, βsCH2, δasMe), 1364, 1327 (δ CH, γsCH2, δsMe), 1252, 1207, 1174, 1129, 1113 (νasC-O-C=O, νasAr-O-Me), 1072, 1050, 1029 (νasC-O-C, νsC-O-C=O, νsAr-O-Me), 864 (1,2,4,5-tetrasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C26H34NaO8 [M+Na]+497.2146, found 497.2145. 1.2.7. General procedure for deacetylation of chiral non-racemic 1-[2-(6,7,8-trimethoxy-3- methylisochroman-5-yl)-4,5-dimethoxyphenyl]propan-2-yl acetate derivatives The corresponding 1-[2-(6,7,8-trimethoxy-3-methylisochroman-5-yl)-4,5-dimethoxyphenyl]-propan-2-yl acetate (1.0 equiv.) was dissolved in a mixture of MeOH:THF:H2O. LiOH (2.0 equiv.) was added to the solution and it was stirred at room temperature. When the starting material was consumed (3-4 hours) on the basis of TLC monitoring, the solvent was evaporated in vacuo, and the residue was dissolved in CH2Cl2. The organic layer was extracted twice with a 10 % aqueous solution of NaHSO4, twice with a saturated aqueous solution of NaHCO3and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the 1-[2-(6,7,8-trimethoxy-3-methylisochroman- 5-yl)-4,5-dimethoxyphenyl]propan-2-ol target derivative. 1.2.7.1. - (2S)-1-{2-[(aS,1S,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-ol [(aS,1S,3S,2’S)-20] (Compound 22a) and (2S)-1-{2-[(aR,1S,3S)-1-(4- fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5-dimethoxy-phenyl}propan-2-ol [(aR,1S,3S,2’S)-20] (Compound 23a)

[0022] Compound 22a Compound 23a Starting from the mixture of (aR,1S,3S,2’S)-19 and (aS,1S,3S,2’S)-19 (893 mg, 1.57 mmol, 1.0 equiv.), a mixture of MeOH:THF:H2O (5:2:3 ml), LiOH (75 mg, 3.14 mmol, 2.0 equiv.), reaction time: 4 hours. (aS,1S,3S,2’S)- 20 (Compound 22a): 327 mg (yield 40%) off-white amorphous solid foam; +36 (c = 0.49; CHCl3). (aR,1S,3S,2’S)-20 (Compound 23a): 440 mg (yield: 53%) white amorphous solid foam; +76 (c = 0.51; CHCl3). Flash chromatography (CH2Cl2 / EtOAc 10:0.1 → 10:0.3 → 10:1 → 9:1 → 7:3). (aS,1S,3S,2’S)-20 (Compound 22a): Rf = 0.28 (hexane / EtOAc 6:4);1H NMR (400 MHz, CDCl3) δ = 7.22 – 7.12 (m, 2H, H-14, H-18), 7.07 – 6.96 (m, 2H, H-15, H-17), 6.88 (s, 1H, H-9’), 6.63 (s, 1H, H-6’), 6.03 (s, 1H, H-1), 3.95 (s, 3H, H-11’), 3.93 – 3.89 (m, 1H, H-2’), 3.88 (s, 3H, H-10), 3.86 (s, 3H, H-10’), 3.68 (s, 3H, H-9), 3.63 (s, 3H, H-11), 3.62 – 3.54 (m, 1H, H-3), 2.63 (dd, J = 13.9, 3.2 Hz, 1H, H-1’-a), 2.29 (dd, J = 13.9, 9.4 Hz, 1H, H-1’-b), 2.24 (dd, J = 17.1, 11.0 Hz, 1H, H-4ax), 2.02 (dd, J = 17.1, 3.5 Hz, 1H, H-4eq), 1.16 (d, J = 6.1 Hz, 3H, H-3’), 1.06 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.8 (d, JC-F = 246.1 Hz, 1C, C-16), 150.4 (1C, C-6), 149.4 (1C, C-8), 148.5 (1C, C-8’), 147.5 (1C, C-7’), 144.2 (1C, C-7), 138.1 (d, JC-F= 3.0 Hz, 1C, C-13), 130.2 (d, JC-F= 8.0 Hz, 2C, C-14, C-18), 129.7 (1C, C-4’), 129.6 (1C, C- 5), 129.0 (1C, C-4a), 128.1 (1C, C-5’), 124.6 (1C, C-8a), 114.9 (d, JC-F = 21.3 Hz, 2C, C-15, C-17), 113.0 (1C, C-6’), 112.7 (1C, C-9’), 73.3 (1C, C-1), 68.7 (1C, C-2’), 63.2 (1C, C-3), 61.3 (1C, C-9), 61.0 (1C, C-10), 60.3 (1C, C-11), 56.1 (1C, C-10’), 55.9 (1C, C-11’), 43.0 (1C, C-1’), 34.4 (1C, C-4), 23.8 (1C, C-3’), 21.7 (1C, C-12); IR (KBr) ν = 3461 (ν OH), 2967, 2935 (νasMe, νasCH2), 2843 (νsCH2), 1605, 1577, 1508, 1464, 1421, 1409 (ν Ar C=C, βsCH2, δasMe), 1363, 1330 (δ CH, γsCH2), 1250, 1221, 1199, 1171, 1158, 1110 (νas Ar-O-Me, ν Ar C-F, ν C-OH), 1070, 1024 (νas C-O-C, νs Ar-O-Me) cm-1; ESI-TOF-HRMS: m / z calculated for C30H35FNaO7 [M+Na]+549.2259, found 549.2255. (aR,1S,3S,2’S)-20 (Compound 23a): Rf= 0.19 (hexane / EtOAc 6:4);1H NMR (400 MHz, CDCl3) δ = 7.30 – 7.20 (m, 2H, H-14, H-18), 7.08 – 6.97 (m, 2H, H-15, H-17), 6.90 (s, 1H, H-9’), 6.64 (s, 1H, H-6’), 6.02 (s, 1H, H-1), 3.94 (s, 3H, H-11’), 3.90 – 3.80 (m, 1H, H-2’), 3.89 (s, 3H, H-10’), 3.84 (s, 3H, H-10), 3.73 (s, 3H, H-9), 3.73 – 3.60 (m, 1H, H-3), 3.53 (s, 3H, H-11), 2.43 (dd, J = 13.7, 7.7 Hz, 1H, H-1’-a), 2.41 (dd, J = 13.7, 5.1 Hz, 1H, H-1’-b), 2.23 (dd, J = 17.0, 3.5 Hz, 1H, H-4eq), 2.03 (dd, J = 17.0, 10.7 Hz, 1H, H-4ax), 1.94 (bs, 1H, OH), 1.10 (d, J = 6.1 Hz, 3H, H-3’), 1.06 (d, J = 6.1 Hz, 3H, H-12);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F= 245.9 Hz, 1C, C-16), 151.1 (1C, C-6), 149.4 (1C, C-8), 148.1 (1C, C-8’), 147.4 (1C, C-7’), 143.8 (1C, C-7), 138.3 (d, JC-F = 2.9 Hz, 1C, C-13), 130.4 (d, JC-F = 8.0 Hz, 2C, C-14, C-18), 129.9 (1C, C-4’), 129.8 (1C, C-5), 128.9 (1C, C-4a), 128.3 (1C, C- 5’), 124.4 (1C, C-8a), 114.8 (d, JC-F = 21.2 Hz, 2C, C-15, C-17), 113.8 (1C, C-9’), 113.2 (1C, C-6’), 73.5 (1C, C-1), 67.5 (1C, C-2’), 63.3 (1C, C-3), 61.2 (1C, C-9), 60.6 (1C, C-10), 60.1 (1C, C-11), 56.2 (1C, C-10’), 55.9 (1C, C-11’), 43.2 (1C, C-1’), 33.7 (1C, C-4), 23.1 (1C, C-3’), 21.6 (1C, C-12); IR (KBr) ν = 3430 (ν OH), 2966, 2934 (νasMe, νasCH2), 2843 (νs CH2), 1604, 1578, 1508, 1464, 1421, 1409 (ν Ar C=C, βs CH2, δas Me), 1360, 1330 (δ CH, γs CH2), 1251, 1220, 1158, 1112 (νas Ar-O-Me, ν Ar C-F, ν C-OH), 1069, 1026 (νas C-O-C, νs Ar-O-Me) cm-1; ESI-TOF- HRMS: m / z calculated for C30H36FNaO7[M+H]+527.2440, found 527.2431. 1.2.7.2. - (2R)-1-{2-[(aR,1R,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-ol [(aR,1R,3R,2’R)-20] (Compound 24a) and (2R)-1-{2-[(aS,1R,3R)-1-(4- fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5-dimethoxy-phenyl}propan-2-ol [(aS,1R,3R,2’R)-20] (Compound 25a) Compound 24a Compound 25a Starting from the mixture of (aR,1R,3R,2’R)-19 and (aS,1R,3R,2’R)-19 (899 mg, 1.58 mmol, 1.0 equiv.), a mixture of MeOH:THF:H2O (5:2:3 ml), LiOH (76 mg, 3.16 mmol, 2.0 equiv.), reaction time: 4 hours. (aR,1R,3R,2’R)-20 (Compound 24a): 353 mg (yield 42%), off-white amorphous solid foam; [α]^^^−48 (c = 0.42; CHCl3). (aS,1R,3R,2’R)-20 (Compound 25a): 447 mg (yield: 54%), white amorphous solid foam; [α]^^^−80 (c = 0.52; CHCl3). Chromatographic and spectral data except for the chiroptical ones were identical with those of the mixture of (aS,1S,3S,2’S)-20 (Compound 22a) and (aR,1S,3S,2’S)-20 (Compound 23a). 1.2.7.3. - (2S)-1-{2-[(aS,1R,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-ol [(aS,1R,3S,2’S)-20] (Compound 26a)

[0023] 11), 2.78 (bs, 1H, OH), 2.58 (dd, J = 14.1, 3.1 Hz, 1H, H-1’-a), 2.36 (ddd, J = 16.4, 10.9, 1.4 Hz, 1H, H-4ax), 2.18 (dd, J = 14.1, 9.7 Hz, 1H, H-1’-b), 2.03 (d, J = 16.4 Hz, 1H, H-4eq), 1.21 (d, J = 6.1 Hz, 3H, H-12), 1.13 (d, J = 6.1 Hz, 3H, H-3’);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F = 245.2 Hz, 1C, C-16), 149.9, 149.8 (2C, C-6, C-8), 148.6 (1C, C-8’), 147.5 (1C, C-7’), 144.6 (1C, C-7), 140.1 (d, JC-F= 2.9 Hz, 1C, C-13), 130.2 (d, JC-F= 8.0 Hz, 2C, C-14, C-18), 130.1, 130.0, 129.1, 128.1, 127.2 (5C, C-4’, C-5’, C- 4a, C-5, C-8a), 115.0 (d, JC-F= 21.4 Hz, 2C, C- 15, C-17), 113.2, 112.3 (2C, C-6’, C-9’), 77.5 (1C, C-1), 70.5, 68.6 (2C, C-2’, C-3), 61.2 (1C, C-9), 60.8 (1C, C-10), 59.4 (1C, C-11), 56.2 (1C, C-10’), 55.9 (1C, C-11’), 42.7 (1C, C-1’), 35.4 (1C, C-4), 24.0, 21.7 (2C, C-12, C-3’); IR (KBr) ν = 3493 (ν OH), 2968, 2936 (νasMe, νasCH2), 2845 (νsCH2), 1606, 1574, 1512, 1462, 1421, 1410 (ν Ar C=C, βsCH2, δasMe), 1352, 1329 (δ CH, γsCH2), 1251, 1222, 1171, 1155, 1118 (νasAr-O-Me, ν Ar C-F, ν C-OH), 1075, 1049, 1026 (νas C-O-C, νs Ar-O-Me), 854 (1,2,4,5-tetrasubstituated γs Ar =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C30H35FNaO7 [M+Na]+549.2259, found 549.2259. 1.2.7.4. - (2R)-1-{2-[(aR,1S,3R)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-ol [(aR,1S,3R,2’R)-20] (Compound 27a)

[0024] 4-a or H-1’-a), 2.49 (dd, J = 13.7, 8.3 Hz, 1H, H-4-b or H-1’-b), 2.32 – 2.19 (m, 2H, H-4 or H-1’), 1.78 (bs, 1H, OH), 1.20, 1.13 (2d, J = 6.1 Hz, J = 6.2 Hz, 2 x 3H, H-12, H-3’);13C NMR (100 MHz, CDCl3) δ = 162.3 (d, JC-F= 245.4 Hz, 1C, C-16), 150.9, 149.7, 148.2, 147.4, 144.5, 129.8, 129.1, 128.4, 126.7 (10C, C-4a, C-5, C-6, C-7, C-8, C-8a, C-4’, C-5’, C-7’, C-8’) , 140.2 (d, JC-F= 3.0 Hz, 1C, C-13), 129.9 (d, JC-F= 8.4 Hz, 2C, C-14, C-18), 115.2 (d, JC-F= 21.4 Hz, 2C, C-15, C-17), 113.6, 113.5 (2C, C-6’, C-9’), 77.2 (1C, C-1), 70.4, 67.7 (2C, C-3, C-2’), 61.1, 60.5, 59.4, 56.2, 56.0 (5C, C-9, C-10, C-11, C-10’, C-11’), 43.3 (1C, C-1’), 34.8 (1C, C-4), 23.2, 21.7 (2C, C-12, C-3’); IR (KBr) ν = 3443 (ν OH), 2967, 2935 (νas Me, νas CH2), 2847 (νs CH2), 1606, 1577, 1512, 1463, 1422, 1408 (ν Ar C=C, βs CH2, δasMe), 1352, 1330 (δ CH, γsCH2), 1251, 1221, 1171, 1154, 1114 (νasAr-O-Me, ν Ar C-F, ν C-OH), 1074, 1049, 1027 (νasC-O-C, νsAr-O-Me), 867 (1,2,4,5-tetrasubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C30H35FNaO7 [M+Na]+549.2259, found 549.2254. 1.2.7.6. - (2S)-1-{2-[(aR,3S)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5-dimethoxy-phenyl}propan- 2-ol (Compound 29a) and (2S)-1-{2-[(aS,3S)-6,7,8-trimethoxy-3-methylisochroman-5-yl]-4,5- dimethoxyphenyl}propan-2-ol (Compound 30a) [the mixture of (aR,3S,2’S)-27 and (aS,3S,2’S)-27] Compound 29a Compound 30a Starting from the mixture of (aR,3S,2’S)-26 and (aS,3S,2’S)-26 (338 mg, 0.71 mmol, 1.0 equiv.), MeOH:THF:H2O (7:2:2 ml), LiOH (34 mg, 1.43 mmol, 2.0 equiv.), reaction time: 3 hours. The mixture of (aR,3S,2’S)-27 (Compound 29a) and (aS,3S,2’S)-27 (Compound 30a): 281 mg (yield: 91%), light yellow goo. Purification was not required for the crude product. Rf= 0.18 (hexane / EtOAc 6:4);1H NMR (400 MHz, CDCl3) δ = 6.91, 6.88 [2s, 2 x 1H, (aR), (aS) H-9’], 6.61, 6.59 [2s, 2 x 1H, (aR), (aS) H-6’], 4.98 [d, J = 14.8 Hz, 1H, (aR) or (aS) H-1-a], 4.94 [d, J = 14.6 Hz, 1H, (aR) or (aS) H-1-a], 4.70 [d, J = 14.7 Hz, 1H, (aR) or (aS) H-1-b], 4.66 [d, J = 14.7 Hz, 1H, (aR) or (aS) H-1-b], 3.94, 3.89, 3.88, 3.85, 3.84, 3.69, 3.63 [9s, 10 x 3H, (aR), (aS) H-10’, H-11’, H-9, H-10, H-11], 3.87 – 3.78 [m, 2 x 1H, (aR), (aS) H-2’ or H-3], 3.68 – 3.56 [m, 2 x 1H, (aR), (aS) H-2’ or H-3], 2.91 [s, 2H, (aR), (aS) OH], 2.56, 2.44, 2.38, 2.32 – 2.16, 2.10 – 1.96 [dd, J = 14.0, 3.4 Hz, 1H, dd, J = 13.7, 8.0 Hz, dd, J = 13.7, 4.9 Hz, 2m, 3H, (aR), (aS) H-1’-a,b, H-1-a,b, H-4-a,b], 1.21 [2d, J = 5.9 Hz, J = 5.8 Hz, 2 x 3H, (aR), (aS) H-12], 1.12, 1.07 [2d, J = 6.0 Hz, J = 6.1 Hz, 2 x 3H, (aR), (aS) H-3’];13C NMR (100 MHz, CDCl3) δ = 150.1, 149.2 [2C, (aR), (aS) C-6], 148.4, 148.2, 147.7, 147.1, 147.0 [6C, (aR), (aS) C-7’, C-8’, C-8], 143.6, 143.5 [2C, (aR), (aS) C-7], 129.8, 129.7, 129.6, 128.1, 128.0, 127.9, 127.8 [8C, (aR), (aS) C-4’, C-5’, C-4a, C-5], 123.9, 123.5 [2C, (aR), (aS) C- 8a], 113.4, 112.8, 112.7, 112.1 [4C, (aR), (aS) C-6’, C-9’], 70.5, 70.4, 68.3, 67.3 [4C, (aR), (aS) C-3, C-2’], 64.5, 64.3 [2C, (aR), (aS) C-1], 60.9, 60.9, 60.8, 60.5, 60.3, 55.8, 55.6 [10C, (aR), (aS) C-9, C-10, C-11, C-10’, C-11’], 42.7, 42.4 [2C, (aR), (aS) C-1’], 34.2, 33.4 [2C, (aR), (aS) C-4], 23.6, 22.9 [2C, (aR), (aS) C-12], 21.4, 21.3 [2C, (aR), (aS) C-3’]; IR (KBr) ν = 3499 (ν OH), 2935 (νas CH2), 2844 (νs CH2), 2049, 1958, 1715 (γ Ar =CH, γ Ar C=C overtone and combination bands), 1606, 1579, 1515, 1465, 1409 (ν Ar C=C, βs CH2, δas Me), 1391, 1363, 1328 (δs Me, δ CH, γs CH2), 1253, 1219, 1174, 1111 (νas Ar-O-Me, ν C-OH), 1073, 1029 (νas C-O-C, νs Ar-O-Me), 866 (1,2,4,5- tetrasubstituated γsAr =CH) cm-1; ESI-TOF-HRMS: m / z calculated for C24H32NaO7[M+Na]+455.2040, found 455.2040. EXAMPLE 2: Synthesis I The optically active coupling partners of the biaryl cross-coupling reactions, the boronate ester (S)-8 and the diastereomeric 1-aryl-5-iodoisochromans (1S,3S)-18 and (1R,3S)-18 were prepared in short sequences from (S)- propylene oxide (Scheme 3). Scheme 3: Synthesis of the cross-coupling partners for the Suzuki reaction. Reagents and conditions: i) a) n- BuLi, Ar / N2, THF, −80 °C, 20 min, b) (S)-propylene oxide, Ar / N2, −80 °C, 20 min, c) BF3.Et2O, Ar / N2, −80 °C, 30 min, (S)-11 (66%), (S)-16 (90%); ii) AcCl, C5H5N, CH2Cl2, rt, 2.5 h, (S)-12 (84%); iii) NIS, F3CCOOH, MeCN, rt, 16h, (S)-13 (96%); iv) NBS, MeCN, rt, 16h, (S)-14 (97%); v) a) (Ph3P)2PdCl2, PPh3, KOAc, Ar / N2, DMF, rt, 15 min, b) B2Pin2, Ar / N2, 150 °C, 3 h, (S)-8 (95%); vi) a) (Ph3P)2PdCl2, PPh3, NaOAc, Ar / N2, DMF, rt, 15 min, b) B2Pin2, Ar / N2, 150 °C, 1 h, (S)-8 (56%); vii) 4-F-C6H4CHO, BF3.Et2O, CH2Cl2, 0 °C, 2 h → rt, 4 h, (1R,3S)-17 (36%), (1S,3S)- 17 (61%); viii) NIS, F3CCOOH, MeCN, rt, 16h, (1R,3S)-18 (69%), (1S,3S)-18 (92%). In the first step, the aryl lithium reagents, formed in situ in the reaction of 4-bromoveratrole (9) or 1-bromo- 3,4,5-trimethoxy-benzene (15) with n-butyllithium, opened the epoxide ring regioselectively producing the (S)-1- arylpropan-2-ol derivatives (S)-11 and (S)-16 [Ren et al., 2004]. Acetylation of (S)-11 [Kerti et al., 2007] and subsequent regioselective halogenation with N-halosuccinimide afforded the substrates (S)-13, (S)-14 of the Miyaura borylation. The Miyaura borylation of the iodo derivative (S)-13 resulted in the product (S)-8 with low yield (56%) due to the competing dehalogenation side-reaction. Thus the bromo derivative was used instead as the substrate, which improved the yield of (S)-8 to 95%. For the preparation of the 1-aryl-5-iodoisochroman coupling partners, an oxa-Pictet-Spengler cyclization of (S)-16 was carried out with 4-fluorobenzaldehyde to produce the diastereomers cis-(1R,3S)-17 and trans-(1S,3S)-17 with a ratio 1.0:1.7. The cis- and trans- diastereomers were separated by column chromatography and the absolute configuration of the cis-(1R,3S) isomer was determined by the NOE correlation of the 1-H and 3-H protons. The Suzuki biaryl coupling of trans-(1S,3S)-18 and (S)-8 was carried out with Pd(OAc)2 and different phosphine ligands such as SPhos (66%, dr 1.0:1.2), Xantphos (79%, dr 1.0:1.4) and (S)-BINAP (54%, dr 1.0:1.7) resulting in the mixture of axially chiral biaryls (aR)- and (aS)-19 with slight atropodiastereoselectivity favouring the (aR) atropdiastereomer (Scheme 4). The duplication of some characteristic1H- and13C-NMR signals such as those of the 3-Me indicated the presence of the atropodiastereomers due to ortho-trisubstituated biaryl axis. The low atropodiastereoselectivity was exploited to prepare two series of atropodiastereomeric bis-isochromans, since after the removal of the O-acetyl group, (aR)- and (aS)-20 could be separated by column chromatography and they were used for further cyclization. Scheme 4: Suzuki cross-coupling reactions of trans-(1S,3S)-18 and subsequent cyclizations. Reagents and conditions: i) a) trans-(1S,3S)-18, Xantphos, Pd(OAc)2, Ar / N2, DMF, rt, 1 h, b) (S)-8, CsF, Ar / N2, DMF, rt 30 min, c) a + b, Ar / N2, 150 °C, 1.5 h, mixture of (aS,1S,3S,2'S)-19 and (aR,1S,3S,2'S)-19 79% (dr 1.0:1.4); ii) LiOH, MeOH:THF:H2O (5:2:3), rt, 4h, (aS,1S,3S,2'S)-20 (Compound 22a) (40%), (aR,1S,3S,2'S)-20 (Compound 23a) (53%); iii) MOMCl, ZnCl2, Et2O, 0 °C, 4 h, (aR,1S,3S,3'S)-21 (Compound 3a) (99%), 6 h, (aS,1S,3S,3'S)-21 (Compound 1a) (96%); iv), (Et2O)2CHCOOEt, BF3.Et2O, toluene, (aR,1S,3S,1'S,3'S)-22 (Compound 12a) (71%), (aS,1S,3S,1'S,3'S)-22 (Compound 9a) (38%); v) (Et2O)2CHCH2COOEt, BF3.Et2O, toluene, 0 °C → rt, 3 h, (aR,1S,3S,1'R,3'S)-23 (Compound 16a) (94%), 4 h, (aS,1S,3S,1'R,3'S)-23 (Compound 14a) (90%).

[0025] Then oxa-Pictet-Spengler cyclization of (aR)- and (aS)-20 with methoxy-methyl chloride (MOMCl) afforded the 5,5’-linked atropodiastereomeric bis-isochromans heterodimers (aR)- and (aS)-21 with identical absolute configuration at the three chirality centers but different axial chirality. The cyclization was also performed with ethyl diethoxyacetate and ethyl 3,3-diethoxypropionate in the presence of boron trifluoride to produce the atropodiastereomeric pairs (aR)- / (aS)-22 and (aR)- / (aS)-23, respectively, in which an additional C-3’ chirality center was introduced with 1,3 cis-diastereoselectivity. The observed NOE correlation of the axial 1’-H and 3’-H protons allowed determining their cis relative configuration, which on the basis of the known (3’S) absolute configuration also afforded the absolute configuration of the C-1’ chirality center. The planar structure and absolute configuration (aR,1S,3S,3’S)-21 (Compound 3a) (ωC-6,C-5,C-5’,C-4a’= −74.8°) were also determined by single crystal X-ray diffraction analysis (CCDC deposition no.: 2249290). The Suzuki biaryl coupling of cis-(1R,3S)-17 and (S)-8 was carried out with Pd(OAc)2and Xantphos to yield the atropodiastereomers (aR,1R,3S,2'S)-19 (11%) and (aS,1R,3S,2'S)-19 (68%) with diastereomeric ratio 1.4:8.6 favoring the (aS) atropodiastereomer (Scheme 5). The atropodiastereomers could be separated by column chromatography and after deacylation (19 → 20), both of them were cyclized with MOMCl to produce the bis- isochromans heterodimers (aR,1R,3S,3'S)- and (aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a). The oxa-Pictet- Spengler cyclizations with ethyl diethoxyacetate and ethyl 3,3-diethoxypropionate were achieved with the (aS,1R,3S,2'S)-20 (Compound 26a) atropodiastereomer to afford the bis-isochromans (aS,1R,3S,1'S,3'S)-22 (Compound 8a) and (aS,1R,3S,1'R,3'S)-23, respectively. Scheme 5: Suzuki cross-coupling reaction of cis-(1R,3S)-18 and subsequent cyclizations. Reagents and conditions: i) a) cis-(1R,3S)-18, Xantphos, Pd(OAc)2, N2, DMF, rt, 1 h, b) (S)-8, CsF, N2, DMF, rt 30 min, c) a + b, N2, 150 °C, 1.5 h, (aR,1R,3S,2'S)-19 (11%) and (aS,1R,3S,2'S)-19 (68%); ii) LiOH, MeOH:THF:H2O (1:0.8:0.5), rt, 4 h, (aR,1R,3S,2'S)-20 (Compound 28a) (94%) and LiOH, MeOH:THF:H2O (5:2:3), rt, 4 h, (aS,1R,3S,2'S)-20 (Compound 26a) (96%). iii) MOMCl, ZnCl2, Et2O, 0 °C, 3 h, (aR,1R,3S,3'S)-21 (Compound 7a) (89%), 4 h, (aS,1R,3S,3'S)-21 (Compound 5a) (97%); iv) (Et2O)2CHCOOEt, BF3.Et2O, toluene, (aS,1R,3S,1'S,3'S)-22 (Compound 8a) (23%); v) (Et2O)2CHCH2COOEt, BF3.Et2O, toluene, 0 °C → rt, 16 h, (aS,1R,3S,1'R,3'S)-23 Compound 18a) (91%). The present inventors repeated the sequences presented in scheme 3 to 5 starting from the (R)-propylene oxide [(R)-10] to produce enantiomeric pairs for 21-23, which could help identifying weak transitions and artefacts in the VCD spectra and hence validated their chiroptical approach to determine parallel axial and central chirality. The planar structure and absolute configuration (aS,1R,3R,3’R)-21 (Compound 4a) (ωC-6,C-5,C-5’,C-4a’ = 75.1°, CCDC deposition no.: 2249291) and (aS,1R,3R,1’R,3’R)-22 (Compound 13a) (ωC-6,C-5,C-5’,C-4a’ = 80.7°, CCDC deposition no.: 2249292) were also determined by single crystal X-ray diffraction analysis. In order to prepare axially chiral bis-isochromans lacking both the C-1 and C-1’ chirality centers, the present inventors converted the 1-arylpropan-2-ol derivative (S)-16 to the substituted 5-iodoisochroman (S)-25 in two steps, which was used for the Suzuki cross-coupling reaction with (S)-8 (Scheme 6). The two atropodiastereomers (aR,3S,2'S)-26 and (aS,3S,2'S)-26 were obtained in 1.0:1.1 ratio as a mixture, which could not be separated by column chromatography. The diastereomeric mixture was deacetylated (26 → 27) and the oxa-Pictet-Spengler cyclization with MOMCl afforded the 5,5’-linked atropodiastereomeric bis-isochroman heterodimers (aR,3S,3'S)-28 and (aS,3S,3'S)-28, which contained a stereogenic biaryl axis and only two chirality centers. Preparative chiral HPLC analysis using Chiralpak IA column allowed separation of (aR,3S,3'S)-28 and (aS,3S,3'S)-28, which were used for chiroptical analysis. Scheme 6: Suzuki cross-coupling reaction of (S)-25 and subsequent cyclization. Reagents and conditions: i) MOMCl, ZnCl2, Et2O, 0 °C, 2 h, (S)-24 (91%); ii) NIS, F3CCOOH, MeCN, rt, 1.5 h, (S)-25 (93%) iii) a) (S)-25, SPhos, Pd(OAc)2, Ar, DMF, rt, 1 h, b) (S)-8, CsF, Ar, DMF, rt, 30 min, c) a + b, Ar, 150 °C, 1.5 h, (aR,3S,2'S)-26 and (aS,3S,2'S)-26 (66%); ii) LiOH, MeOH:THF:H2O (7:2:2), rt, 3 h, mixture of (aR,3S,2'S)-27 and (aS,3S,2'S)-27 (91%); v) MOMCl, ZnCl2, Et2O, 0 °C, 4 h, mixture of (aR,3S,2'S)-28 and (aS,3S,2'S)-28 (86%). EXAMPLE 3: Stereochemical analysis Seven stereoisomers of 21 (Compounds 1a to 7a, see Table 1a), containing three known chirality centers along with the stereogenic biaryl axis, were used as model compounds for ECD, VCD and OR measurements and calculations to test how to determine the axial chirality in the presence of central chirality elements or vice versa. Six stereoisomers of both 22 (Compounds 8a to 13a, see Table 1a) and 23 (Compounds 14a to 19a, see Table 1a), consisting in three enantiomeric pairs, were prepared for the stereochemical analysis, which contained four known chirality centers along with the stereogenic biaryl axis. The present inventors studied two atropodiastereomers of 28 Compounds 20a and 21a, see Table 1a), which had only two central chirality elements with the same (S) absolute configuration. The enantiomeric pairs of 21-23 provided mirror image experimental ECD and VCD curves, which allowed validating the weak Cotton effects (CEs) and artefacts as well as the present inventors’ VCD measurement protocol. Experimental and computed ECD, VCD and OR data of atropodiastereomers of 21 were compared to identify chiroptical features that can deduce the axial chirality in the presence of central chirality elements. Surprisingly, the atropodiastereomeric cis-(aR,1R,3S,3'S)-21 and cis-(aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) showed near identical ECD spectra with a broad negative couplet below 300 nm, which were not suitable to distinguish the atropodiasteromers and assign the axial chirality. The experimental ECD curves of cis-(aR,1R,3S,3'S)-21 and cis- (aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) differed only in the intensities and they were reproduced well by the corresponding computed B3LYP / TZVP PCM / MeCN ECD spectra. In axially chiral biaryl natural products the sign and magnitude of the biaryl dihedral angle usually governs primarily the exciton-coupled ECD spectrum, the pattern of which is characteristic of the axial chirality even in the presence of central chirality elements. The anomalous ECD behaviour of the atropodiastereomeric cis-(aR,1R,3S,3'S)-21 and cis-(aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) could be attributed to either the presence of the C-14-fluorophenyl group, which could interact with the biaryl chromophore with exciton coupling or the substitution pattern of the 5,5’-linked biaryl, which provided near parallel orientation of the interacting electric transition moments. In contrast, the experimental VCD spectra of cis-(aR,1R,3S,3'S)-21 and cis-(aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) showed almost mirror image curves in the wavenumber range 1100-1450 cm−1, which reflected the different axial chirality of the atropodiastereomers and they could be reproduced well by the VCD calculations. On the basis of the good agreements, the axial chirality could be assigned to the near mirror image VCD curves. The ECD spectra of the atropodiastereomeric trans-(aR,1R,3S,3'S)-21 and trans-(aS,1R,3S,3'S)-21 had also quite similar pattern; they had a negative CE around 240 nm and a more intense positive one below 210 nm. The weak negative CE at 215 nm of trans-(aS,1S,3S,3'S)-21 (Compound 1a) represented the sole slight difference that could be reproduced well by the ECD calculations to differentiate the (aS) and (aR) atropodiastereomers. However, the experimental ECD spectra of both atropodiastereomers and enantiomers were required for this assignment and if only was one of the two atropodiastereomers available for ECD measurement, a reliable assignment of the axial chirality could not be achieved by the ECD calculations. There were much more apparent differences in the experimental VCD spectra of trans-(aR,1R,3S,3'S)-21 and trans-(aS,1R,3S,3'S)-21, since near mirror image VCD transitions were recorded in the range of 1050-1450 cm−1. The VCD transitions were clearly determined by the opposite axial chirality, which were reproduced well by the DFT VCD calculations. The agreement of the experimental and computed VCD spectra was utilized to determine the axial chirality. The OR values of the four stereoisomers cis-(aR / aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) and trans-(aR / aS,1S,3S,3'S)-21 (Compound 3a and Compound 1a) were recorded in acetonitrile at 589, 578, 546, 436 and 365 nm and computed with BH&HLYP / TZVP PCM / MeCN method. Both atropodiastereomers cis-(aR / aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) gave monotonously increasing positive ORD curves in the 589-365 nm wavelength range, with cis-(aR,1R,3S,3'S)-21 (Compound 7a) giving significantly larger magnitudes, which could be reproduced well by the OR calculations. The reproduction of the differences in the intensity of the positive OR values of cis-(aR / aS,1R,3S,3'S)-21 (Compound 7a and Compound 5a) by OR calculations may be used to assign the (aR) / (aS) axial chirality. However, this approach would be only feasible when the experimental OR values of both atropodiastereomers are available, which is usually not the case. The two atropodiastereomers trans-(aR / aS,1S,3S,3'S)-21 (Compound 3a and Compound 1a) showed monotonously decreasing ORD curve with the same negative signs but different intensities. The ORD curve of trans-(aR,1S,3S,3'S)- 21 (Compound 3a) ran above that of trans-(aS,1S,3S,3'S)-21 (Compound 1a), which were reproduced well by the OR calculations. The OR values recorded at five wavelengths showed identical positive and negative signs for the atropodiastereomeric pairs cis-(aR / aS,1R,3S,3'S)- and trans-(aR / aS,1S,3S,3'S)-21 (Compound 3a and Compound 1a), respectively. Although there were consistent differences in the magnitudes, they could not be used to distinguish and assign the atropodiastereomers efficiently. In contrast, the C-1 epimeric pairs cis-(aR,1R,3S,3'S)-21 / trans- (aR,1S,3S,3'S)-21 (Compound 7a / Compound 3a) and cis-(aS,1R,3S,3'S)-21 / trans-(aS,1S,3S,3'S)-21 (Compound 5a / Compound 1a) differing only in the absolute configuration of the C-1 chirality center had oppositely signed OR values at all the tested wavelengths, which could be used to assign the AC of C-1. The comparison of the experimental ECD of the four stereoisomers cis-(aR / aS,1R,3S,3'S)-21 and trans- (aR / aS,1S,3S,3'S)-21 (Compound 3a and Compound 1a) showed that there are significant differences in the sign, shape and intensity of the ECD bands for the C-1 epimeric pairs cis-(aR,1R,3S,3'S)-21 / trans-(aR,1S,3S,3'S)-21 (Compound 7a / Compound 3a) and cis-(aS,1R,3S,3'S)-21 / trans-(aS,1S,3S,3'S)-21 (Compound 5a / Compound 1a) in the wavelength range 210-230 nm. For instance, the cis-(aS,1R,3S,3'S)-21 (Compound 5a) had an intense negative CE at 224 nm, while the epimeric trans-(aS,1S,3S,3'S)-21 (Compound 1a) showed a weak positive CE at 221 nm and a weak negative one at 215 nm. Similarly, the cis-(aR,1R,3S,3'S)-21 (Compound 7a) exhibited an intense negative CE at 226 nm, while the epimeric trans-(aR,1S,3S,3'S)-21 (Compound 3a) had a positive shoulder at that wavelength. When aided with TDDFT-ECD calculations the ECD spectra could distinguish and assign efficiently the C-1 epimers of 21 but they cannot be used to determine the axial chirality. In contrast, the VCD spectra of the four stereoisomers cis-(aR / aS,1R,3S,3'S)- and trans-(aR / aS,1S,3S,3'S)-21b showed near mirror image VCD transitions for the (aR) / (aS) atropodiastereomeric pairs allowing the assignment of the axial chirality with the aid of DFT VCD calculations. Regarding the C-1 epimeric pairs cis-(aR,1R,3S,3'S)- 21 / trans-(aR,1S,3S,3'S)-21 (Compound 7a / Compound 3a) and cis-(aS,1R,3S,3'S)-21 / trans-(aS,1S,3S,3'S)-21 (Compound 5a / Compound 1a), the VCD showed only minor differences in weak transitions in the range of 1250- 1270 cm−1. When considering diastereomeric pairs differing in the absolute configuration of one, two or three chirality centers but having identical axial chirality, the ECD spectra were markedly different or near mirror image, while the VCD spectra showed no or only minor differences especially in the 1200-1300 cm−1wavenumber range. Compared to the stereoisomers of 21, the atropodiastereomeric (aR,1S,3S,1’S,3'S)-22 (Compound 12a) and (aS,1S,3S,1’S,3'S)-22 (Compound 9a) possessed an additional chirality center at C-1’ with an ethoxycarbonyl substituent and both of them had cis relative configuration in the dimethoxyisochroman subunit and trans one in the trimethoxyisochroman. The ECD spectra of the (aR) and (aS) atropodiastereomers of 22 were quite similar showing negative CEs above 210 nm and an intense positive one below it. The differences of the ECD spectra in the relative intensities and shape could not be used to assign the axial chirality even with the aid of TDDFT-ECD calculations, which however reproduced well the experimental ECD curves. The experimental VCD spectra of the atropodiastereomeric (aR,1S,3S,1’S,3'S)-22 (Compound 12a) and (aS,1S,3S,1’S,3'S)-22 (Compound 9a) differing only in the axial chirality had near mirror image VCD transitions in the 1000-1500 cm−1wavenumber range. The VCD calculations gave good agreements with the experimental curves, which allowed determining the axial chirality. Due to the large similarity with the VCD spectra of the stereoisomers of 21, the axial chirality of (aR)- and (aS)-22 could have been deduced by simple comparison of the characteristic VCD transitions. The experimental ECD and VCD spectra of the (aS,1R,3S,1'S,3'S)-22 (Compound 8a) were also compared with those of (aR,1S,3S,1’S,3'S)-22 (Compound 12a) and (aS,1S,3S,1’S,3'S)-22 (Compound 9a). The ECD spectra of the C-1 epimeric (aS,1R,3S,1'S,3'S)-22 (Compound 8a) and (aS,1S,3S,1’S,3'S)-22 (Compound 9a) had similarly negative CEs above and positive ones below 210 nm. However, the broad negative transition of (aS,1R,3S,1'S,3'S)- 22 (Compound 8a) (225 nm ∆ε = −27.82) was much more intense than the corresponding one of (aS,1S,3S,1'S,3'S)- 22 (Compound 9a) (231 nm ∆ε = −7.84) and they had also different shapes and shoulders. These distinct differences can be used to assign the AC of the C-1 chirality centers in the C-1 epimers. The VCD spectra of the C-1 epimeric (aS,1R,3S,1'S,3'S)-22 (Compound 8a) and (aS,1S,3S,1’S,3'S)-22 (Compound 9a) showed the same signs for most of the CEs in the range of 1000-1500 cm−1reflecting their identical (aS) axial chirality and VCD differences were even more subtle than those in the ECD spectra. These differences consisted in three weak oppositely signed VCD transitions in the 1220-1290 cm−1range and the B3LYP / TZVP PCM / CHCl3VCD spectrum of (aS,1S,3S,1’S,3'S)-22 (Compound 9a) reproduced the signs and shapes for two of them, which can be used to distinguish the C-1 epimers of 22 with VCD. Stereoisomeric pairs with identical axial chirality but different AC of three or four chirality centers such as (aS,1S,3S,1’S,3'S)-22 (Compound 9a) / (aS,1R,3R,1’R,3'R)-22 (Compound 13a), (aR,1S,3S,1’S,3'S)-22 (Compound 12a) / (aR,1R,3R,1’R,3'R)-22 (Compound 11a), (aR,1S,3S,1’S,3'S)-22 (Compound 12a) / (aR,1S,3R,1’R,3'R)-22 Compound 10a), (aS,1R,3S,1’S,3'S)-22 (Compound 8a) / (aS,1R, -22 (Compound 13a) had near mirror image ECD reflecting the different central chirality elements and almost congruent VCD spectra with minor differences in the 1200-1300 cm−1wavelength range. In some cases, the1H NMR signals of the diastereotopic 4-Ha / 4-Hb and 4’-Ha / 4’-Hb protons appeared separately and their characteristic NOE correlations could be measured with aromatic or methoxy protons of the other isochroman residue, which could be used to determine the axial chirality in the knowledge of the AC of the central chirality elements. In contrast to the VCD spectra, this approach could not be applied universally to assign the axial chirality. As an example, the characteristic NOE correlations are shown for (aS,1R,3S,1’S,3’S)-22 (Compound 8a) suggesting (aS) axial chirality. The stereoisomers (aR,1S,3S,1'R,3'S)-23 (Compound 16a), (aS,1S,3S,1'R,3'S)-23 (Compound 14a) and (aS,1R,3S,1'R,3'S)-23 (Compound 18a) had a C-1 ethoxycarbonylmethyl substituent and they were homochiral with the corresponding stereoisomers of 22. Similarly to the stereoisomers of 22, the experimental ECD spectra of atropodiastereomeric (aR,1S,3S,1'R,3'S)-23 (Compound 16a), (aS,1S,3S,1'R,3'S)-23 (Compound 14a) showed the same pattern, by which they could not be distinguished. In contrast, the C-1 epimeric (aS,1S,3S,1'R,3'S)-23 (Compound 14a) and (aS,1R,3S,1'R,3'S)-23 (Compound 18a) had quite different ECD spectra, since (aS,1R,3S,1'R,3'S)-23 (Compound 18a) showed an intense broad negative band at 225 nm [225 nm (−25.77), 250sh (−6.47)], while (aS,1S,3S,1'R,3'S)-23 (Compound 14a) exhibited a weak positive transition at 220 nm (−2.65), a negative trough at 244 nm (6.93) with a shoulder at 264 nm (2.30). The VCD spectra of atropodiastereomeric isomers (aS,1S,3S,1'R,3'S)-23 (Compound 14a) / (aR,1S,3S,1'R,3'S)- 23 (Compound 16a) and (aR,1R,3R,1'S,3'R)-23 (Compound 15a) / (aS,1R,3R,1'S,3'R)-23 (Compound 17a) showed opposite CEs for most of the transitions, while the C-1 epimers (aS,1S,3S,1'R,3'S)-23 (Compound 14a) and (aS,1R,3S,1'R,3'S)-23 (Compound 18a) had only minor differences in the 1200-1350 cm−1wavelength range. Stereoisomeric pairs differing in the AC of all the four central chirality elements but having identical axial chirality represented by (Compound 17a) 23 (Compound 14a) and -23 (Compound 16a) / (a (Compound 15a) had the same sign for most of the CEs including the most intense ones reflecting the axial chirality. However, some distinct VCD transitions could be identified with opposite CE for the pairs, which reported the opposite configuration of the isochroman residues. The VCD spectra of the (aR) and (aS) atropisomers of 21-23 were compared and it was found that regardless the type of the C-1’ substitution (H, COOEt or CH2COOEt) and AC of the central chirality elements, there are conserved characteristic VCD transitions, which reflect the different axial chirality of the biaryl axis. Four characteristic wavelength ranges can be found but there are additional characteristic bands above 1400 cm−1and below 1100 cm−1. For example, two intense positive VCD couplets were identified centered around 1350 cm−1and 1100 cm−1for the (aR) atropisomers of 21-23, which had opposite signs for the corresponding (aS) atropodiastereomers. The analysis of the computed VCD transitions revealed that almost all the VCD bands had some contributions from different vibrational modes of the biaryl subunit, especially from carbon-carbon stretching vibrations. These contributions are responsible for the mirror-image VCD signals of the atropodiastereomers, while VCD bands reflecting central chirality elements had significant vibrational components from the aliphatic moieties. In order to test the effect of the C-1 aryl substituent, which may have an exciton coupled ECD interaction with the substituted biphenyl chromophore and influence VCD spectrum as well, ECD and VCD spectra of the atropodiastereomeric (aR,3S,3'S)-28 and (aS,3S,3'S)-28 were analysed. The experimental ECD spectra of the atropodiastereomeric (aR,3S,3'S)-28 and (aS,3S,3'S)-28b showed the same pattern with negative CEs at higher and a positive one at lower wavelength, which confirmed that it is not the presence of the C-1 aryl group and a C-1 chirality center that is responsible for the near identical ECD spectra of the atropodiastereomers. ECD spectra were characteristic of the C-3 and C-3’ chirality centers, which determined the preferred helicity of the condensed heteroring. The (aS) and (aR) atropodiastereomers of all the prepared axially chiral bis-isochromans showed anomalous ECD behaviour, since their ECD spectra were not mirror image curves and they did not reflect the chirality of the stereogenic biaryl axis. The near identical ECD spectra of atropodiastereomeric (aR,3S,3'S)-28 and (aS,3S,3'S)-28 proved that 5,5’ biaryl linkage and the 6,7,8,7’,8’-pentamethoxy substitution pattern were responsible for the ECD discrepancy, which oriented the electric transition moments of the isochroman residues in a way that efficient exciton coupled interaction was not possible. Thus ECD spectrum was governed by the central chirality elements, which is usually not the case in biaryls containing both central and axial chirality elements. Interestingly, the experimental ECD spectra of the atropisomeric penicisteckins A,B (2,3) and penicisteckins C,D (4,5), biaryl-type hetero- and homodimeric bis-isochroman natural products with 7,5′- and 7,7′-linkages differing only in the axial chirality, showed opposite CEs for the corresponding ECD transitions of the atropodiastereomers. Similarly to 28, penicisteckins A-D (2-5) had a methylene group at C-1 and C-1’ but the different ECD behaviour was attributed to the different biaryl linkage and aromatic substitution pattern, which enabled a better interaction of the two aryl moiety. The VCD spectra of the atropodiastereomers (aR,3S,3'S)-28 and (aS,3S,3'S)-28 had oppositely signed CEs for the major transitions and simple comparison with those of the stereoisomers of 21-23 allowed assignment of the axial chirality. The (aS,3S,3'S)-28 stereoisomer had two intense negative VCD couplets centered at 1350 (negative CE at 1315 cm−1, positive CE at 1362 cm−1) and 1100 cm−1and (negative CE at 1084 cm−1and a positive one at 1115 cm−1). The special and complex chiroptical properties of the compounds or the invention makes them particularly interesting tools in chiroptical spectroscopy as reference compounds. Similarly, in chiral chromatography, the compounds of the invention can be used as standards. In particular, the presence of multiple asymmetric carbons in these compounds which have a special symmetrical or near-simmetrical property together with a potential axial symmetry renders them useful for these purposes. The potential to prepare several enantiomers and atropoenantiomers of very similar chemistry would allow the preparation of standard sets in both chiroptical spectroscopy and chiral chromatography. Example 4: Material and Methods in Synthesys II The notation of the compounds (e.g. (S)-16) used in this section should be understood based on Schemes 7- 14. 4.1. Syntheses and characterization of the compounds 4.1.1. - General procedure for synthesis of chiral non-racemic 1-arylpropan-2-ols The corresponding aryl bromide (1.5 equiv) was dissolved in anhydrous THF (~1 g aryl bromide / 10 ml anhydrous THF) under argon athmosphere and the solution was cooled to −78 °C. Then 2.5 M n-BuLi in hexane (1.5 equiv.) was added and after stirring for 20 minutes, (S)-propylene oxide (1.0 equiv., ≥98.0 ee%) was added and the reaction was stirred for 20 minutes at −78 °C. Next BF3.Et2O (1.1 equiv.) was added to the solution, which was stirred further for 30 minutes at −78 °C. Then the cooling was stopped and a saturated solution of NH4Cl was added to the reaction mixture. The mixture was stirred for 10 minutes and concentrated in vacuo. The suspension was diluted with EtOAc and water. The two layers were separated in a separatory funnel. The aqueous phase was washed three times with EtOAc. The combined organic phases were washed with brine. The organic phase was dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the optically active 1-arylpropan-2-ol derivative. 4.1.1.1. - (S)-1-(3,4-dibenzyloxyphenyl)propan-2-ol [(S)-16] Flash chromatography: hexane / acetone 4:1. CZ-243-1, CZ-297, HK-8: 5.38 g (yield: 90%) colorless oil. Rf= 0.27 (hexane / acetone 4:1). [α]20 D +10 (c = 0.32; CHCl3).1H NMR (500 MHz, CDCl3) δ = 7.44 – 7.40 (m, 4H, H- 12, H-16, H-19, H-23), 7.33 (t, J = 7.3 Hz, 4H, H-13, H-15, H-20, H-22), 7.27 (t, J = 7.3 Hz, 2H, H-14, H-21), 6.87 (d, J = 8.1 Hz, 1H, H-8), 6.79 (d, J = 1.9 Hz, 1H, H-5), 6.70 (dd, J = 8.1, 1.9 Hz, 1H, H-9), 5.13, 5.11 (2s, 2 × 2H, H- 10, H-17), 3.93 – 3.86 (m, 1H, H-2), 2.65 (dd, J = 13.6, 4.7 Hz, 1H, H-1-a), 2.55 (dd, J = 13.6, 7.9 Hz, 1H, H-1-b), 1.53 (s, 1H, OH), 1.16, (d, J = 6.2 Hz, 3H, H-3);13C NMR (125 MHz, CDCl3) δ = 149.0, 148.0 (2C, C-6, C-7), 137.6, 137.4 (2C, C-11, C-18), 132.0, (1C, C-4), 128.5, 127.5, 127.4 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 127.9, 127.8 (2C, C-14, C-21), 122.4, 116.9, 115.6 (3C, C-5, C-8, C-9), 71.6, 71.5 (2C, C-10, C-17), 68.9 (1C, C-2), 45.3 (1C, C-1), 22.8 (1C, C-3). IR (KBr): 3390, 2960, 1514, 1260, 1232, 1136, 1117, 1012, 1000, 742, 697 cm–1. HRMS (ESI) calcd. for C23H24NaO3 [M+Na]+371.1618, found 371.1616. 4.1.1.2. - (S)-1-(3,5-dimethoxyphenyl)propan-2-ol [(S)-11] Flash chromatography: hexane / EtOAc 4:1 → 3:1. CZ-242-1, CZ-265, MK-95: 3.62 g (yield: 92%) colorless oil. Rf = 0.24 (hexane / EtOAc 3:1). [α]^^^+18, (c = 0.34; CHCl3).1H NMR (400 MHz, CDCl3) δ = 6.36 (d, J = 2.3 Hz, 2H, H-5, H-9), 6.34 (t, J = 2.3 Hz, 1H, H-7), 4.05 – 3.95 (m, 1H, H-2), 3.77 (s, 6H, H-10, H-11), 2.70 (dd, J = 13.4, 4.9 Hz, 1H, H-1-a), 2.62 (dd, J = 13.4, 8.0 Hz, 1H, H-1-b), 1.23 (d, J = 6.2 Hz, 3H, 3-H);13C NMR (100 MHz, CDCl3) δ = 160.9 (2C, C-6, C-8), 141.0 (1C, C-4), 107.4 (2C, C-5, C-9), 98.5 (1C, C-7), 68.8 (1C, C-2), 55.3 (2C, C-10, C-11), 46.1 (1C, C-1), 22.8 (1C, C-3). IR (KBr): 3419, 2965, 2934, 2839, 1596, 1205, 1150, 1068, 827, 701 cm–1. HRMS (ESI) calcd. for C11H16NaO3[M+Na]+219.0992, found 219.0983. 4.1.2. General procedure for acetylation of chiral non-racemic 1-arylpropan-2-ols The corresponding 1-arylpropan-2-ol derivative (1.0 equiv.) was dissolved in anhydrous CH2Cl2and anhydrous C5H5N (1.5 equiv.) was added to the solution. The mixture was cooled to 0 °C and AcCl (1.2 equiv.) was added, then the reaction was stirred at room temperature. After the starting material was consumed (1.5-3 hours) on the basis of TLC monitoring, water was added to the mixture and stirred for 5 minutes. The mixture was diluted with CH2Cl2and extracted with a 6N solution of HCl. The aqueous phase was washed three times with CH2Cl2, then the combined organic phases were washed with brine, dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the 1-arylpropan-2-yl acetate target derivative. 4.1.2.1. - (S)-1-(3,4-dibenzyloxyphenyl)propan-2-yl acetate [(S)-17] Flash chromatography: hexane / EtOAc 10:1. CZ-244-1, CZ-329, HK-9: 4.92 g (yield: 82%) colorless oil. Rf = 0.55 (hexane / EtOAc 4:1). [α]^^^−10 (c = 0.38; CHCl3).1H NMR (500 MHz, CDCl3) δ = 7.46 – 7.41 (m, 4H, H-12, H-16, H-19, H-23), 7.34 (t, J = 7.6 Hz, 4H, H-13, H-15, H-20, H-22), 7.28 (t, J = 7.3 Hz, 2H, H-14, H-21), 6.85 (d, J = 8.2 Hz, 1H, H-8), 6.79 (d, J = 2.0 Hz, 1H, H-5), 6.69 (dd, J = 8.2, 2.0 Hz, 1H, H-9), 5.13, 5.12 (2s, 2 × 2H, H-10, H-17), 5.06 – 4.99 (m, 1H, 2-H), 2.81 (dd, J = 13.7, 6.5 Hz, 1H, H-1-a), 2.62 (dd, J = 13.7, 6.7 Hz, 1H, H-1-b), 1.95 (s, 3H, H-25), 1.14 (d, J = 6.3 Hz, 3H, H-3);13C NMR (125 MHz, CDCl3) δ = 170.6 (1C, C-24), 148.8, 147.8 (2C, C-6, C-7), 137.5, 137.4 (2C, C-11, C-18), 131.1 (1C, C-4), 128.6, 127.5, 127.4 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 127.9, 127.8 (2C, C-14, C-21), 122.5, 116.7, 115.3 (3C, C-5, C-8, C-9), 71.6 (1C, C-2), 71.5 (2C, C-10, C-17), 41.8 (1C, C-1), 21.4, 19.4 (2C, C-3, C-25). IR (KBr): 3445, 1734, 1511, 1373, 1246, 1137, 1017, 737, 697 cm–1. HRMS (ESI) calcd. for C25H26NaO4 [M+Na]+413.1723, found 413.1720. 4.1.2.2. - (S)-1-(3,5-dimethoxyphenyl)propan-2-yl acetate [(S)-12] Flash chromatography: hexane / EtOAc 8:1. CZ-245 / 1, CZ-330, MK-96: 3.68 g (yield: 91%) colorless oil. Rf= 0.55 (hexane / EtOAc 4:1). −11 (c = 0.33; CHCl3).1H NMR (400 MHz, CDCl3) δ = 6.35 (d, J = 2.3 Hz, 2H, H-5, H-9), 6.33 (t, J = 2.3 Hz, 1H, H-7), 5.16 – 5.05 (m, 1H, H-2), 3.77 (s, 6H, H-10, H-11), 2.88 (dd, J = 13.5, 6.6 Hz, 1H, H-1-a), 2.66 (dd, J = 13.5, 6.7 Hz, 1H, H-1-b), 2.01 (s, 3H, H-13), 1.21 (d, J = 6.3 Hz, 3 H, 3-H);13C NMR (100 MHz, CDCl3) δ = 170.6 (1C, C-12), 160.8, (2C, C-6, C-8), 140.0 (1C, C-4), 107.5 (2C, C-5, C-9), 98.6 (1C, C- 7), 71.4 (1C, C-2), 55.3 (2C, C-10, C-11), 42.6 (1C, C-1), 21.4, 19.6 (2C, C-3, C-13). IR (KBr): 3447, 2934, 2839, 1732, 1595, 1240, 1203, 1149, 1054, 831, 702 cm–1. HRMS (ESI) calcd. for C13H18NaO4[M+Na]+261.1097, found 261.1092. 4.1.3. General procedure for the halogenation of 1-arylpropan-2-yl acetates with N-halosuccinimides (NXS, X = I: iodo, B: bromo) The corresponding 1-arylpropan-2-yl acetate (1.0 equiv.) was dissolved in anhydrous MeCN (20-30 ml), then NIS (1.2 equiv.) and F3CCOOH (0.3 equiv.) or NBS (1.05 equiv.) were added, and the mixture was stirred at room temperature. When the starting material was consumed (1.5-16 hours) on the basis of TLC monitoring, the solvent was evaporated in vacuo. EtOAc and water were added to the residual solid, and the phases were separated in a separatory funnel. The aqueous phase was washed three times with EtOAc, then the combined organic phases were washed with a 10% aqueous solution of Na2S2O3and with brine. The organic phase was dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by trituration or flash chromatography to yield the 1-(2-haloaryl)propan-2-yl-acetate target derivatives. 4.1.3.1. - (S)-1-[(4,5-dibenzyloxy)-2-iodophenyl]propan-2-yl acetate [(S)-18] The crude brown-orange oil was purified by trituration with hexane. CZ-246-1, CZ-332, HK-10: 6.23 g (yield: 96%) white-beige amorphous solid. Rf= 0.41 (hexane / EtOAc 6:1). [α]^^^+3 (c = 0.41; CHCl3).1H NMR (500 MHz, CDCl3) δ = 7.46 – 7.23 (m, 10H, H-12, H-13, H-14, H-15, H-16, H-19, H-20, H-21, H-22, H-23), 7.33, 6.80 (2s, 2 × 1H, H-6, H-9), 5.18 – 5.09 (m, 1H, H-2), 5.10, 5.07 (2s, 2 × 2H, H-10, H-17), 2.90 (dd, J = 14.0, 7.6 Hz, 1H, H-1-a), 2.81 (dd, J = 14.0, 5.8 Hz, 1H, H-1-b), 1.92 (s, 3H, H-25), 1.20 (d, J = 6.3, 3H, H-3);13C NMR (125 MHz, CDCl3) δ = 170.5 (1C, C-24), 149.0, 148.5 (2C, C-7, C-8), 137.0, 136.8 (2C, C-11, C-18), 133.9 (1C, C-4), 128.6, 127.5, 127.4 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 128.1, 128.0 (2C, C-14, C-21), 125.3, 117.2 (2C, C-6, C-9), 90.0 (1C, C-5), 71.6, 71.5 (2C, C-10, C-17), 70.8 (1C, C-2), 46.0 (1C, C-1), 21.4, 19.7 (2C, C-3, C-25). IR (KBr): 3432, 2973, 1722, 1502, 1384, 1373, 1262, 1220, 732, 695 cm–1. HRMS (ESI) calcd. for C25H25INaO4 [M+Na]+539.0690, found 539.0684. 4.1.3.2. - (S)-1-[(4,5-dibenzyloxy)-2-bromophenyl]propan-2-yl acetate [(S)-19] Flash chromatography: hexane / EtOAc 95:5 → 85:15. MK-64: 466 mg (yield: 97%) white solid, mp 42-45 °C. Rf= 0.41 (hexane / EtOAc 6:1). [α]^^^+1 (c = 0.48; CHCl3).1H NMR (500 MHz, CDCl3) δ = 7.45 – 7.23 (m, 10H, H-12, H-13, H-14, H-15, H-16, H-19, H-20, H-21, H-22, H-23), 7.10, 6.80 (2s, 2 × 1H, H-6, H-9), 5.15 – 5.06 (m, 1H, H-2), 5.10, 5.09 (2s, 2 × 2H, H-10, H-17), 2.92 – 2.80 (m, 2H, H-1-a,b), 1.92 (s, 3H, H-25), 1.19 (d, J = 6.3 Hz, 3H, H-3);13C NMR (125 MHz, CDCl3) δ = 170.5 (1C, C-24), 148.6, 148.1 (2C, C-7, C-8), 137.0, 136.8 (2C, C-11, C-18), 130.0 (1C, C-4), 128.6, 127.5, 127.4 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 128.1, 128.0 (2C, C-14, C-21), 119.0, 118.2 (2C, C-6, C-9), 115.8 (1C, C-5), 71.7, 71.6 (2C, C-10, C-17), 70.6 (1C, C-2), 41.6 (1C, C- 1), 21.4, 19.7 (2C, C-3, C-25). IR (KBr): 3424, 2980, 1721, 1512, 1390, 1371, 1221, 1179, 734, 696 cm–1. HRMS (ESI) calcd. for C25H25BrNaO4[M+Na]+491.0828, found 491.0824. 4.1.3.3. - (S)-1-(2-bromo-3,5-dimethoxyphenyl)propan-2-yl acetate [(S)-14] Flash chromatography: hexane / acetone 9:1. CZ-293 / 1: 2.12 g (yield: 94%) colorless oil. Rf= 0.38 (hexane / acetone 5:1). [α]^^^+3 (c = 0.35; CHCl3).1H NMR (400 MHz, CDCl3) δ = 6.42, 6.38 (d, J = 2.8 Hz, 1H, d, J = 2.8 Hz, 1H, H-7, H-9), 5.22 (m, 1H, H-2), 3.85, 3.78 (2s, 2 × 3H, H-10, H-11), 3.01 (d, J = 6.6 Hz, 2H, H-1), 1.99 (s, 3H, H-13), 1.27 (d, J = 6.3 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 170.4 (1C, C-12), 159.4, 156.8 (2C, C-6, C-8), 139.2 (1C, C-4), 107.7, 98.2 (2C, C-7, C-9), 105.5 (1C, C-5), 70.5 (1C, C-2), 56.3, 55.5 (2C, C-10, C-11), 42.3 (1C, C-1), 21.4, 19.8 (2C, C-3, C-13). IR (KBr): 3453, 3084, 2932, 1731, 1584, 1455, 1328, 1237, 950, 830, 605 cm–1. HRMS (ESI) calcd. for C13H17BrNaO4[M+Na]+339.0202, found 339.0201. 4.1.3.4. - (S)-1-(2-iodo-3,5-dimethoxyphenyl)propan-2-yl acetate [(S)-13a] and (S)-1-(4-iodo-3,5- dimethoxyphenyl)propan-2-yl acetate [(S)-13b] regioisomeric mixture (ratio 1:1) Flash chromatography: hexane / EtOAc 8:1. Colorless oil. Rf = 0.39 (hexane / acetone 5:1). 1H NMR (360 MHz, CDCl3) δ = 6.46 (d, J = 2.6 Hz, 1H, H-9), 6.35 (s, 2H, H-5’, H-9’), 6.32 (d, J = 2.6 Hz, 1H, H-7), 5.26 – 5.17 (m, 1H, H-2), 5.17 – 5.08 (m, 1H, H-2’), 3.87 (s, 6H, H-10’, H-11’), 3.85, 3.79 (2s, 2 × 3H, H- 10, H-11), 3.07 (dd, J = 13.9, 5.9 Hz, 1H, H-1-a), 3.01 (dd, J = 13.9, 7.5 Hz, 1H, H-1-b), 2.92 (dd, J = 13.6, 6.9 Hz, 1H, H-1’-a), 2.72 (dd, J = 13.6, 6.5 Hz, 1H, H-1’-b), 2.01 (1s, 3H, H-13’), 1.99 (s, 3H, H-13), 1.30 (d, J = 6.3 Hz, 3H, H-3), 1.23 (d, J = 6.3 Hz, 3H, H-3’);13C NMR (90 MHz, CDCl3) δ = 170.6 (1C, C-12’), 170.5 (1C, C-12), 160.8, 159.0, 142.8 (3C, C-4, C-6, C-8), 159.5, 140.2 (3C, C-4’, C-6’, C-8’), 107.7, 97.3 (2C, C-7, C-9), 105.5 (2C, C-5’, C-9’), 100.1 (1C, C-7’), 82.8 (1C, C-5), 71.2 (1C, C-2’), 70.9 (1C, C-2), 56.7 (2C, C-10’, C-11’), 56.6, 55.6 (2C, C- 10, C-11), 46.8 (1C, C-1), 42.7 (1C, C-1’), 21.5, 20.0, 19.7 (4C, C-3, C-13, C-3’, C-13’). IR (KBr): 2975, 2935, 2839, 1732, 1578, 1238, 1200, 1162, 1120, 1056, 1010, 952, 830, 735 cm–1. HRMS (ESI) calcd. for C13H17INaO4[M+Na]+387.0064, found 387.0061. 4.1.3.5. - (S)-1-(2,6-diiodo-3,5-dimethoxyphenyl)propan-2-yl acetate [(S)-13c] Flash chromatography: hexane / EtOAc 8:1. CZ-247 / 2: white amorphous solid. Rf= 0.24 (hexane / acetone 5:1). −25 (c = 0.31; CHCl3).1H NMR (360 MHz, CDCl3) δ = 6.31 (s, 1H, H-7), 5.43 – 5.30 (m, 1H, H-2), 3.89 (s, 6H, H-10, H-11), 3.67 (dd, J = 13.8, 9.1 Hz, 1H, H-1-a), 3.42 (dd, J = 13.9, 4.2 Hz, 1H, H-1-b), 1.96 (s, 3H, H-13), 1.38 (d, J = 6.2 Hz, 3H, H-3);13C NMR (90 MHz, CDCl3) δ = 170.5 (1C, C-12), 159.4 (2C, C-6, C-8), 144.4 (C-4), 93.7 (1C, C-7), 83.0 (2C, C-5, C-9), 71.0 (C-2), 56.9 (2C, C-10, C-11), 51.2 (1C, C-1), 21.5, 20.3 (2C, C-3, C-13). IR (KBr): 3432, 1728, 1566, 1321, 1249, 1213, 1083, 800 cm–1. HRMS (ESI) calcd. for C13H16I2NaO4[M+Na]+512.9030, found 512.9026. 4.1.4. General procedure for Miyaura borylation of chiral non-racemic 1-(2-haloaryl)propan-2-yl acetates To the solution of the corresponding 1-(2-haloaryl)propan-2-yl acetate (1.0 equiv.) in anhydrous DMF (30-40 ml) Ph3P (0.2 equiv.), (Ph3P)2PdCl2(0.1 equiv.) and freshly annealed KOAc (4.0 equiv.) were added under Ar atmosphere, and the mixture was stirred for 15 minutes with inert gas bubbling at room temperature. Then B2pin2(3.0 equiv.) was added and the temperature was raised to 150 °C. After the starting material was consumed (1 hour- 3 hours) on the basis of TLC monitoring, the reaction mixture was poured on ice and diluted with Et2O. The mixture was filtered on a short pad of Celite®using glass filter. The Celite®was washed three times with Et2O. Next, the two layers were extracted and separated in a separatory funnel. The aqueous phase was washed three times with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography to yield the 1-[2- (pinacolatoboryl)aryl]propan-2-yl acetate target derivative. 4.1.4.1. - (S)-1-[4,5-bis(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl acetate [(S)-20]

[0026] Conventional column chromatography: hexane / acetone 16:1 → 15:1 → 12:1. CZ-263 / 1, HK-13: 5.69 g (yield: 92%) colorless oil. Rf= 0.23 (toluene / EtOAc 10:0.25). [α]^^^−1 (c = 0.45; CHCl3).1H NMR (400 MHz, CDCl3) δ = 7.50 – 7.40, 7.38 – 7.23 (2m, 10H, H-12, H-13, H-14, H-15, H-16, H-19, H-20, H-21, H-22, H-23), 7.43, 6.78 (2s, 2 × 1H, H-6, H-9), 5.16, 5.13 (2s, 2 × 2H, H-10, H-17), 5.07 – 4.97 (m, 1H, H-2), 3.13 (dd, J = 13.2, 5.8 Hz, 1H, H-1- a), 2.99 (dd, J = 13.2, 7.5 Hz, 1H, H-1-b), 1.89 (s, 3H, H-25), 1.32 (1s, 12H, H-31, H-32, H-33, H-34), 1.16 (d, J = 6.2 Hz, 3H, H-3);13C NMR (100 MHz, CDCl3) δ = 170.5 (1C, C-24), 150.9, 146.9, 139.5, 137.6, 137.2 (5C, C-4, C- 7, C-8, C-11, C-18), 128.5, 128.4, 127.7, 127.2 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 127.8 (2C, C- 14, C-21), 122.4, 117.0 (2C, C-6, C-9), 83.5 (2C, C-29, C-30), 73.2 (1C, C-2), 71.5, 70.8 (2C, C-10, C-17), 41.2 (1C, C-1), 25.0 (4C, C-31, C-32, C-33, C-34), 21.4, 19.6 (2C, C-3, C-25). IR (KBr): 3433, 2979, 2931, 1734, 1411, 1372, 1247, 1144, 850, 741, 696 cm–1. HRMS (ESI) calcd. for C31H37BNaO6[M+Na]+539.2575, found 539.2574. 4.1.4.2. - (S)-1-[3,5-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl acetate [(S)-8] Flash chromatography: hexane / EtOAc 6:1 → 5:1. CZ-277 / 1, MK-98: 2.66 g (yield: 62%) colorless oil. Rf = 0.23 (hexane / EtOAc 5:1). [α]^^^−5 (c = 0.51; CHCl3).1H NMR (360 MHz, CDCl3) δ = 6.34, 6.26 (d, J = 2.1 Hz, 1H, d, J = 2.1 Hz, 1H, H-7, H-9), 5.16 – 5.04 (m, 1 H, H-2), 3.78, 3.74 (2s, 2 × 3H, H-10, H-11), 3.00 (dd, J = 13.4, 7.5 Hz, 1H, H-1-a), 2.73 (dd, J = 13.4, 6.2 Hz, 1H, H-1-b), 2.00 (s, 3H, H-13), 1.38, 1.37 (2s, 2 × 6H, H-19, H-20, H-21, H-22), 1.21 (d, J = 6.2 Hz, 3H, H-3);13C NMR (90 MHz, CDCl3) δ = 170.6 (1C, C-12), 164.7, 161.9 (2C, C-6, C-8), 144.4 (1C, C-4), 106.6, 96.1 (2C, C-7, C-9), 83.6 (2C, C-17, C-18), 72.2 (1C, C-2), 55.7, 55.2 (2C, C-10, C-11), 42.4 (1C, C-1), 25.1, 24.7 (4C, C-19, C-20, C-21, C-22), 21.5, 19.8 (2C, C-3, C-13). IR (KBr): 2977, 2930, 2842, 1729, 1602, 1575, 1318, 1233, 1213, 1144, 964, 860, 837, 805, 687 cm–1. HRMS (ESI) calcd. for C19H29BNaO6 [M+Na]+387.1949, found 387.1945. 4.1.5. Suzuki coupling reaction of (S)-1-[(4,5-dibenzyloxy)-2-iodophenyl]propan-2-yl acetate and (S)-1-[3,5- dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl acetate To the solution of (S)-1-[(4,5-dibenzyloxy)-2-iodophenyl]propan-2-yl acetate (3.74 g, 7.25 mmol, 1.06 equiv.) in anhydrous DMF (30 ml), Xantphos (396 mg, 0.684 mmol, 0.1 equiv.) and Pd(OAc)2 (185 mg, 0.821 mmol, 0.12 equiv.) were added under Ar atmosphere, and the solution was stirred for 1 hour with inert gas bubbling at room temperature. To the solution of (S)-1-[3,5-dimethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan- 2-yl acetate (2.49 g, 6.84 mmol, 1.0 equiv.) in anhydrous DMF (30 ml), CsF (2.28 g, 15.0 mmol, 2.2 equiv.) was added under Ar atmosphere, and the solution was stirred for 30 minutes with inert gas bubbling at room temperature. The first solution was merged with the second, and the reaction was stirred at 150 °C. When one of the starting material was consumed (1.5-2 hours) on the basis of TLC monitoring, the reaction mixture was poured on ice and diluted with Et2O. The mixture was filtered on a short pad of Celite®using glass filter. The Celite®was washed three times with Et2O. The two layers were extracted and separated in a separatory funnel. The aqueous phase was washed three times with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the {4,5- bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’-diyl}bis(propane-2,1-diyl) diacetate target derivative. 4.1.5.1. - (aS,2S,2’S)-{(aS)-4,5-bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’-diyl}bis(propane- 2,1-diyl) diacetate [(aS,2S,2’S)-21] Flash chromatography: hexane / EtOAc 5:1 → 4:1. CZ-309-1, CZ-308-1: 2.70 g (yield: 63%) brown oil. Rf= 0.28 (hexane / EtOAc 3:1). [α]^^^−35, (c = 0.26; CHCl3).1H NMR (400 MHz, CDCl3) δ = 7.50 – 7.45, 7.44 – 7.39, 7.38 – 7.23 (3m, 10H, H-12, H-13, H-14, H-15, H-16, H-19, H-20, H-21, H-22, H-23), 6.90, 6.70 (2s, 2 × 1H, H-6, H-9), 6.46, 6.40 (d, J = 2.4 Hz, 1H, d, J = 2.4 Hz, 1H, H-7’, H-9’), 5.18, 5.12, 5.09 (3s, 4H, H-10, H-17), 5.05 – 4.97, 4.93 – 4.83 (2m, 2 × 1H, H-2, H-2’), 3.81, 3.65 (2s, 2 × 3H, H-10’, H-11’), 2.56, 2.50 (dd, J = 14.1, 6.7 Hz, 1H, dd, J = 14.4, 8.0 Hz, 1H, H-1-a, H-1’-a), 2.40, 2.35 (dd, J = 14.3, 5.5 Hz, 1H, dd, J = 14.1, 7.0 Hz, 1H, H-1-b, H-1’-b), 1.93, 1.90 (2s, 2 × 3H, H-25, H-13’), 1.06, 0.99 (d, J = 6.2 Hz, 3H, d, J = 6.2 Hz, 3H, H-3, H-3’);13C NMR (100 MHz, CDCl3) δ = 170.2 (2C, C-24, C-12’), 159.7, 158.0, 147.7, 147.1, 138.3, 137.5, 137.4, 130.2, 129.8, 122.3 (10C, C-4, C-5, C-7, C-8, C-11, C-18, C-4’, C-5’, C-6’, C-8’), 128.4, 128.3, 127.4, 127.3 (8C, C-12, C-13, C-15, C-16, C- 19, C-20, C-22, C-23), 127.7, 127.6 (2C, C-14, C-21), 118.0, 116.6, 105.4, 96.6 (4C, C-6, C-9, C-7’, C-9’), 71.3, 71.1 (2C, C-10, C-17), 70.7, 70.6 (2C, C-2, C-2’), 55.4, 55.2 (2C, C-10’, C-11’), 38.9, 38.8 (2C, C-1, C-1’), 21.3, 20.0, 19.5 (4C, C-3, C-25, C-3’, C-13’). IR (KBr): 3032, 2979, 2933, 1733, 1604, 1455, 1372, 1244, 1158, 1056, 698 cm–1. HRMS (ESI) calcd. for C38H42NaO8[M+Na]+649.2772, found 649.2768. 4.1.6. Deacetylation reaction of (aS,2S,2’S)-{(aS)-4,5-bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’- diyl}bis(propane-2,1-diyl) diacetate To the solution of (aS,2S,2’S)-{4,5-bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’-diyl}bis(propane- 2,1-diyl) diacetate (2.70 g, 4.31 mmol, 1.0 equiv.) in MeOH (25 ml) LiOH (413 mg, 17.2 mmol, 4.0 equiv.) was added and it was stirred at room temperature for 1.5 hours. After the starting material was consumed on the basis of TLC monitoring, the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and it was extracted with water. The aqueous phase was washed three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography to yield the product. 4.1.6.1. - (aS,2S,2’S)-1,1’-{(aS)-4,5-bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’- diyl}bis(propan-2-ol) [(aS,2S,2’S)-22] Flash chromatography: hexane / EtOAc 1:1. CZ-303 / 4: 2.00 g (yield: 85%) white-pale yellow oil. Rf = 0.39 (hexane / EtOAc 1:2). [α]^^^+55 (c = 0.28; CHCl3).1H NMR (360 MHz, CDCl3) δ = 7.51 – 7.45, 7.42 – 7.24 (2m, 10H, H-12, H-13, H-14, H-15, H-16, H-19, H-20, H-21, H-22, H-23), 6.90, 6.62 (2s, 2 × 1H, H-6, H-9), 6.46 , 6.42 (d, J = 2.4 Hz, 1H, d, J = 2.4 Hz, 1H, H-7’, H-9’), 5.19, 5.14, 5.09 (3s, 4H, H-10, H-17), 3.90 – 3.78, 3.68 – 3.58 (2m, 2 × 1H, H-2, H-2’), 3.83, 3.65 (2s, 2 × 3H, H-10’, H-11’), 2.43, 2.33 (dd, J = 13.9, 3.2 Hz, 1H, dd, J = 13.6, 5.0 Hz, 1H, H-1-a, H-1’-a), 2.25, 2.16 (dd, J = 13.6, 8.2 Hz, 1H, dd, J = 13.9, 9.5 Hz, 1H, H-1-b, H-1’-b), 1.06, 0.98 (d, J = 6.1 Hz, 3H, d, J = 6.1 Hz, 3H, H-3, H-3’);13C NMR (90 MHz, CDCl3) δ = 159.9, 157.8, 148.3, 147.1, 139.4, 137.5, 137.4, 131.0, 130.0, 122.6 (10C, C-4, C-5, C-7, C-8, C-11, C-18, C-4’, C-5’, C-6’, C-8’), 128.6, 128.5, 127.6, 127.4 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 127.9, 127.7 (2C, C-14, C-21), 117.8, 116.0, 106.7, 96.9 (4C, C-6, C-9, C-7’, C-9’), 71.4, 71.0 (2C, C-10, C-17), 68.9, 67.7 (2C, C-2, C-2’), 55.7, 55.4 (2C, C-10’, C- 11’), 43.2, 42.6 (2C, C-1, C-1’), 23.2 (2C, C-3, C-3’). IR (KBr): 3433, 2965, 2930, 1603, 1455, 1318, 1202, 1157, 737, 698 cm–1. HRMS (ESI) calcd. for C34H38NaO6[M+Na]+565.2561, found 565.2555. 4.1.7. General procedure for debenzylation (hydrogenation) of benzyl-protected biaryl bis(propan-2-ol) derivatives Pd / C catalyst (10 w / w%, 0.26 equiv.) was disperged in THF and it was stirred at room temperature for 20 minutes under hydrogen atmosphere. The corresponding benzyl-protected biaryl derivative (1.0 equiv.) was added to the suspension, and the reaction mixture was stirred further under H2atmosphere at room temperature until the end of hydrogen lessening. After that, the mixture was filtered through a short pad of Celite®. The Celite®was washed with THF, and the solvent was evaporated in vacuo. The residue was purified by column chromatography to yield the pyrocatechol target derivatives. 4.1.7.1. - (aS)-2’,6-bis[(S)-2-hydroxypropyl]-4’,6’-dimethoxy-[1,1’-biphenyl]-3,4-diol [(aS,2S,2’S)-23] Flash chromatography: hexane / acetone 1.5:1. CZ-341-1: 1.00 g (yield: 97%) white foam. Rf= 0.78 (hexane / acetone 1:1). +55 (c = 0.1 20; CHCl3). H NMR (400 MHz, CDCl3) δ = 6.71, 6.51 (2s, 2 x 1H, H-6, H- 9), 6.44, 6.40 (d, J = 2.2 Hz, 1H, d, J = 2.2 Hz, 1H, H-7’, H-9’), 3.90 – 3.75 (m, 2H, H-2, H-2’), 3.83, 3.63 (2s, 2 × 3H, H-10’, H-11’), 2.48 – 2.34 (m, 3H, H-1-a, H-1’-a, H-1-b or H-1’-b), 2.15 (dd, J = 13.8, 9.6 Hz, 1H, H-1-b or H- 1’-b), 1.08, 1.04 (d, J = 6.1 Hz, 3H, d, J = 6.0 Hz, 3H, H-3, H-3’);13C NMR (100 MHz, CDCl3) δ = 159.8, 157.8, 143.8, 142.6, 139.4, 129.9, 128.8, 122.8 (8C, C-4, C-5, C-7, C-8, C-4’, C-5’, C-6’, C-8’), 118.4, 116.5, 106.7, 96.9 (4C, C-6, C-9, C-7’ C-9’), 68.9, 68.6 (2C, C-2, C-2’), 55.7, 55.5 (2C, C-10’, C-11’), 43.2, 42.2 (2C, C-1, C-1’), 23.2, 22.9 (2C, C-3, C-3’). IR (KBr): 3376, 2970, 2932, 2841, 1606, 1456, 1158, 1068, 831 cm–1. HRMS (ESI) calcd. for C20H26NaO6[M+Na]+385.1622, found 385.1619. 4.1.7.2. - (aS,3S,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-7,8-diol [(aS,3S,3’S)-29] (Compound 13) Conventional column chromatography: hexane / acetone 3:1. CZ-338-1: 70 mg (yield: 80%) white crystals, mp 122-124 °C. Rf= 0.15 (hexane / acetone 3:1). [α]^^^+71 (c = 0.28; CHCl3). ECD: (c = 1.98×10−4M; MeCN) λ [nm], (Δε) = 289sh (−1.34), 237 (−7.92), 213 (24.79), 199sh (19.06).1H NMR (400 MHz, CDCl3) δ = 7.60 (bs, 1H, OH), 6.36, 6.35 (2s, 2 x 1H, H-6, H-7’), 5.77 (bs, 1H, OH), 5.06, 5.00 (d, J = 15.6 Hz, 1H, d, J = 15.2 Hz, 1H, H-1-a, H- 1’-a), 4.75, 4.67 (d, J = 15.6 Hz, 1H, d, J = 15.3 Hz, 1H, H-1-b, H-1’-b), 3.83, 3.71 (2s, 2 × 3H, H-9’, H-10’), 3.74 – 3.60 (m, 2H, H-3, H-3’), 2.43 – 2.23, 2.06 – 1.93 (2m, 2 × 2H, H-4, H-4’), 1.25, 1.23 (d, J = 6.5 Hz, 3H, d, J = 6.4 Hz, 3H, H-9, H-11’);13C NMR (100 MHz, CDCl3) δ = 156.6, 155.4, 140.7, 139.8, 133.7, 126.5, 125.3, 121.5, 120.2, 114.8 (10C, C-4a, C-5, C-7, C-8, C-8a, C-4a’, C-5’, C-6’, C-8’, C-8a’), 115.3, 92.8 (2C, C-6, C-7’), 71.4, 71.0 (2C, C-3, C-3’), 64.9, 64.8 (2C, C-1, C-1’), 56.0, 55.3 (2C, C-9’, C-10’), 35.5, 33.3 (2C, C-4, C-4’), 21.7, 21.4 (2C, C-9, C-11’). IR (KBr): 3419, 2969, 2838, 1597, 1455, 1317, 1209, 1121, 1069, 936, 838 cm−1. HRMS (ESI) calcd. for C22H26NaO6[M+Na]+409.1622, found 409.1621. 4.1.8. Cyclization reaction by chloromethyl methyl ether (MOMCl) of benzyl-protected (aS,2S,2’S)-1,1’-{(aS)- 4,5-bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’-diyl}bis(propan-2-ol) The benzyl-protected (aS,2S,2’S)-1,1’-{(aS)-4,5-bis(benzyloxy)-4’,6’-dimethoxy-[1,1’-biphenyl]-2,2’- diyl}bis(propan-2-ol) (300 mg, 0.553 mmol, 1.0 equiv.) was dissolved in anhydrous THF (10 ml). The mixture was cooled to 0 °C then MOMCl (134 mg, 127 µl, 1.66 mmol, 3.0 equiv.) and freshly annealed ZnCl2(23 mg, 0.166 mmol, 0.3 equiv.) were added under Ar atmosphere. The reaction mixture was stirred at room temperature until the starting material was consumed (ca.20 hours) on the basis of TLC monitoring. Then the mixture was quenched and stirred with water for 5 minutes. The mixture was diluted with EtOAc and the phases were separated in a separatory funnel. The aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with a saturated solution of NaHCO3 and brine, dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the C1 – C1’ unsubstituted bis-isochroman target derivative. 4.1.8.1. - (aS,3S,3’S)-7,8-bis(benzyloxy)-6’,8’-dimethoxy-3,3’-dimethyl-5,5’-bis-isochroman [(aS,3S,3’S)-28] Compound 54 Flash chromatography: hexane / EtOAc 6.5:1 → 3:1. CZ-334-2: 130 mg (yield: 42%) white powder, mp 59-62 °C. Rf = 0.71 (hexane / EtOAc 2:1). [α]^^^+72 (c = 0.23; CHCl3).1H NMR (400 MHz,CDCl3) δ = 7.45 – 7.37, 7.39 – 7.27 (2m, 10H, H-12, H-13, H-14, H-15, H-16, H-19, H-20, H-21, H-22, H-23), 6.64, 6.39 (2s, 2 × 1H, H-7, H-6’), 5.20, 5.12, 5.07, 5.03 (d, J = 11.1 Hz, 1H, d, J = 11.9 Hz, 1H, d, J = 11.8 Hz, 1H, d, J = 10.6 Hz, 1H, H-10, H-17), 5.06, 4.94 (d, J = 15.8 Hz, 1H, d, J = 15.3 Hz, 1H, H-1-a, H-1’-a), 4.68, 4.63 (d, J = 15.8 Hz, 1H, d, J = 15.4 Hz, 1H, H-1-b, H-1’-b), 3.85, 3.72 (2s, 2 × 3H, H-9’, H-10’), 3.65 – 3.51 (m, 2H, H-3, H-3’), 2.30, 2.17, 2.01, 1.87, (dd, J = 16.3, 10.9 Hz, 1H, dd, J = 16.5, 11.4 Hz, 1H, dd, J = 16.4, 2.7 Hz, 1H, dd, J = 16.5, 1.5 Hz, 1H, H-4, H-4’), 1.22, 1.21 (d, J = 5.9 Hz, 3H, d, J = 5.9 Hz, 3H, H-9, H-11’);13C NMR (100 MHz, CDCl3) δ = 156.3, 155.6, 148.8, 142.8, 138.1, 137.2, 134.1, 131.5, 128.8, 126.4, 120.1, 115.6 (12C, C-4a, C-5, C-7, C-8, C-8a, C-11, C-18, C-4a’, C-5’, C- 7’, C-8’, C-8a’), 128.6, 128.4, 128.3, 127.5 (8C, C-12, C-13, C-15, C-16, C-19, C-20, C-22, C-23), 128.0 (2C C-14, C-21), 115.0, 92.7 (2C, C-7, C-6’), 74.3, 70.7 (2C, C-10’, C-17’), 70.8, 70.6 (2C, C-3, C-3’), 65.4, 64.8 (2C, C-1, C- 1’), 56.0, 55.3 (2C, C-9’, C-10’), 35.0, 33.3 (2C, C-4, C-4’), 21.8, 21.7 (2C, C-11, C-9’). IR (KBr): 3446, 2967, 2931, 2836, 1598, 1454, 1316, 1209, 1122, 1078, 736, 697 cm−1. HRMS (ESI) calcd. for C36H38NaO6 [M+Na]+589.2561, found 589.2557. 4.1.9. General procedure for Brønsted-acid catalyzed oxa-Pictet-Spengler reaction by aromatic aldehydes To the solution of the corresponding bis(propan-2-ol) derivative (1.0 equiv.) in MeOH toluene was added (toluene / MeOH 4:1). Then aromatic aldehyde (6.0 equiv) and (1S)-(+)-10-camphorsulfonic acid (1.0 equiv.) were added. The reaction mixture was stirred at 80 °C until the starting material and the mono-cyclized intermediate products were consumed (ca.8-16 heating hours of 24-48 hours stirring) on the basis of TLC monitoring. After that, a saturated solution of NaHCO3 was added to the reaction and the mixture was stirred for 10 minutes, then it was concentrated in vacuo. The suspension was diluted with EtOAc and the mixture was extracted with water. The aqueous phase was washed three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography and preparative chiral HPLC to yield the 5,5’-linked bis-isochroman target derivatives. 4.1.9.1. - (aS,1R,3S,1’R,3’S)-1,1’-bis(4-fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol Compound 1 Flash chromatography: hexane / acetone 4:1. CZ-313 / 2, CZ-328 / 1, CZ-342 / 1: 234 mg (yield: 59%) white crystals, mp 225-228 °C. Rf = 0.53 (hexane / acetone 1.5:1) −147 (c = 0.25; CHCl3). ECD: (c = 1.25×10−4M; MeCN) λ [nm], (Δε) = 294 (−2.21), 251sh (−5.36), 223 (−28.04), 215sh (−14.91), 199 (0.68), 193 (−12.64). Crystals were grown in CHCl3:MeOH 4:1 at room temperature.1H NMR (400 MHz, CDCl3) δ = 7.45 – 7.35 (m, 2H, H-11, H-15), 7.30 – 7.21 (m, 2H, H-13’, H-17’), 7.10 – 7.00 (m, 2H, H-12, H-14), 6.92 – 6.82 (m, 2H, H-14’, H-16’), 6.40 (s, 1H, H-6), 6.36 (s, 1H, H-7’), 5.88 (s, 1H, H-1’), 5.85 (s, 1H, H-1), 5.72 (bs, 1H, OH), 4.67 (bs, 1H, OH), 3.82- 3.70 (m, 2H, H-3, H-3’), 3.75 (s, 3H, H-9’), 3.52 (s, 3H, H-10’), 2.55 (dd, J = 16.3, 10.4 Hz, 1H, H-4’ax), 2.47 (dd, J = 15.6, 10.4 Hz, 1H, H-4ax), 2.10 – 2.00 (m, 2H, H-4eq, H-4’eq), 1.23 (d, J = 5.8 Hz, 2 × 3H, H-9, H-11’);13C NMR (100 MHz, CDCl3) δ = 162.7 (d, JC-F = 246.6 Hz, C-13), 163.2 (d, JC-F = 245.0 Hz, C-15’), 157.1 (1C, C-6’), 156.5 (1C, C-8’), 141.7, 139.4 (2C, C-7, C-8), 139.7 (d, JC-F = 2.6 Hz, 1C, C-12’), 138.0 (d, JC-F = 2.7 Hz, 1C, C-10), 135.6 (1C, C-4a’), 130.5 (d, JC-F= 8.2 Hz, 2C, C-11, C-15), 129.7 (d, JC-F= 8.1 Hz, 2C, C-13’, C-17’), 127.3 (1C, C-4a), 127.2 (1C, C-5), 123.9 (1C, C-8a), 120.2 (1C, C-5’), 118.4 (C-8a’), 116.6 (1C, C-6), 115.7 (d, JC-F= 21.5 Hz, 2C, C- 12, C-14), 114.9 (d, JC-F = 21.4 Hz, 2C, C-14’, C-16’), 94.1 (C-7’), 77.2 (1C, C-1’), 77.0 (1C, C-1), 71.1 (1C, C-3), 70.7 (1C, C-3’), 56.0 (1C, C-9’), 55.3 (1C, C-10’), 36.9 (1C, C-4’), 34.5 (1C, C-4), 21.9 (1C, C-9), 21.6 (1C, C-11’). IR (KBr): 3476, 2972, 2934, 2841, 1595, 1509, 1321, 1224, 1208, 1114, 830, 556 cm−1. HRMS (ESI) calcd. for C34H32F2NaO6[M+Na]+597.2059, found 597.2054. Fluorescence spectroscopy:1λex= 290 nm →1λem= 328 nm,1intensity [a.u.]: 9258.2λex= 230 nm →2λem= 328 nm,2intensity [a.u.]: 7468. c = 6.38×10−5M; MeCN. 4.1.9.2. - (aS,1R,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochro pound 10 Flash chromatography: hexane / acetone 4:1. CZ-321-1 / CZ-343-1: 317 mg (yield 66% → highest) white crystals, mp 213-215 °C. Rf: 0.69 (hexane / acetone 1.5:1). −158 (c = 0.20; CHCl3). ECD: (c = 7.69×10−5M; MeCN) λ [nm], (Δε) = 293 (−2.93), 272 (−0.19), 230 (−49.41), 214 (7.19), 207sh (1.30), 204 (−3.14), 192 (41.01). Crystals were grown in MeOH:H2O 5:2 at room temperature.1H NMR (700 MHz, acetonitrile-d3) δ = 7.53 – 7.50 (m, 2H, H-12, H-14), 7.50 – 7.47 (m, 2H, H-14’, H-16’), 7.27 – 7.26 (m, 2H, H-13’, H-17’), 7.26 – 7.24 (m, 2H, H- 11, H-15), 6.62 (s, 1H, H-6), 6.52 (s, 1H, H-7’), 5.89 (s, 1H, H-1), 5.81 (s, 1H, H-1’), 3.79 (s, 3H, H-9’), 3.77 – 3.72 (m, 1H, H-3), 3.72 – 3.67 (m, 1H, H-3’), 3.57 (s, 3H, H-10’), 2.49 (dd, J = 16.1, 10.8 Hz, 1H, H-4’ax), 2.39 (ddd, J = 15.8, 10.9, 0.8 Hz, 1H, H-4ax), 2.09 (dd, J = 15.7 Hz, 1H, H-4’eq), 2.06 (dd, J = 15.8, 1.0 Hz, 1H, H-4eq), 1.18 (d, J = 6.1 Hz, 3H, H-11’), 1.16 (d, J = 6.1 Hz, 3H, H-9);13C NMR (175 MHz, acetonitrile-d3) δ = 158.1 (1C, C-6’), 157.3 (1C, C-8’), 145.0 (1C, C-12’), 144.2 (1C, C-10), 142.6, 141.2 (2C, C-7, C-8), 136.7 (1C, C-4a’), 131.8 (2C, C-12, C- 14), 131.6 (2C, C-14’, C-16’), 131.3 (2C, C-11, C-15), 131.1 (2C, C-13’, C-17’), 128.2 (1C, C-4a), 127.8 (1C, C-5), 125.0 (1C, C-8a), 121.4 (1C, C-13), 121.1 (1C, C-15’), 120.8 (1C, C-5’), 118.7 (1C, C-8a’), 117.4 (1C, C-6), 95.0 (1C, C-7’), 77.5 (1C, C-1’), 77.3 (1C, C-1), 71.2 (1C, C-3), 70.9 (1C, C-3’), 56.3 (1C, C-9’), 55.8 (1C, C-10’), 37.0 (1C, C-4’), 35.2 (1C, C-4), 21.8 (2C, C-9, C-11’). IR (KBr): 3433, 2970, 2929, 1594, 1485, 1321, 1208, 1071, 1012, 817 cm−1. HRMS (ESI) calcd. for C34H32Br2NaO6[M+Na]+717.0458, found 717.0453. 4.1.9.3. - (aS,1R,3S,1’S,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aS,1R,3S,1’S,3’S)-25 CZ-321 / 2.1]

[0027] Flash chromatography: hexane / acetone 4:1. HPLC. Lux i-Cellulose-5 (150×21.2 mm), heptane / 2-PrOH 90:10, 215 nm, tR, prep= 3.56 min. CZ-321-2.1, CZ-378-4.1: 27 mg (yield: 8%) white-biege crystals, mp 117-120 °C. Rf= 0.62 (hexane / acetone 1.5:1). [α]^^^−63 (c = 0.15; CHCl3). ECD: (c = 1.05×10−4M; MeCN) λ [nm], (Δε) = 284sh (−2.69), 237 (−35.86), 217 (21.74), 205 (9.99), 197 (28.20).1H NMR (700 MHz, acetonitrile-d3) δ = 7.56 – 7.48 (m, 4H, H-12, H-14, H-14’, H-16’), 7.29 – 7.22 (m, 2H, H-11, H-15), 7.18 – 7.10 (m, 2H, H-13’, H-17’), 6.65 (s, 1H, H- 7’), 6.53 (s, 1H, H-6), 5.93 (s, 1H, H-1’), 5.88 (s, 1H, H-1), 3.83 (s, 3H, H-9’), 3.77 – 3.73 (m, 1H, H-3), 3.73 (s, 3H, H-10’), 3.54 – 3.49 (m, 1H, H-3’), 2.37 (ddd, J = 16.0, 10.8, 1.5 Hz, 1H, H-4ax), 2.33 (dd, J = 17.0, 11.1 Hz, 1H, H- 4’ax), 2.16 (dd, J = 16.0, 1.0 Hz, 1H, H-4eq), 2.04 (dd, J = 17.0, 3.3 Hz, 1H, H-4’eq), 1.19 (d, J = 6.1 Hz, 3H, H-9), 1.05 (d, J = 6.1 Hz, 3H, H-11’);13C NMR (175 MHz, acetonitrile-d3) δ = 158.4 (1C, C-6’), 157.1 (1C, C-8’), 144.3 (1C, C-10), 143.0 (1C, C-12’), 142.7, 141.2 (2C, C-7, C-8), 135.8 (1C, C-4a’), 131.8 (4C, C-12, C-14, C-14’, C-16’), 131.4 (2C, C-13’, C-17’), 131.3 (2C, C-11, C-15), 127.9 (1C, C-4a), 127.7 (1C, C-5), 125.0 (1C, C-8a), 121.6 (1C, C-15’), 121.4 (1C, C-13), 121.0 (1C, C-5’), 117.0 (1C, C-6), 116.2 (1C, C-8a’), 94.4 (1C, C-7’), 77.4 (1C, C-1), 73.7 (1C, C-1’), 71.2 (1C, C-3), 64.2 (1C, C-3’), 56.5 (1C, C-9’), 56.1 (1C, C-10’), 35.7 (1C, C-4), 35.1 (1C, C-4’), 21.9 (1C, C-9), 21.8 (1C, C-11’). IR (KBr): 3434, 2968, 2928, 1595, 1485, 1321, 1207, 1118, 1071, 1011, 816 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’- dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 10) stereoisomer. 4.1.9.4. - (aS,1S,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aS,1S,3S,1’R,3’S)-25 CZ-321 / 2.2]

[0028] Compound 45 Flash chromatography: hexane / acetone 4:1. HPLC: Lux i-Cellulose-5 (150×21.2 mm), heptane / 2-PrOH 90:10, 215 nm, tR, prep= 5.67 min. CZ-321-2.2, CZ-371-4.2: 20 mg (yield: 6%) white-beige crystals, mp 211-214 °C. Rf= 0.62 (hexane / acetone 1.5:1). [α]^^^−40, (c = 0.22; CHCl3). ECD: (c = 8.46×10−5M; MeCN) λ [nm], (Δε) = 292 (−3.94), 251 (4.51), 228 (−40.42), 214 (1.88), 205 (−9.15), 195 (49.08).1H NMR (700 MHz, acetonitrile-d3) δ = 7.44 – 7.42 (m, 2H, H-12, H-14), 7.41 – 7.38 (m, 2H, H-14’, H-16’), 7.17 – 7.14 (m, 2H, H-13’, H-17’), 7.09 – 7.06 (m, 2H, H-11, H-15), 6.56 (s, 1H, H-6), 6.40 (s, 1H, H-7’), 5.90 (s, 1H, H-1), 5.69 (s, 1H, H-1’), 3.64 (s, 3H, H-9’), 3.63 – 3.59 (m, 1H, H-3’), 3.46 (s, 3H, H-10’), 3.45 – 3.41 (m, 1H, H-3), 2.36 (dd, J = 16.2, 10.8 Hz, 1H, H-4’ax), 2.09 (dd, J = 17.0, 11.5 Hz, 1H, H-4ax), 2.06 (dd, J = 16.5, 0.9 Hz, 1H, H-4’eq), 1.91 (dd, J = 16.6, 3.5 Hz, 1H, H-4eq), 1.10 (d, J = 6.1 Hz, 3H, H-11’), 0.93 (d, J = 6.2 Hz, 3H, H-9);13C NMR (175 MHz, acetonitrile-d3) δ = 157.8 (1C, C-6’), 157.2 (1C, C-8’), 145.0 (1C, C-10), 142.4, 141.1 (2C, C-7, C-8), 142.3 (1C, C-12’), 136.6 (1C, C-4a’), 131.9 (2C, C- 12, C-14), 131.6 (4C, C-14’, C-16’, C-11, C-15), 131.1 (2C, C-13’, C-17’), 128.5 (1C, C-5), 126.6 (1C, C-4a), 123.1 (1C, C-8a), 121.8 (1C, C-13), 121.1 (1C, C-15’), 120.8 (1C, C-5’), 118.7 (1C, C-8a’), 117.6 (1C, C-6), 94.9 (1C, C- 7’), 77.5 (1C, C-1’), 73.8 (1C, C-1), 70.9 (1C, C-3’), 64.2 (1C, C-3), 56.2 (1C, C-9’), 55.8 (1C, C-10’), 36.6 (1C, C- 4’), 33.7 (1C, C-4), 21.8 (2C, C-9, C-11’). IR (KBr): 3328, 2925, 1592, 1484, 1451, 1306, 1207, 811, 486 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’- dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 10) stereoisomer. 4.1.9.5. - (aR,1R,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aR,1R,3S,1’R,3’S)-25 CZ-321 / 3]

[0029] Compound 46 Flash chromatography: hexane / acetone 4:1. HPLC: Lux i-Cellulose-5 (150×21.2 mm), hexane / (MeOH:2- PrOH 1:1) 80:20, 254 nm, tR, prep= 7.30 min. CZ-321-3, CZ-371-4.3: 15 mg (yield: 2%) white-beige crystals, mp 108- 111 °C. Rf = 0.58 (hexane / acetone 1.5:1). [α]^^^−186 (c = 0.08; CHCl3). ECD: (c = 1.34×10−4M; MeCN) λ [nm], (Δε) = 292 (−2.06), 230 (−77.69), 213 (−8.00), 207 (−15.18), 195 (66.65).1H NMR (700 MHz, acetonitrile-d3) δ = 7.45 – 7.43 (m, 2H, H-12, H-14), 7.43 – 7.40 (m, 2H, H-14’, H-16’), 7.21 – 7.18 (m, 2H, H-11, H-15), 7.18 – 7.16 (m, 2H, H-13’, H-17’), 6.46 (s, 1H, H-7’), 6.45 (s, 1H, H-6), 5.85 (s, 1H, H-1), 5.76 (s, 1H, H-1’), 3.71 – 3.67 (m, 2H, H-3, H-3’), 3.66 (s, 3H, H-9’), 3.52 (s, 3H, H-10’), 2.36 – 2.31 (m, 3H, H-4, H-4’ax), 2.15 – 2.14 (m, 1H, H-4’eq), 1.15 (d, J = 6.2 Hz, 3H, H-11’), 1.15 (d, J = 6.2 Hz, 3H, H-9);13C NMR (175 MHz, acetonitrile-d3) δ = 157.6 (1C, C-6’), 157.2 (1C, C-8’), 145.0 (1C, C-12’), 144.1 (1C, C-10), 142.7, 141.2 (2C, C-7, C-8), 137.4 (1C, C-4a’), 131.8 (2C, C-12, C-14), 131.6 (2C, C-14’, C-16’), 131.3 (2C, C-11, C-15), 131.1 (2C, C-13’, C-17’), 128.1 (2C, C-5, C- 4a), 125.3 (1C, C-8a), 121.4 (1C, C-13), 121.1 (1C, C-15’), 120.9 (1C, C-5’), 118.8 (1C, C-8a’), 116.9 (1C, C-6), 95.3 (1C, C-7’), 77.3 (2C, C-1, C-1’), 71.2 (1C, C-3), 70.8 (1C, C-3’), 56.3 (1C, C-9’), 55.8 (1C, C-10’), 35.5 (1C, C-4’), 35.2 (1C, C-4), 21.8 (2C, C-9, C-11’). IR (KBr): 3356, 2968, 2927, 2853, 1593, 1484, 1321, 1208, 815, 736 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy- 3,3’-dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 10) stereoisomer. 4.1.9.6. - (aS,1R,3S,1’R,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’-bis- isochroman]-7,8-diol [(aS,1R,3S,1’R,3’S)-26 CZ-322 / 1.1]

[0030] Compound 36 Flash chromatography: CHCl3 / MeOH 90:0.5. HPLC: Lux i-Amilose-5 (150×10mm), heptane / (MeOH:2- PrOH 1:1) 80:20, 230 nm, tR, prep = 5.07 min. CZ-322 / 1.1: 10 mg (yield: 5%) white-beige crystals, mp 113-117 °C. Rf = 0.20 (CHCl3 / MeOH 90:1). 140 (c = 0.21; CHCl3). ECD: (c = 7.30×10−5M; MeCN) λ [nm], (Δε) = 292 (−2.27), 234sh (−40.98), 220 ), 201sh (34.73), 198 (43.62).1H NMR (700 MHz, CDCl3) δ = 6.70 (s, 2H, H- 11, H-15), 6.68 (s, 1H, H-6), 6.55 (s, 2H, H-13’, H-17’), 6.36 (s, 1H, H-7’), 5.81 (s, 1H, H-1’), 5.78 (s, 1H, H-1), 5.46 (bs, 1H, OH), 4.54 (bs, 1H, OH), 3.86 (s, 6H, H-16, H-18), 3.85 (s, 3H, H-17), 3.81 (s, 6H, H-18’, H-20’), 3.80 (s, 3H, H-19’), 3.83 – 3.78 (m, 1H, H-3), 3.73 (s, 3H, H-9’), 3.74 – 3.69 (m, 1H, H-3’), 3.55 (s, 3H, H-10’), 2.58 (dd, J = 16.3, 10.9 Hz, 1H, H-4’ax), 2.50 (ddd, J = 16.3, 11.1, 1.5 Hz, 1H, H-4ax), 2.11 – 2.06 (m, 1H, H-4’eq), 2.09 – 2.06 (m, 1H, H-4eq), 1.27 (d, J = 6.1 Hz, 6H, H-9, H-11’);13C NMR (175 MHz, CDCl3) δ = 156.9 (1C, C-6’), 156.8 (1C, C-8’), 154.0 (2C, C-12, C-14), 152.9 (2C, C-14’, C-16’), 142.8, 138.8 (2C, C-7, C-8), 139.9 (1C, C-12’), 138.7 (1C, C-13), 137.4 (1C, C-15’), 136.6 (1C, C-10), 135.8 (1C, C-4a’), 128.3 (1C, C-5), 127.0 (1C, C-4a), 124.2 (1C, C-8a), 120.2 (1C, C-5’), 118.8 (1C, C-8a’), 116.7 (1C, C-6), 105.7 (2C, C-11, C-15), 105.5 (2C, C-13’, C-17’), 94.3 (1C, C-7’), 78.2 (1C, C-1), 78.0 (1C, C-1’), 71.5 (1C, C-3), 70.6 (1C, C-3’), 60.9 (2C, C-17, C-19’), 56.2 (4C, C-18’, C- 20’, C-16, C-18), 56.0 (1C, C-9’), 55.5 (1C, C-10’), 36.6 (1C, C-4’), 34.3 (1C, C-4), 21.9 (2C, C-9, C-11’). IR (KBr): 3442, 2966, 2935, 2838, 1593, 1505, 1462, 1421, 1328, 1231, 1124, 1009, 831, 734 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’S,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’- bis-isochroman]-7,8-diol (Compound 37) stereoisomer. 4.1.9.7. - (aS,1R,3S,1’S,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’-bis- isochroman]-7,8-diol [(aS,1R,3S,1’S,3’S)-26 CZ-322 / 1.3]

[0031] Compound 37 Flash chromatography: CHCl3 / MeOH 90:0.5. HPLC: Lux i-Amilose-5 (150×10mm), heptane / (MeOH:2- PrOH 1:1) 80:20, 230 nm, tR, prep = 8.66 min. CZ-322 / 1.3: 23 mg (yield: 12%) white-beige crystals, mp 118-121 °C. Rf = 0.20 (CHCl3 / MeOH 90:1). 68 (c = 0.23; CHCl3). Crystals were grown in CHCl3:hexane 1:3 at room temperature. ECD: (c = 8.80×10−5M; MeCN) λ [nm], (Δε) = 278sh (−3.15), 240 (−37.15), 219 (−5.88), 208 (48.10), 196 (13.84).1H NMR (700 MHz, CDCl3) δ = 6.67 (s, 2H, H-11, H-15), 6.62 (s, 1H, H-6), 6.47 (s, 1H, H-7’), 6.42 (s, 2H, H-13’, H-17’), 6.04 (s, 1H, H-1’), 5.83 (s, 1H, H-1), 4.93 (bs, 1H, OH), 3.86 (s, 6H, H-16, H-18), 3.85 (s, 3H, H- 19’), 3.84 (s, 3H, H-17), 3.79 – 3.74 (m, 1H, H-3), 3.77 (s, 3H, H-9’), 3.77 (s, 6H, H-18’, H-20’), 3.73 (s, 3H, H-10’), 3.70 – 3.65 (m, 1H, H-3’), 2.49 (ddd, J = 15.9, 11.2, 1.1 Hz, 1H, H-4ax), 2.46 (dd, J = 15.9, 11.2 Hz, 1H, H-4’ax), 2.08 – 2.01 (m, 2H, H-4eq, H-4’eq), 1.21 (d, J = 6.2 Hz, 3H, H-9), 1.12 (d, J = 6.1 Hz, 3H, H-11’);13C NMR (175 MHz, CDCl3) δ = 157.4 (1C, C-6’), 156.3 (1C, C-8’), 153.6 (2C, C-12, C-14), 152.9 (2C, C-14’, C-16’), 142.3, 139.6 (2C, C-7, C-8), 138.1 (1C, C-13), 137.7 (1C, C-12’), 137.6 (1C, C-10), 137.4 (1C, C-15’), 134.6 (1C, C-4a’), 127.2 (1C, C-5), 126.6 (1C, C-4a), 124.1 (1C, C-8a), 120.3 (1C, C-5’), 116.1 (1C, C-8a’), 116.0 (1C, C-6), 105.8 (2C, C-13’, C- 17’), 105.7 (2C, C-11, C-15), 93.5 (1C, C-7’), 78.0 (1C, C-1), 73.8 (1C, C-1’), 71.0 (1C, C-3), 64.0 (1C, C-3’), 60.9 (2C, C-19’, C-17), 56.2 (1C, C-9’), 56.1 (4C, C-16, C-18, C-18’, C-20’), 55.6 (1C, C-10’), 35.5 (1C, C-4’), 34.5 (1C, C-4), 22.0 (1C, C-9), 21.7 (1C, C-11’). IR (KBr): 3435, 2966, 2935, 2837, 1595, 1505, 1462, 1419, 1324, 1233, 1207, 1125, 1008 cm−1. HRMS (ESI) calcd. for C40H46NaO12[M+Na]+741.2881, found 741.2881. Fluorescence spectroscopy:1λex= 290 nm →1λem= 328 nm,1intensity [a.u.]: 6344.2λex= 240 nm →2λem= 328 nm,2intensity [a.u.]: 5988. c = 6.03×10−5M; MeCN. 4.1.9.8. - (aS,1S,3S,1’R,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’-bis- isochroman]-7,8-diol [(aS,1S,3S,1’R,3’S)-26 CZ-322 / 4.1]

[0032] Compound 38 Flash chromatography: CHCl3 / MeOH 90:0.5. HPLC: Lux i-Amilose-5 (150×10mm), heptane / (MeOH:2- PrOH 1:1) 80:20, 254 nm, tR, prep = 4.98 min. CZ-322 / 4.1: 9 mg (yield: 5%) white-beige crystals, mp 133-136 °C. Rf = 0.15 (CHCl3 / MeOH 90:1). −29 (c = 0.19; CHCl ). ECD: (c = 8.09×10−5M; MeCN) λ [nm], (Δε) = 290 3(−4.18), 272sh (−0.56), 252 (4.96), 231 (−26.97), 203 (47.32).1H NMR (700 MHz, CDCl3) δ = 6.65 (s, 1H, H-6), 6.54 (s, 2H, H-13’, H-17’), 6.51 (s, 2H, H-11, H-15), 6.37 (s, 1H, H-7’), 6.04 (s, 1H, H-1), 5.80 (s, 1H, H-1’), 5.07 (bs, 1H, OH), 3.85 (s, 3H, H-17), 3.80 (s, 3H, H-19’), 3.78 (s, 6H, H-18’, H-20’), 3.76 (s, 6H, H-16, H-18), 3.75 (s, 3H, H-9’), 3.74 – 3.70 (m, 1H, H-3’), 3.70 – 3.64 (m, 1H, H-3), 3.54 (s, 3H, H-10’), 2.53 (dd, J = 16.1, 11.0 Hz, 1H, H-4’ax), 2.33 (dd, J = 16.6, 11.1 Hz, 1H, H-4ax), 2.03 (d, J = 16.1 Hz, 1H, H-4’eq), 2.02 (dd, J = 16.6, 3.4 Hz, 1H, H- 4eq), 1.19 (d, J = 6.2 Hz, 3H, H-11’), 1.13 (d, J = 6.1 Hz, 3H, H-9);13C NMR (175 MHz, CDCl3) δ = 156.9 (1C, C- 6’), 156.8 (1C, C-8’), 153.2 (2C, C-12, C-14), 153.0 (2C, C-14’, C-16’), 141.3139.6 (2C, C-7, C-8), 139.7 (1C, C- 12’), 137.8 (1C, C-13), 137.6 (1C, C-15’), 136.7 (1C, C-10), 135.5 (1C, C-4a’), 128.1 (1C, C-5), 126.3 (1C, C-4a), 122.8 (1C, C-8a), 119.9 (1C, C-5’), 118.4 (1C, C-8a’), 117.0 (1C, C-6), 105.9 (2C, C-11, C-15), 105.6 (2C, C-13’, C-17’), 94.1 (1C, C-7’), 78.2 (1C, C-1’), 73.8 (1C, C-1), 70.4 (1C, C-3’), 64.0 (1C, C-3), 61.0 (1C, C-17), 60.9 (1C, C-19’), 56.3 (2C, C-18’, C-20’), 56.0 (2C, C-16, C-18), 55.8 (1C, C-9’), 55.6 (1C, C-10’), 36.4 (1C, C-4’), 33.2 (1C, C-4), 21.8 (1C, C-9), 21.7 (1C, C-11’). IR (KBr): 3448, 2965, 2934, 2836, 1593, 1505, 1461, 1419, 1324, 1232, 1209, 1125, 1067, 1007 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’S,3’S)-6’,8’-dimethoxy-3,3’- dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’-bis-isochroman]-7,8-diol (Compound 37) stereoisomer. 4.1.9.9. - (aS,1S,3S,1’S,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’-bis- isochroman]-7,8-diol [(aS,1S,3S,1’S,3’S)-26 CZ-322 / 4.2]

[0033] Compound 39 Flash chromatography: CHCl3 / MeOH 90:0.5. HPLC: Lux i-Amilose-5 (150×10mm), heptane / (MeOH:2- PrOH 1:1) 80:20, 254 nm, tR, prep = 9.95 min. CZ-322 / 4.2: 12 mg (yield: 6%) white-beige crystals, mp 111-114 °C. Rf = 0.15 (CHCl3 / MeOH 90:1) +25 (c = 0.21; CHCl3). ECD: (c = 8.36×10−5M; MeCN) λ [nm], (Δε) = 290 (−1.80), 268 (0.36), 240 (−8.12), 219 (56.17), 210 (−7.29), 201 (37.95).1H NMR (700 MHz, CDCl3) δ = 6.84 (bs, 1H, OH), 6.57 (s, 1H, H-6), 6.48 (s, 2H, H-11, H-15), 6.47 (s, 1H, H-7’), 6.40 (s, 2H, H-13’, H-17’), 6.09 (s, 1H, H- 1), 6.04 (s, 1H, H-1’), 5.50 (bs, 1H, OH), 3.83 (s, 3H, H-19’), 3.82 (s, 3H, H-17), 3.80 (s, 3H, H-9’), 3.74 (s, 6H, H- 18’, H-20’), 3.74 (s, 3H, H-10’), 3.73 (s, 6H, H-16, H-18), 3.69 – 3.62 (m, 2H, H-3’, H-3), 2.36 (dd, J = 17.2, 11.3 Hz, 1H, H-4’ax), 2.29 (dd, J = 16.7, 11.3 Hz, 1H, H-4ax), 1.99 (dd, J = 16.9, 3.3 Hz, 2H, H-4eq, H-4’eq), 1.07 (d, J = 6.1 Hz, 2 × 3H, H-9, H-11’);13C NMR (175 MHz, CDCl3) δ = 157.2 (1C, C-6’), 156.4 (1C, C-8’), 153.1 (2C, C-12, C-14), 152.9 (2C, C-14’, C-16’), 141.2, 140.3 (2C, C-7, C-8), 137.7 (1C, C-13), 137.6 (1C, C-12’), 137.5 (1C, C- 15’), 136.7 (1C, C-10), 134.4 (1C, C-4a’), 127.6 (1C, C-5), 125.7 (1C, C-4a), 122.7 (1C, C-8a), 120.1 (1C, C-5’), 116.6 (1C, C-6), 116.1 (1C, C-8a’), 105.8 (4C, C-11, C-15, C-13’, C-17’), 93.2 (1C, C-7’), 73.8 (2C, C-1, C-1’), 63.8 (2C, C-3, C-3’), 60.9 (2C, C-19’, C-17), 56.1 (2C, C-18’, C-20’), 56.0 (2C, C-16, C-18), 55.9 (1C, C-9’), 55.6 (1C, C-10’), 35.1 (1C, C-4’), 33.2 (1C, C-4), 21.9 (1C, C-9), 21.7 (1C, C-11’). IR (KBr): 3420, 2965, 2934, 2836, 1593, 1505, 1461, 1418, 1322, 1233, 1207, 1125, 1062, 1008 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’S,3’S)-6’,8’-dimethoxy-3,3’-dimethyl-1,1’-bis(3,4,5-trimethoxyphenyl)-[5,5’-bis-isochroman]-7,8-diol (Compound 37) stereoisomer. 4.1.9.10. - (aR,1S,3S,1’S,3’S)-1,1’-bis(benzo[d][1,3]dioxol-5-yl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aR,1S,3S,1’S,3’S)-27 CZ-344 / 1.1] Compound 6 Flash chromatography: CHCl3 / hexane 10:0.6 → CHCl3. HPLC: Lux i-Cellulose-5 (150×21.2 mm), hexane / (MeOH:2-PrOH=1:3) 80:20, 296 nm, tR, prep= 10.77 min. CZ-344 / 1.1: 5 mg (yield: 3%) white-yellow crystals, mp 131-133 °C. Rf = 0.33 (CHCl3 / MeOH 10:0.2) +36 (c = 0.17; CHCl ). ECD: (c = 9.26×10−5M; MeCN) λ 3[nm], (Δε) = 283 (−1.38), 264 (−0.36), 245 (−6.47), 231 (4.08), 211 (20.74), 205sh (11.31), 195 (−1.58), 194 (−3.16).1H NMR (700 MHz, CDCl3) δ = 6.87 (d, J = 1.1 Hz, 1H, H-11), 6.82 (dd, J = 8.0, 1.1 Hz, 1H, H-16), 6.79 (d, J = 8.0 Hz, 1H, H-15), 6.77 (d, J = 1.1 Hz, 1H, H-13’), 6.74 (d, J = 8.0 Hz, 1H, H-17’), 6.66 (dd, J = 8.0, 1.1 Hz, 1H, H-18’), 6.64 (s, 1H, H-6), 6.43 (s, 1H, H-7’), 5.98 (s, 2H, H-13), 5.96 – 5.94 (m, 2H, H-15’), 5.94 (2s, 2 × 1H, H-1, H-1’), 5.20 (bs, 1H, OH), 4.74 (bs, 1H, OH), 3.77 (s, 3H, H-9’), 3.76 – 3.73 (m, 1H, H-3), 3.72 (s, 3H, H-10’), 3.69 – 3.64 (m, 1H, H-3’), 2.39 (dd, J = 17.1, 3.3 Hz, 1H, H-4’eq), 2.24 (dd, J = 16.5, 3.3 Hz, 1H, H-4eq), 2.08 (dd, J = 16.5, 10.7 Hz, 1H, H-4ax), 2.03 (dd, J = 17.1, 11.0 Hz, 1H, H-4’ax), 1.11 (d, J = 6.1 Hz, 1H, H-9), 1.09 (d, J = 6.1 Hz, 1H, H- 11’);13C NMR (175 MHz, CDCl3) δ = 156.5 (1C, C-6’), 156.3 (1C, C-8’), 148.0, 147.7 (2C, C-11a, C-14a), 147.5, 146.8 (2C, C-13a’, C-16a’), 141.5, 138.9 (2C, C-7, C-8), 136.7 (1C, C-12’), 135.5 (1C, C-4a’), 134.8 (1C, C-10), 128.9 (1C, C-5), 126.9 (1C, C-4a), 123.3 (1C, C-8a), 122.6 (1C, C-16), 122.1 (1C, C-18’), 120.6 (1C, C-5’), 116.8 (1C, C-8a’), 116.3 (1C, C-6), 109.6 (1C, C-11), 109.2 (1C, C-13’), 108.2 (1C, C-15), 107.6 (1C, C-17’), 101.3 (1C, C-13), 101.1 (1C, C-15’), 93.1 (1C, C-7’), 73.7 (1C, C-1), 73.4 (1C, C-1’), 63.9 (1C, C-3), 63.4 (1C, C-3’), 56.1 (1C, C-9’), 55.6 (1C, C-10’), 34.1 (1C, C-4’), 33.3 (1C, C-4), 21.9 (1C, C-11’), 21.6 (1C, C-9). IR (KBr): 3291, 2968, 2928, 2896, 1710, 1594, 1502, 1487, 1438, 1319, 1287, 1234, 1040, 935, 737 cm−1. HRMS (ESI) data was identical with that of the (aS,1S,3S,1’S,3’S)-1,1’-bis(benzo[d][1,3]dioxol-5-yl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol (Compound 9) stereoisomer. 4.1.9.11. - (aS,1S,3S,1’R,3’S)-1,1’-bis(benzo[d][1,3]dioxol-5-yl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aS,1S,3S,1’R,3’S)-27 CZ-344 / 1.3]

[0034] Flash chromatography: CHCl3 / hexane 10:0.6 → CHCl3. HPLC: Lux i-Cellulose-5 (150×21.2 mm), hexane / (MeOH:2-PrOH=1:3) 80:20, 296 nm, tR, prep= 16.04 min.. CZ-344 / 1.3: 18 mg (yield: 10%) white-yellow crystals, mp 131-134 °C. Rf = 0.31 (CHCl3 / MeOH 10:0.2). −21 (c = 0.22; CHCl ). ECD: (c = 9.18×10−5M; 3MeCN) λ [nm], (Δε) = 291 (−4.04), 249 (1.69), 234 (−11.72), 216 (−8.19), 198 (35.80).1H NMR (700 MHz, CDCl3) δ = 6.82 (dd, J = 8.0, 1.5 Hz, 1H, H-18’), 6.80 (d, J = 1.5 Hz, 1H, H-11), 6.76 (d, J = 8.0 Hz, 1H, H-15), 6.74 (d, J = 1.5 Hz, 1H, H-13’), 6.71 (dd, J = 8.0, 1.5 Hz, 1H, H-16), 6.69 (d, J = 8.0 Hz, 1H, H-17’), 6.55 (s, 1H, H-6), 6.35 (s, 1H, H-7’), 6.00 (s, 1H, H-1), 5.97 – 5.94 (m, 2H, H-13), 5.90 – 5.86 (m, 2H, H-15’), 5.80 (s, 1H, H-1’), 5.22 (bs, 1H, OH), 3.74 (s, 3H, H-9’), 3.73 – 3.69 (m, 1H, H-3’), 3.69 – 3.63 (m, 1H, H-3), 3.55 (s, 3H, H-10’), 2.49 (dd, J = 16.5, 10.8 Hz, 1H, H-4’ax), 2.32 (dd, J = 16.7, 11.1 Hz, 1H, H-4ax), 2.05 (d, J = 16.1 Hz, 1H, H-4’eq), 1.99 (dd, J = 16.7, 3.3 Hz, 1H, H-4eq), 1.24 (d, J = 6.2 Hz, 3H, H-11’), 1.10 (d, J = 6.2 Hz, 3H, H-9);13C NMR (175 MHz, CDCl3) δ = 156.7 (1C, C-6’), 156.6(1C, C-8’), 147.9, 147.4 (2C, C-11a, C-14a), 147.3, 146.8 (2C, C-13a’, C-16a’), 141.1, 139.9 (2C, C-7, C-8), 138.2 (1C, C-12’), 135.8 (1C, C-4a’), 135.2 (1C, C-10), 127.8 (1C, C-5), 126.5 (1C, C-4a), 122.7 (1C, C-8a), 122.3 (1C, C-16), 121.8 (1C, C-18’), 120.0 (1C, C-5’), 118.7 (1C, C-8a’), 117.2 (1C, C-6), 109.3 (1C, C- 11), 108.6 (1C, C-13’), 108.0 (1C, C-15), 107.9 (1C, C-17’), 101.2 (1C, C-13), 100.9 (1C, C-15’), 94.0 (1C, C-7’), 77.5 (1C, C-1’), 73.6 (1C, C-1), 70.5 (1C, C-3’), 63.7 (1C, C-3), 55.7 (1C, C-9’), 55.5 (1C, C-10’), 36.5 (1C, C-4’), 33.3 (1C, C-4), 21.8 (2C, C-11’, C-9). IR (KBr): 3444, 2967, 2893, 1706, 1593, 1503, 1487, 1439, 1237, 1207, 1039, 934, 812 cm−1. HRMS (ESI) data was identical with that of the (aS,1S,3S,1’S,3’S)-1,1’-bis(benzo[d][1,3]dioxol-5- yl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 9) stereoisomer. 4.1.9.12. - (aS,1S,3S,1’S,3’S)-1,1’-bis(benzo[d][1,3]dioxol-5-yl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aS,1S,3S,1’S,3’S)-27 CZ-344 / 6]

[0035] Flash chromatography: CHCl3 / hexane 10:0.6 → CHCl3. HPLC: Lux i-Cellulose-5 (150×21.2 mm), hexane / (MeOH:2-PrOH=1:3) 80:20, 296 nm, tR, prep= 17.23 min. CZ-344 / 6, CZ-344 / 1.4: 65 mg (yield: 36%) white- yellow crystals, mp 133-135 °C. Rf: 0.29 (CHCl3 / MeOH 10:0.2). +90 (c = 0.21; CHCl ). ECD: (c = 1.19×10−4 3M; MeCN) λ [nm], (Δε) = 294 (3.51), 245 (−10.44), 210 (77.56), 200 (−24.38), 193 (−5.47).1H NMR (700 MHz, CDCl3) δ = 7.37 (bs, 1H, OH), 6.79 (d, J = 1.6 Hz, 1H, H-11), 6.73 (d, J = 8.0 Hz, 1H, H-15), 6.71 (dd, J = 7.9, 1.4 Hz, 1H, H-16), 6.71 (d, J = 8.0 Hz, 1H, H-17’), 6.70 (d, J = 1.6 Hz, 1H, H-13’), 6.60 (dd, J = 8.0, 1.6 Hz, 1H, H-18’), 6.48 (s, 1H, H-6), 6.40 (s, 1H, H-7’), 6.04 (s, 1H, H-1), 6.01 (s, 1H, H-1’), 5.94 – 5.91 (m, 4H, H-13, H-15’), 5.41 (bs, 1H, OH), 3.75 (s, 3H, H-9’), 3.72 – 3.66 (m, 2H, H-3’, H-3), 3.69 (s, 3H, H-10’), 2.37 (dd, J = 17.3, 11.3 Hz, 1H, H-4’ax), 2.31 (dd, J = 16.7, 11.2 Hz, 1H, H-4ax), 2.06 (dd, J = 17.3, 3.5 Hz, 1H, H-4’eq), 2.03 (dd, J = 16.7, 3.4 Hz, 1H, H-4eq), 1.14 (d, J = 6.2 Hz, 3H, H-11’), 1.12 (d, J = 6.1 Hz, 3H, H-9);13C NMR (175 MHz, CDCl3) δ = 157.1 (1C, C-6’), 156.1 (1C, C-8’), 147.7, 147.2 (2C, C-11a, C-14a), 147.5, 147.0 (2C, C-13a’, C-16a’), 141.3, 140.2 (2C, C-7, C-8), 135.9 (1C, C-12’), 135.5 (1C, C-10), 134.4 (1C, C-4a’), 127.3 (1C, C-5), 125.7 (1C, C-4a), 122.5 (1C, C- 8a), 122.3 (1C, C-16), 122.1 (1C, C-18’), 120.3 (1C, C-5’), 116.1 (1C, C-6), 115.9 (1C, C-8a’), 109.4 (1C, C-11), 109.1 (1C, C-13’), 107.9 (1C, C-15), 107.8 (1C, C-17’), 101.1 (2C, C-13, C-15’), 93.2 (1C, C-7’), 73.6 (2C, C-1, C- 1’), 63.9 (1C, C-3’), 63.6 (1C, C-3), 55.8 (1C, C-9’), 55.5 (1C, C-10’), 35.3 (1C, C-4’), 33.3 (1C, C-4), 21.7 (2C, C- 9, C-11’). IR (KBr): 3434, 2968, 2897, 1595, 1502, 1487, 1438, 1321, 1235, 1207, 1040, 936, 814 cm−1. HRMS (ESI) calcd. for C36H34NaO10[M+Na]+649.2044, found 649.2044. 4.1.9.13. - (aS)-4-[(1R,3S)-1-(4-fluorophenyl)-6,8-dimethoxy-3-methylisochroman-5-yl]-5-[(S)-2- hydroxypropyl]benzene-1,2-diol [(aS,3S,1‘R,3’S)-30]

[0036] Compound 40 The mono-cyclization reaction was carried out by 4-fluorobenzaldeyde (1.2 equiv.) and (1S)-(+)-10- camphorsulfonic acid (0.5 equiv.). Flash chromatography: hexane / acetone 1.5:1. CZ-314-1, CZ-346-1: 91 mg (yield: 88%) white crystals, mp 88-91 °C. Rf= 0.58 (CH2Cl2 / MeOH 10:1) −40 (c = 0.24; CHCl3). ECD: (c = 1.66×10−4 M; MeCN) λ [nm], (Δε) = 305 (0.20), 296 (−1.14), 275 (0.51), 257sh (1.47), 249 (3.08), 231 (−9.92), 225 (−8.64), 220 (−10.39), 212 (−4.02), 204 (−5.75), 199 (−1.67). Crystals were grown in ethyl acetate at room temperature.1H NMR (400 MHz, acetone-d6) δ = 7.70 (bs, 1H, OH), 7.35 – 7.27 (m, 2H, H-13’, H-17’), 7.05 – 6.97 (m, 2H, H-14’, H-16’), 6.84 (s, 1H, H-6), 6.57 (s, 1H, H-9), 6.53 (s, 1H, H-7’), 5.82 (s, 1H, H-1’), 3.73 – 3.65 (m, 2H, H-2, H-3’), 3.68 (s, 3H, H-9’), 3.55 (s, 3H, H-10’), 2.91 (bs, 1H, OH), 2.88 (bs, 1H, OH), 2.35 – 2.29 (m, 4H, H-1, H-4’), 1.14 (d, J = 6.1 Hz, 3 H, H-11’), 0.92 (d, J = 6.1 Hz, 3H, H-3);13C NMR (100 MHz, acetone-d6) δ = 162.6 (d, JC-F= 242.4 Hz, 1C, C-15’), 157.5 (1C, C-6’) 157.1 (1C, C-8’), 144.8, 144.0 (2C, C-7, C-8), 142.0 (d, JC-F= 2.8 Hz, 1C, C-12’), 136.7 (1C, C-4a’), 130.8 (d, 2C, JC-F = 8.0 Hz, C-13’, C-17’), 130.7 (1C, C-4), 128.8 (1C, C-5), 121.9 (1C, C-5’), 119.0 (1C, C-8a’), 118.7 (1C, C-9), 117.8 (1C, C-6), 114.9 (d, 2C, JC-F = 21.4 Hz, C-14’, C-16’), 94.8 (1C, C-7’), 77.2 (1C, C-1’), 70.7, 68.2 (2C, C-2, C-3’), 55.7 (1C, C-9’), 55.5 (1C, C-10’), 43.6 (1C, C-1), 36.9 (1C, C-4’), 23.6 (1C, C-3), 22.0 (1C, C-11’). IR (KBr): 3433, 2970, 1595, 1509, 1456, 1322, 1209, 830 cm−1. HRMS (ESI) calcd. for C27H29FNaO6 [M+Na]+491.1840, found 491.1840. 4.1.9.14. - (aS,1S,3S,1’R,3’S)-1-(benzo[d][1,3]dioxol-5-yl)-1’-(4-fluorophenyl)-6’,8’-dimethoxy-3,3’- dimethyl-[5,5’-bis-isochroman]-7,8-diol [(aS,1S,3S,1’R,3’S)-31 CZ-347 / 3]

[0037] Compound 15 The second oxa-Pictet-Spengler reaction of the mono-cyclized 4-fluorophenyl derivate was carried out by piperonal (2.0 equiv.) and (1S)-(+)-10-camphorsulfonic acid (1.0 equiv.). Flash chromatography: CHCl3 / MeOH 10:0.025 → 10:0.05 → 10:0.2. CZ-347 / 3: 18 mg (yield 16%) beige-light brown crystals, mp 113-116 °C. Rf= 0.25 (CHCl3 / MeOH 10:0.2).−4 −28 (c = 0.19; CHCl3). ECD: (c = 1.20×10 M; MeCN) λ [nm], (Δε) = 254 (0.47), 248 (1.04), 229 (−8.12), 220 (−13.91), 205sh (9.76), 200 (13.24).1H NMR (700 MHz, CDCl3) δ = 7.28 – 7.23 (m, 2H, H-13’, H-17’), 6.93 – 6.87 (m, 2H, H-14’, H-16’), 6.80 (d, J = 1.7 Hz, 1H, H-11), 6.76 (d, J = 8.0 Hz, 1H, H-15), 6.72 (dd, J = 8.0, 1.7 Hz, 1H, H-16), 6.50 (s, 1H, H-6), 6.35 (s, 1H, H-7’), 6.00 (s, 1H, H-1), 5.97 – 5.93 (m, 2H, H- 13), 5.85 (s, 1H, H-1’), 5.17 (bs, 1H, OH), 3.77 – 3.69 (m, 1H, H-3’), 3.74 (s, 3H, H-9’), 3.70 – 3.62 (m, 1H, H-3), 3.50 (s, 3H, H-10’), 2.51 (dd, J = 16.2, 10.9 Hz, 1H, H-4’ax) 2.33 (dd, J = 16.7, 11.2 Hz, 1H, H-4ax), 2.07 (d, J = 15.6 Hz, 1H, H-4’eq), 2.00 (dd, J = 16.7, 3.3 Hz, 1H, H-4eq), 1.25 (d, J = 6.2 Hz, 3H, H-11’), 1.10 (d, J = 6.1 Hz, 3H, H- 9);13C NMR (175 MHz, CDCl3) δ = 162.2 (d, JC-F = 244.9 Hz, 1C, C-15’), 156.9 (1C, C-6’), 156.5 (1C, C-8’), 147.9, 147.4 (2C, C-11a, C-14a), 141.1, 139.8 (2C, C-7, C-8), 139.8 (d, JC-F = 2.8 Hz, 1C, C-12’), 135.7 (1C, C-4a’), 135.2 (1C, C-10), 129.8 (d, JC-F= 8.1 Hz, 2C, C-13’, C-17’), 127.7 (1C, C-5), 126.4 (1C, C-4a), 122.7 (1C, C-8a), 122.3 (1C, C-16), 120.0 (1C, C-5’), 118.4 (1C, C-8a’), 117.1 (1C, C-6), 114.9 (d, JC-F= 21.4 Hz, 2C, C-14’, C-16’), 109.3 (1C, C-11), 108.0 (1C, C-15), 101.2 (1C, C-13), 93.9 (1C, C-7’), 77.1 (1C, C-1’), 73.6 (1C, C-1), 70.7 (1C, C-3’), 63.6 (1C, C-3), 55.7 (1C, C-9’), 55.3 (1C, C-10’), 36.5 (1C, C-4’), 33.3 (1C, C-4), 21.8 (2C, C-11’, C-9). IR (KBr): 3308, 2968, 2928, 1710, 1662, 1594, 1507, 1486, 1438, 1321, 1234, 1209, 1040, 936 cm−1. HRMS (ESI) calcd. for C35H33FNaO8[M+Na]+623.2052, found 623.2049. 4.1.10. General procedure for oxidation – reduction reaction of bis-isochroman derivatives containing pyrocatechol unit Oxidation: the corresponding pyrocatechol bis-isochroman derivative (1.0 equiv.) was dissolved in MeOH – water (5:1) in an Erlenmeyer-flask and NaIO4(1.0 equiv.) was added to the solution. The reaction mixture was shaken up two-three times in a few minutes while the color of the mixture changed fast from colorless to deep dark brown. After the starting material was consumed on the basis of TLC monitoring, the mixture was diluted with EtOAc and water, then the phases were separated in a separatory funnel. The aqueous phase was washed three times with EtOAc. The combined organic layers were washed with a saturated solution of NaHCO3and with brine, dried over anhydrous MgSO4. After filtration, the solvent was evaporated in vacuo to yield the desired ortho-quinone bis-isochroman. Reduction: the corresponding ortho-quinone bis-isochroman derivate (1.0 equiv.) was dissolved in MeOH – water (5:1) in a penicillin bottle. After adding exceed amount of l-ascorbic acid to the deep dark brown solution and shaking up the reaction mixture two-three times, the color of the deep dark brown mixture changed fast to colorless. The mixture in the penicillin bottle was extracted (microextraction) with EtOAc, water and a saturated solution of NaHCO3. The upper organic phase contained the pyrocatechol bis-isochroman derivative on the basis of TLC monitoring. 4.1.10.1. - (aS,1R,3S,1’R,3’S)-1,1’-bis(4-fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-dione [(aS,1R,3S,1’R,3’S)-32] Purification was not required for the crude product. CZ-348-1: 48 mg (yield: 96%) dark brown crystals, mp 121-123 °C. Rf = 0.47 (hexane / acetone 2:1).−4 −106 (c = 0.25; CHCl3). ECD: (c = 1.26×10 M; MeCN) λ [nm], (Δε) = 485 (−0.94), 375 (2.88), 282 (0.98), 260 (−3.13), 246sh (−7.73), 222 (−25.87), 212 (−13.35), 203sh (−21.57), 196 (−30.05). Crystals were grown in dichloromethane:acetone 1:1 at room temperature.1H NMR (360 MHz, CDCl3) δ = 7.47 – 7.33, 7.30 – 7.20 (2m, 2 × 2H, H-11, H-15, H-13’, H-17’), 7.07 – 7.00, 7.00 – 6.92 (2m, 2 × 2H, H-12, H- 14, H-14’, H-16’), 6.34, 6.26 (2s, 2 × 1H, H-6, H-7’), 5.81, 5.61 (2s, 2 × 1H, H-1, H-1’), 3.89, 3.54 (2s, 2 × 3H, H- 9’, H-10’), 3.85 – 3.65 (m, 2H, H-3, H-3’), 2.75, 2.37, 2.27, 1.87 (dd, J = 16.3, 10.6 Hz, 1H, d, J = 16.8 Hz, 1H, ddd, J = 19.0, 10.1, 3.9 Hz, 1H, dd, J = 19.0, 2.4 Hz, 1H, H-4, H-4’), 1.34, 1.25 (d, J = 6.1 Hz, 3H, d, J = 6.1 Hz, 3H, H- 9, H-11’);13C NMR (90 MHz, CDCl3) δ = 179.3, 177.8 (2C, C-7, C-8), 162.7, 162.2 (d, JC-F = 246.4 Hz, 1C, d, JC-F = 245.1 Hz, 1C, C-13, C-15’), 158.2, 156.1, 151.9, 148.4, 137.1, 135.0, 119.4, 115.6 (8C, C-4a, C-5, C-8a, C-4a’, C- 5’, C-6’, C-8’, C-8a’), 139.3, 136.2 (d, JC-F= 3.0 Hz, 1C, d, JC-F= 3.0 Hz, 1C, C-10, C-12’), 130.1, 129.7 (d, JC-F= 8.4 Hz, 2C, d, JC-F= 8.1 Hz, 2C, C-11, C-15, C-13’, C-17’), 115.4, 114.97 (d, JC-F= 21.5 Hz, 2C, d, JC-F= 21.4 Hz, 2C, C-12, C-14, C-14’, C-16’), 129.6, 93.7 (2C, C-6, C-7’), 77.0, 76.1 (2C, C-1, C-1’), 70.1, 69.5 (2C, C-3, C-3’), 55.9, 55.4 (2C, C-9’, C-10’), 36.4, 35.3 (2C, C-4, C-4’), 21.8, 21.2 (2C, C-9, C-11’). IR (KBr): 3434, 2973, 2932, 2844, 1661, 1595, 1509, 1326, 1211, 1117, 1069, 830, 549 cm−1. HRMS (ESI) calcd. for C34H30F2NaO6[M+Na]+595.1903, found 595.1903. 4.1.10.2. - (aS,1R,3S,1’R,3’S)-1,1’-bis(4-bromophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-dione [(aS,1R,3S,1’R,3’S)-33]

[0038] Purification was not required for the crude product. CZ-349-1: 49 mg (yield: 98%) dark brown crystals, mp 140-143 °C. Rf = 0.53 (hexane / acetone 2:1). −107 (c = 0.21; CHCl3). ECD: (c = 7.87×10−5M; MeCN) λ [nm], (Δε) = 276 (0.93), 228 (−41.78), 213 (6.58), 203 (−19.94). Crystals were grown in methanol at room temperature.1H NMR (360 MHz, CDCl3) δ = 7.47, 7.41, 7.32, 7.16 (d, J = 8.4 Hz, 2H, d, J = 8.3 Hz, 2H, d, J = 8.3 Hz, 2H, d, J = 8.3 Hz, 2H, H-11, H-12, H-14, H-15, H-13’, H-14’, H-16’, H-17’), 6.34, 6.26 (2s, 2 × 1H, H-6, H-7’), 5.78, 5.58 (2s, 2 × 1H, H-1, H-1’), 3.88, 3.56 (2s, 2 × 3H, H-9’, H10’), 3.84 – 3.66 (m, 2H, H-3, H-3’), 2.74, 2.37, 2.28, 1.87 (dd, J = 16.1, 10.8 Hz, 1H, d, J = 16.0 Hz, 1H, ddd, J = 18.9, 10.1, 3.8 Hz, 1H, d, J = 19.1 Hz, 1H, H-4, H-4’), 1.33, 1.25 (d, J = 6.1 Hz, 3H, d, J = 6.1 Hz, 3H, H-9, H-11’);13C NMR (90 MHz, CDCl3) δ = 179.2, 177.7 (2C, C-7, C-8), 158.1, 156.1, 151.7, 148.6, 142.5, 139.3, 136.7, 135.0, 122.3, 121.3, 119.0, 115.6 (12C, C-4a, C-5, C-8a, C-10, C-13, C-4a’, C-5’, C-6’, C-8’, C-8a’, C-12’ C-15’), 131.7, 131.2, 130.1, 129.9 (8C, C-11, C-12, C-14, C-15, C-13’, C-14’, C-16’, C-17’), 129.6, 93.6 (2C, C-6, C-7’), 77.0, 76.1 (2C, C-1, C-1’), 70.1, 69.5 (2C, C-3, C-3’), 55.9, 55.4 (2C, C-9’, C- 10’), 36.3, 35.2 (2C, C-4, C-4’), 21.7, 21.2 (2C, C-9, C-11’). IR (KBr): 3445, 2971, 2930, 2842, 1660, 1594, 1487, 1345, 1326, 1209, 1070, 1012, 816 cm−1. HRMS (ESI) calcd. for C34H30Br2NaO6 [M+Na]+715.0301, found 715.0298. 4.1.11. General procedure for epimerization reaction (isomerization) of C-1 / C-1’ substituted bis-isochroman derivatives Method G: the corresponding C-1 / C-1’ substituted bis-isochroman derivative (stereopure or mixture of C- 1 / C-1’ stereoisomers, 1.0 equiv.) was dissolved in 1,4-dioxane then TfOH (4.0 equiv.) was added to the solution. The mixture was stirred for 3 hours at 100 °C. After that l-ascorbic acid (0.5 equiv.) was added to the mixture at room temperature and stirred for 2 minutes. The solvent was evaporated in vacuo, the residue was diluted with EtOAc and water, then the phases were separated in a separatory funnel. The aqueous phase was washed three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography and preparative chiral HPLC to yield the other stereoisomers in different ratios. Method H: the corresponding C-1 / C-1’ substituted bis-isochroman derivative (stereopure or mixture of C- 1 / C-1’ stereoisomers, 1.0 equiv.) was dissolved in acetic acid – water (9:1) then TfOH (4.5 equiv.) was added to the solution. The mixture was stirred at 100 °C until to reach the maximum conversion of stereoisomers (ca.4 hours) on the basis of TLC monitoring. After that, EtOAc and water were added to the mixture and the phases were separated in a separatory funnel. The aqueous phase was washed three times with EtOAc, and the combined organic phases were washed with a saturated solution of NaHCO3, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue can be purified by column chromatography and preparative chiral HPLC (the detected new stereoisomers by TLC were not isolated). 4.1.11.1. - (aS,1S,3S,1’R,3’S)-1,1’-bis(4-fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochro mpound 2 Prepared by method G. Flash column chromatography: hexane / acetone 4:1. HPLC: Lux i-Cellulose-5 (150×21.2 mm), hexane / (MeOH:2-PrOH 1:1) 80:20, 254 nm, tR, prep = 4.82 min.. CZ-355 / 2.1: 12 mg (yield: 6%) white crystals, mp 233-236 °C. Rf= 0.48 (hexane / acetone 1.5:1). 39 (c = 0.17; CHCl3). ECD: (c = 1.13×10−4 M; MeCN) λ [nm], (Δε) = 291 (−3.04), 276sh (−0.59), 265 (−2.06), 249 (1.77), 233sh (−7.48), 220 (−19.53), 210 (0.66), 204 (−4.02), 200 (−0.21), 194 (−4.25).1H NMR (700 MHz, acetone-d6) δ = 7.32 – 7.29 (m, 2H, H-13’, H- 17’), 7.29 – 7.27 (m, 2H, H-11, H-15), 7.09 – 7.05 (m, 2H, H-12, H-14), 7.03 – 6.99 (m, 2H, H-14’, H-16’), 6.70 (s, 1H, H-6), 6.56 (s, 1H, H-7’), 6.04 (s, 1H, H-1), 5.80 (s, 1H, H-1’), 3.72 (s, 3H, H-9’), 3.71 – 3.65 (m, 1H, H-3’), 3.55 (s, 3H, H-10’), 3.56 – 3.52 (m, 1H, H-3), 2.45 (dd, J = 16.3, 10.8 Hz, 1H, H-4’ax), 2.25 (dd, J = 16.4, 11.2 Hz, 1H, H-4ax), 2.23 (ddd, J = 16.3, 2.3, 1.2 Hz, 1H, H-4’eq), 2.06 – 2.02 (m, 1H, H-4eq), 1.15 (d, J = 6.1 Hz, 3H, H-11’), 1.00 (d, J = 6.1 Hz, 3H, H-9);13C NMR (175 MHz, acetone-d6) δ = 162.9 (d, JC-F= 243.2 Hz, 1C, C-13), 162.6 (d, JC-F= 242.5 Hz, 1C, C-15’), 157.9 (1C, C-6’), 157.2 (1C, C-8’), 142.7, 141.4 (2C, C-7, C-8), 141.9 (d, JC-F= 2.9 Hz, 1C, C-12’), 139.4 (d, JC-F = 2.8 Hz, 1C, C-10), 136.4 (1C, C-4a’), 131.4 (d, JC-F = 8.1 Hz, 2C, C-11, C-15), 130.8 (d, JC-F= 8.1 Hz, 2C, C-13’, C-17’), 128.1 (1C, C-5), 126.1 (1C, C-4a), 123.4 (1C, C-8a), 121.2 (1C, C-5’), 119.1 (1C, C- 8a’), 117.6 (1C, C-6), 115.2 (d, JC-F= 21.3 Hz, 2C, C-12, C-14), 114.9 (d, JC-F= 21.4 Hz, 2C, C-14’, C-16’), 94.9 (1C, C-7’), 77.4 (1C, C-1’), 73.8 (1C, C-1), 70.7 (1C, C-3’), 64.0 (1C, C-3), 55.8 (1C, C-9’), 55.5 (1C, C-10’), 37.0 (1C, C-4’), 34.1 (1C, C-4), 22.1 (2C, C-9, C-11’). IR (KBr): 3421, 2970, 2931, 1595, 1508, 1320, 1210, 1119, 833, 792 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’R,3’S)-1,1’-bis(4-fluorophenyl)-6’,8’- dimethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 1) stereoisomer. 4.1.11.2. - (aS,1R,3S,1’S,3’S)-1,1’-bis(4-fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aS,1R,3S,1’S,3’S)-24]

[0039] Compoud 3 Prepared by method G. Flash column chromatography: hexane / acetone 4:1. HPLC: Lux i-Cellulose-5 (150×21.2 mm), hexane / (MeOH:2-PrOH 1:1) 80:20, 254 nm, tR, prep= 7.32 min.. CZ-355 / 2.2: 14 mg (yield: 7%) white crystals, mp 122-125 °C. Rf = 0.48 (hexane / acetone 1.5:1−4 −85 (c = 0.28; CHCl3). ECD: (c = 1.08×10 M; MeCN) λ [nm], (Δε) = 313 (−0.23), 308 (0.50), 285 (−3.07), 269 (−2.16), 239 (−23.40), 228sh (−4.89), 213 (9.13), 207 (6.20), 198 (22.47), 193 (7.36).1H NMR (700 MHz, acetone-d6) δ = 7.38 – 7.32 (m, 2H, H-11, H-15), 7.23 – 7.17 (m, 2H, H-13’, H-17’), 7.07 – 7.04 (m, 2H, H-14’, H-16’), 7.03 – 7.00 (m, 2H, H-12, H-14), 6.70 (s, 1H, H-7’), 6.59 (s, 1H, H-6), 5.92 (s, 1H, H-1’), 5.91 (s, 1H, H-1), 3.81 (s, 3H, H-9’), 3.73 (s, 3H, H-10’), 3.73 – 3.68 (m, 1H, H-3), 3.53 – 3.46 (m, 1H, H-3’), 2.40 (ddd, J = 15.9, 10.9, 1.4 Hz, 1H, H-4ax), 2.31 (dd, J = 17.0, 11.1 Hz, 1H, H- 4’ax), 2.18 (ddd, J = 15.9, 2.2, 1.0 Hz, 1H, H-4eq), 2.09 (dd, J = 17.0, 3.4 Hz, 1H, H-4’eq), 1.13 (d, J = 6.1 Hz, 3H, H- 9), 1.01 (d, J = 6.1 Hz, 3H, H-11’);13C NMR (175 MHz, acetone-d6) δ = 162.8 (d, JC-F = 243.2 Hz, 1C, C-15’), 162.7 (d, JC-F= 242.2 Hz, 1C, C-13), 158.5 (1C, C-6’), 156.9 (1C, C-8’), 143.0, 141.6 (2C, C-7, C-8), 141.4 (d, JC-F= 2.9 Hz, 1C, C-10), 139.8 (d, JC-F= 2.9 Hz, 1C, C-12’), 135.6 (1C, C-4a’), 131.2 (d, JC-F= 8.1 Hz, 2C, C-11, C-15), 131.1 (d, JC-F= 8.1 Hz, 2C, C-13’, C-17’), 127.3 (1C, C-4a), 127.1 (1C, C-5), 125.1 (1C, C-8a), 121.4 (1C, C-5’), 116.7 (1C, C-6), 116.6 (1C, C-8a’), 115.2 (d, JC-F = 21.3 Hz, 2C, C-14’, C-16’), 114.9 (d, JC-F = 21.4 Hz, 2C, C-12, C-14), 94.4 (1C, C-7’), 77.4 (1C, C-1), 73.5 (1C, C-1’), 71.0 (1C, C-3), 63.9 (1C, C-3’), 56.2 (1C, C-9’), 55.7 (1C, C-10’), 36.0 (1C, C-4’), 35.5 (1C, C-4), 22.1 (2C, C-9), 22.0 (1C, C-11’). IR (KBr): 3247, 2969, 2930, 2840, 1596, 1508, 1322, 1305, 1208, 1118, 829 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’R,3’S)-1,1’-bis(4- fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 1) stereoisomer. 4.1.11.3. - (aS,1S,3S,1’S,3’S)-1,1’-bis(4-fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis- isochroman]-7,8-diol [(aS,1S,3S,1’S,3’S)-24]

[0040] Prepared by method G. Flash column chromatography: hexane / acetone 4:1. CZ-355 / 4: 36 mg (yield: 18%) white crystals, mp 117-120 °C. Rf= 0.45 (hexane / acetone 1.5:1)−4 +40 (c = 0.19; CHCl3). ECD: (c = 1.11×10 M; MeCN) λ [nm], (Δε) = 289 (−3.30), (240 (−16.47), 214 (48.57), 203sh (27.34).1H NMR (700 MHz, acetone-d6) δ = 7.29 – 7.25 (m, 2H, H-11, H-15), 7.22 – 7.18 (m, 2H, H-13’, H-17’), 7.06 – 7.03 (m, 2H, H-12, H-14), 7.04 – 7.01 (m, 2H, H-14’, H-16’), 6.70 (s, 1H, H-7’), 6.63 (s, 1H, H-6), 6.04 (s, 1H, H-1), 5.92 (s, 1H, H-1’), 3.78 (s, 3H, H-9’), 3.73 (s, 3H, H-10’), 3.58 – 3.53 (m, 1H, H-3), 3.53 – 3.49 (m, 1H, H-3’), 2.29 (dd, J = 17.2, 11.0 Hz, 1H, H- 4’ax), 2.25 (dd, J = 16.5, 11.1 Hz, 1H, H-4ax), 2.18 (dd, J = 17.2, 3.4 Hz, 1H, H-4’eq), 2.15 (dd, J = 16.5, 3.7 Hz, 1H, H-4eq), 1.01 (d, J = 6.1 Hz, 3H, H-11’), 1.01 (d, J = 6.1 Hz, 3H, H-9);13C NMR (175 MHz, acetone-d6) δ = 162.9 (d, JC-F= 243.2 Hz, 1C, C-13), 162.8 (d, JC-F= 243.2 Hz, 1C, C-15’), 158.2, 156.9 (2C, C-6’, C-8’), 142.7, 141.3 (2C, C-7, C-8), 139.7 (d, JC-F = 2.9 Hz, 1C, C-12’), 139.3 (d, JC-F = 2.9 Hz, 1C, C-10), 135.6 (1C, C-4a’), 131.4 (d, JC-F = 8.1 Hz, 2C, C-11, C-15), 131.1 (d, JC-F= 8.1 Hz, 2C, C-13’, C-17’), 128.1 (1C, C-5), 125.9 (1C, C-4a), 123.5 (1C, C-8a), 121.3 (1C, C-5’), 117.1 (1C, C-6), 116.7 (1C, C-8a’), 115.2 (d, JC-F= 21.3 Hz, 2C, C-12, C-14, d, JC-F= 21.3 Hz, 2C, C-14’, C-16’), 94.3 (1C, C-7’), 73.8 (1C, C-1), 73.5 (1C, C-1’), 64.0 (1C, C-3), 63.9 (1C, C-3’), 55.9 (1C, C-9’), 55.7 (1C, C-10’), 35.8 (1C, C-4’), 34.1 (1C, C-4), 22.1 (2C, C-9, C-11’). IR (KBr): 3421, 2969, 2930, 2839, 1599, 1507, 1320, 1222, 1207, 1120, 837 cm−1. HRMS (ESI) data was identical with that of the (aS,1R,3S,1’R,3’S)- 1,1’-bis(4-fluorophenyl)-6’,8’-dimethoxy-3,3’-dimethyl-[5,5’-bis-isochroman]-7,8-diol (Compound 1) stereoisomer. Example 5: Synthesis II The optically active coupling partners of the biaryl cross-coupling reactions, the boronate ester (S)-8 and the aryl iodide derivative (S)-18 were prepared in short sequences from (S)-propylene oxide (Scheme 7). Scheme 7: Synthesis of the cross-coupling partners for the Suzuki reaction. Reagents and conditions: i) a) n- BuLi, Ar / N2, THF, −80 °C, 20 min, b) (S)-propylene oxide, Ar / N2, −80 °C, 20 min, c) BF3.Et2O, Ar / N2, −80 °C, 30 min, (S)-11 (86%), (S)-16 (90%); ii) AcCl, C5H5N, CH2Cl2, rt, 3 h, (S)-12 (91%), 3 h, (S)-17 (82%); iii) NIS, F3CCOOH, MeCN, rt, x h, (S)-13a-c (x%), 16 h, (S)-18 (96%); iv) NBS, MeCN, rt, 16 h, (S)-14 (94%), 16 h, (S)-19 (97%); v) a) (Ph3P)2PdCl2, PPh3, KOAc, Ar / N2, DMF, rt, 15 min, b) B2pin2, Ar / N2, 150 °C, 2 h, (S)-8 (from (S)-13a: 35%, from (S)-14: 62%), 3h, (S)-20 (92%). A yield of 35% was determined based on the integral values of the mass and1H NMR spectrum of the compound obtained from the reaction, taking into account the corresponding regioisomer. In the first step, the aryl lithium reagents, formed in situ in the reaction of 1-bromo-3,5-dimethoxybenzene (9) or 4-bromo-1,2-dibenzyloxybenzene (15) with n-butyllithium, opened the epoxide ring regioselectively producing the (S)-2-arylpropan-2-ol derivatives (S)-11 and (S)-16. Acetylation of (S)-11 and (S)-16 subsequent halogenation with N-halosuccinimide afforded the aryl halides. Using N-iodosuccinimide in the reaction of (S)-11, inseparable mixture of (S)-13a-b iodo regioisomers and (S)-13c diiodo derivatives were formed. Thus, Miyaura borylation of the mixture of iodo derivatives (S)-13a-b resulted in the desired product (S)-8 with low yield (35%) due to the starting mixture and also the competing dehalogenation side-reaction in which (S)-12 was also observed in the reaction mixture. Improving the yields, (S)-14 was also synthetized by the regioselective bromination of (S)-12 with N- bromosuccinimide. In this way, (S)-8 was obtained with 68% in the Miyaura borylation (read arrows in Scheme 7). On the other hand, the halogenations of (S)-17 were carried out regioselectively to obtain the iodo (S)-18 and bromo (S)-19 derivatives. (S)-18 proved to be more reactive in Suzuki biaryl coupling reaction which was carried out with Pd(OAc)2and different phosphine ligands such as PPh3(36%), XPhos (47%) and Xantphos (63%) resulting in the mixture of axially chiral biaryls (aR,2S,2’S)- and (aS,2S,2’S)-21 with very high atropdiastereoselectivity (de > 90%) favouring the (aS) atropdiastereomer (Scheme 8 and Table I, Deposition numbers 2249290 [for (aR,1S,3S,3’S)- 21], 2249291 [for (aS,1R,3R,3’R)-21], and 2249292 for [(aS,1R,3R,1’R,3’R)-22]). Table I. Optimalization of Suzuki biaryl coupling reaction of aryl halogenid (S)-18 or (S)-19 and aryl pinacolatoboronate ester (S)-8. Scheme 8: Suzuki cross-coupling reactions of (S)-8 and (S)-18, and subsequent removal of the protecting groups (Wuts, P. G. M. and Greene, T. W.2006.). Reagents and conditions: i) a) (S)-18, phosphine ligand, Pd(OAc)2, Ar / N2, DMF, rt, 1 h, b) (S)-8, CsF, Ar / N2, DMF, rt 30 min, c) a + b, Ar / N2, 150 °C, 1.5 h; ii) LiOH, MeOH, rt, 1.5 h, (aS,2S,2’S)-22 (85%); iii) H2, Pd(C), THF, rt, 6 h, (aS,2S,2’S)-23 (97%); (aS) de > 90%. After the removal of the acetyl and benzyl groups, oxa-Pictet-Spengler cyclizations were carried out with different aromatic aldehydes such as 4-bromo-, 4-fluoro, 3,4-methylenedioxy- and 3,4,5-trimethoxybenzaldehyde catalysed by (1S)-(+)-10-camphorsulfonic acid in the mixture of toluene:MeOH (4:1) at 80 °C to result in same aryl substituents in positions C-1 and C-1’ (Scheme 9). Evolving two new stereocentrums, four diastereomers were observed in the reaction favouring the cis,cis-(1R,3S,1’R,3’R) absolute configurations which were assigned by the NOE correlation of the H-1 and H-3 protons. The structures of (aS,1R,3S,1’R,3’S)-24 (Compound 1) and (aS,1R,3S,1’R,3’S)-25 (Compound 10) were also determined by X-ray crystallography. Scheme 9: Bis-oxa-Pictet-Spengler cyclizations of (aS / aR,2S,2’S)-23 with various type of substituated benzaldehydes. Reagents and conditions: i) ArCHO, (1S)-(+)-10-camphorsulfonic acid, toluene:MeOH (4:1), 80 °C, 8-16 h. Table II. Structures and isolated yields of axially chiral bis-isochromans (24-27) synthetized by Brønsted acid catalyzed bis-oxa-Pictet-Spengler cyclizations.

[0041] In case of the oxa-Pictet-Spengler reaction of (aS,2S,2’S)-23 with 4-fluorobenzaldehyde (aS,1R,3S,1’R,3’S)- 24 (Compound 1) was formed as the major stereoisomer in higher yield than the other three stereoisomers which were not isolated. Henceforth, optimization reactions were worked out to improve the ratio of the other stereoisomers to the stereochemical and biological investigations. Brønsted acid catalyzed isomerization reaction of the stereopure (aS,1R,3S,1’R,3’S)-24 (Compound 1) and -25 (Compound 10) was carried out to result in (aS,1R,3S,1’S,3’S)-24 (Compound 3), -25 (Compound 44), (aS,1S,3S,1’R,3’S)-24 (Compoud 2), -25 (Compound 45) and (aS,1S,3S,1’S,3’S)- 24 (Compound 4), -25. Solvents, temperature and the quality and the quantity of Brønsted acids were examined in the isomerization reactions. In summary, high temperature (100 °C in AcOH:H2O = 9:1, reflux in 1,4-dioxane) was required in all cases. Four Brønsted acids were used: three as catalysts [in decreasing order by the acidity: TfOH > HCl > (1S)-(+)-10-camphorsulfonic acid] and one as a solvent too (AcOH). Although, the conversion of the starting stereoisomers to other diastereomers was lower (~80%) in case of AcOH:H2O = 9:1 but decomposition was still not observed over a longer reaction time at 100 °C. In contrast, significant decomposition was observed using 1,4-dioxane and TfOH by ~ 90% of conversion and three hours at reflux temperature. Scheme 10: Brønsted acid catalyzed isomerization reaction of (aS,1R,3S,1’R,3’S)-24 CZ-313 / 2 (Compound In order to prepare axially chiral bis-isochromans lacking both the C-1 and C-1’ chirality centers, before the removal of the benzyl protecting groups oxa-Pictet-Spengler cyclization was carried out with MOMCl afforded (aS,3S,3’S)-28 (Compound 54) from which (aS,3S,3’S)-29 (Compound 13) was obtained after catalytic hydrogenation (Scheme 11). Scheme 11: Bis-oxa-Pictet-Spengler cyclization reaction of (aS,2S,2’S)-22 with MOMCl and subsequent debenzylation. Reagents and conditions: i) MOMCl, ZnCl2, THF, 0 °C → rt, 20 h, (aS,3S,3’S)-28 (Compound 54) (42%); ii) H2, Pd(C), THF, rt, 1.5 h, (aS,3S,3’S)-29 (Compound 13) (80%); (aS) de > 90%. On the other hand, monofunctionalized biaryl derivative can be synthetized using one equivalent of the aromatic aldehyde in oxa-Pictet-Spengler reaction. In case of using 4-fluorobenzaldehyde (aS,3S,1’R,3’S)-30 was produced with good yield and high cis-diastereoselectivity which can be explained the chiral induction of the applied Brønsted acid just like in case of bis-oxa-Pictet-Spengler cyclizations. In addition, full regioselectivity was observed in the kinetic controlled reaction due to the activating ability of the electrondonating methoxy group in para position. Moreover, there is an activating hydroxyl group on the other aromatic ring in ortho position which causes however steric hindrance too because of being in peri position and there is no activating group in para position (Scheme 12). Scheme 12: Regio- and diastereoselective mono-oxa-Pictet-Spengler cyclization reaction of (aS,2S,2’S)-23 with 4-fluorobenzaldehyde. Reagents and conditions: i) 4-F-C6H4CHO, (1S)-(+)-10-camphorsulfonic acid, toluene:MeOH (4:1), 80 °C, x h, (aS,3S,1‘R,3’S)-30 (Compound 40) (88%); (aS) de > 90%.

[0042] This regio- and diastereoselective reaction facilitates the synthesis of variously substituated heterodimeric bis- isochroman derivatives. However, using one equivalent of another aromatic aldehyde under the earlier reaction conditions isomerization of the C-1’ caused by the acid catalysis was also observed. From this reaction only (aS,1S,3S,1’R,3’S)-31 CZ-347 / 3 (Compound 15) could be isolated in low yield (16%) (Scheme 13). Scheme 13: Synthesis of heterodimeric bis-isochroman with oxa-Pictet-Spengler cyclizations of (aS,1R,3S,2’S)-30 with piperonal. Reagents and conditions: i) 3,4-(OCH2O)C6H3CHO, (1S)-(+)-10-camphorsulfonic acid, toluene:MeOH (4:1), 80 °C, 8-16 h, (aS,1S,3S,1’R,3’S)-31 CZ-347 / 3 (Compound 15) (16%); (aS) de > 90%. The oxidation of the 7,8-catechol moiety to ortho-quinone was observed to a certain extent during the oxa- Pictet-Spengler ring formation reactions in solution. The catechol type bis-isochroman derivatives are stable in solid phase but our purpose was to carry out the oxidation reaction of (aS,1R,3S,1’R,3’S)-24 (Compound 1) and (aS,1R,3S,1’R,3’S)-25 (Compound 10) by sodium metaperiodate in preparative scale to result in the suitable ortho- quinone derivatives with excellent yields. On the other hand, the reduction of the ortho-quinone derivatives were also carried out by l-ascorbic acid in a quick reaction (Scheme 14) which can be used to stabilize the catechol derivatives just like in the parenteral pharmaceutical products e.g. adrenaline injection. These compounds could be valuable ones in pharmacological studies to study structure-activity relationships. Scheme 14: Redox reaction of axially chiral haloaryl bis-isochroman derivatives.

[0043] EXAMPLE 5: 7,8,7’,8’ OH substituted bis-isochroman derivatives and their preparation 5.1. Materials and Methods The materials and methods in the present example have been carried out as described in Example 1, mutatis mutandis. 5.2. Syntheses and characterization of the compounds 5.2.1. General procedures for the preparation of 7,8,7’,8’ OH bis isochromane compounds Scheme 15 5.2.2. General procedure for synthesis of chiral non-racemic halogenated 1-arylpropan-2-yl acetates Scheme 16: Preparation of chiral non-racemic halogenated 1-arylpropan-2-yl acetates 5.2.3. General procedure for Suzuki-Miyaura coupling reaction of halogenated 1-arylpropan-2-yl acetates Scheme 17: Miyaura borylation and Suzuki biaryl coupling reaction; i) anhydrous DMF, 1. PPh3, 2. (PPh3)2PdCl2, 3. anhydrous NaOAc, 4. B2Pin2[Bis(pinacolato)diborone], 150°C; ii-1) anhydrous DMF, rt, 120°C, SPhos, Pd(OAc)2, CsF; ii-2) anhydrous DMF, rt, 120°C, SPhos, Pd(OAc)2, CsF; XPhos = Dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′- biphenyl]-2-yl]phosphane (CAS No.: 564483-18-7); SPhos = Dicyclohexyl(2′,6′-dimethoxy[1,1′-biphenyl]-2- yl)phosphane (CAS No.: 657408-07-6).

[0044] 5.2.3.1. - Suzuki-Miyaura coupling reaction of (S)-1-[(4,5-dibenzyloxy)-2-iodophenyl]propan-2-yl acetate (14 on Scheme 17) and (S)-1-[4,5-bis(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]propan-2-yl acetate (16 on Scheme 17) To the solution of (S)-1-[(4,5-dibenzyloxy)-2-iodophenyl]propan-2-yl acetate (759 mg, 1.47 mmol, 1.1 equiv.) in anhydrous DMF (5 ml), XPhos (129 mg, 0.270 mmol, 0.2 equiv.) and Pd(OAc)2 (36 mg, 0.161 mmol, 0.12 equiv.) were added under Ar atmosphere, and the solution was stirred for 1 hour with inert gas bubbling at room temperature. To the solution of (S)-1-[(4,5-bis(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-yl acetate (690 mg, 1.34 mmol, 1.0 equiv.) in anhydrous DMF (5 ml), CsF (448 mg, 2.95 mmol, 2.2 equiv.) was added under Ar atmosphere, and the solution was stirred for 30 minutes with inert gas bubbling at room temperature. The first solution was merged with the second, and the reaction was stirred at 150 °C. When one of the starting material was consumed (1.5-2 hours) on the basis of TLC monitoring, the reaction mixture was poured on ice and diluted with Et2O. The mixture was filtered on a short pad of Celite®using glass filter. The Celite®was washed three times with Et2O. The two layers were extracted and separated. The aqueous phase was washed three times with Et2O. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography to yield the desired (2S,2'S)-{4,4',5,5'- tetrakis(benzyloxy)-[1,1'-biphenyl]-2,2'-diyl}bis(propane-2,1-diyl) diacetate (see Scheme 17). (2S,2'S)-{4,4',5,5'-tetrakis(benzyloxy)-[1,1'-biphenyl]-2,2'-diyl}bis(propane-2,1-diyl) diacetate [17 on Sheme 17]

[0045] Conventional column chromatography: hexane / EtOAc 4:1. CZ-225-1: 755 mg (yield: 72%) pale yellow oil. Rf = 0.33 and 0.37 (hexane / EtOAc 4:1). 1H NMR (400 MHz, CDCl3) δ = 7.51 – 7.45, 7.45 – 7.40, 7.40 – 7.26 [3m, 40H, (aR), (aS) H-12, H-12', H-13, H-13', H-14, H-14', H-15, H-15', H-16, H-16', H-19, H-19', H-20, H-20', H-21, H-21', H-22, H-22', H-23, H-23'], 6.88, 6.87, 6.71, 6.70 [2 × 2s, 8H, (aR), (aS) H-6, H-6', H-9, H-9'], 5.17, 5.16 – 5.06 [s, m, 2 × 8H, (aR), (aS) H-10, H-10', H-17, H-17'], 4.95 – 4.83 [m, 4H, (aR), (aS) H-2, H-2'], 2.53 [dd, J = 13.8, 7.6 Hz, 2H, (aR) or (aS) H-1-a, H- 1'-a], 2.47 [dd, J = 14.3, 7.7 Hz, 2H, (aR) or (aS) H-1-a, H-1'-a], 2.40 [dd, J = 14.3, 5.9 Hz, 2H, (aR) or (aS) H-1-b, H-1'-b], 2.29 [dd, J = 13.8, 6.4 Hz, 2H, (aR) or (aS) H-1-b, H-1'-b], 1.89, 1.87 (2s, 2 × 6H, (aR), (aS) H-25, H-25'], 0.95, 0.86 [2d, J = 6.2 Hz, J = 6.2 Hz, 2 × 6H, (aR), (aS) H-3, H-3'];13C NMR (100 MHz, CDCl3) δ = 170.4, 170.3 [4C, (aR), (aS) C-24, C-24'], 148.0, 147.9, 147.1, 146.8 [8C, (aR), (aS) C-6, C-7, C-6', C-7'], 137.4, 137.3, 134.0, 129.2, 128.8 [16C, (aR), (aS) C-4, C-11, C-18, C-5, C-4', C-11', C-18', C-5'], 128.6, 128.5, 127.9, 127.8, 127.5 [40C, (aR), (aS) C-12, C-13, C-14, C-15, C-16, C-19, C-20, C-21, C-22, C-23, C-12', C-13', C-14', C-15', C-16', C-19', C- 20', C-21', C-22', C-23'], 117.4, 117.2, 116.4, 116.3 [8C, (aR), (aS) C-6, C-9, C-6', C-9'], 71.5, 71.3, 71.2 [8C, (aR), (aS) C-10, C-17, C-10', C-17'], 71.2, 71.1 [4C, (aR), (aS) C-2, C-2'], 38.7, 38.4 [4C, (aR), (aS) C-1, C-1'], 21.4, 21.3, 19.8 [8C, (aR), (aS) C-3, C-25, C-3', C-25']. IR (KBr): 3032, 2979, 2930, 2349, 2309, 1731, 1603, 1500, 1454, 1371, 1241, 1045, 1014, 736, 696 cm−1. HRMS (ESI) calcd. for C50H50NaO8[M+Na]+801.3398, found 801.3405. 5.2.4. General procedure for deprotecting and ring-closing reaction of tetrakis(benzyloxy)-[1,1'-biphenyl] derivatives Scheme 18: Deprotecting and ring-closing reaction.

[0046] 5.2.4.1. - Deacetylation reaction of (aS / aR,2S,2'S)-{4,4',5,5'-tetrakis(benzyloxy)-[1,1'-biphenyl]-2,2'- diyl}bis(propane-2,1-diyl) diacetate [17 on Scheme 17] To the solution of (aS / aR,2S,2'S)-{4,4',5,5'-tetrakis(benzyloxy)-[1,1'-biphenyl]-2,2'-diyl}bis(propane-2,1- diyl) diacetate (875 mg, 1.12 mmol, 1.0 equiv.) in MeOH (25 ml) LiOH (108 mg, 4.48 mmol, 4.0 equiv.) was added and it was stirred at room temperature for 2 hours. After the starting material was consumed on the basis of TLC monitoring, the solvent was evaporated in vacuo. The residue was dissolved in EtOAc and it was extracted with water and a 6N solution of HCl. The aqueous phase was washed three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. (aS / aR,2S,2'S)-1,1'-{4,4',5,5'-tetrakis(benzyloxy)-[1,1'-biphenyl]-2,2'-diyl}bis(propan-2-ol) [20 on Scheme 18]

[0047] Purification was not required for the crude product. CZ-227: 640 mg (yield: 82%) white solid. Rf = 0.33 (toluene / MeOH 10:1). 1H NMR (360 MHz, CDCl3) δ = 7.50 – 7.24 [m, 40H, (aR), (aS) H-12, H-12', H-13, H-13', H-14, H-14', H- 15, H-15', H-16, H-16', H-19, H-19', H-20, H-20', H-21, H-21', H-22, H-22', H-23, H-23'], 6.85, 6.83, 6.70, 6.63 [4s, 4 × 2H, (aR), (aS) H-6, H-6', H-9, H-9'], 5.25 – 5.02 [m, 2 × 8H, (aR), (aS) H-10, H-10', H-17, H-17'], 3.64 – 3.50 [m, 4H, (aR), (aS), H-2, H-2'], 2.39 – 2.18 [m, 8H, (aR), (aS) H-1, H-1'], 1.45, 1.13 [3s, 2 × 2H, (aR), (aS) 4 × OH], 0.91 [2 × d, J = 6.0 Hz and J = 5.8 Hz, 2 × 6H, (aR), (aS) H-3, H-3'];13C NMR (90 MHz, CDCl3) δ = 148.0, 147.8, 146.8, 146.7 [8C, (aR), (aS) C-6, C-7, C-6', C-7'], 137.4, 137.3, 134.1, 130.0, 129.7 [16C, (aR), (aS) C-4, C-11, C- 18, C-5, C-4', C-11', C-18', C-5'], 128.6, 128.0, 127.9, 127.8, 127.6, 127.4 [40C, (aR), (aS) C-12, C-13, C-14, C-15, C-16, C-19, C-20, C-21, C-22, C-23, C-12', C-13', C-14', C-15', C-16', C-19', C-20', C-21', C-22', C-23'], 117.7, 117.4, 116.9, 116.5 [8C, (aR), (aS) C-6, C-9, C-6', C-9'], 71.5, 71.4, 71.3, 71.1 [8C, (aR), (aS) C-10, C-17, C-10', C-17'] 68.4, 68.1 [4C, (aR), (aS) C-2, C-2'], 42.3 [4C, (aR), (aS) C-1, C-1'], 23.3, 23.0 [4C, (aR), (aS) C-3, C-25, C-3', C- 25']. IR (KBr): 3330, 3028, 2961, 2913, 2349, 2309, 1502, 1453, 1372, 1248, 1210, 1116, 1024, 830, 730, 691, 627 cm−1. HRMS (ESI) calcd. for C46H46NaO6 [M+Na]+717.3187, found 717.3190. 5.2.4.2. - Procedure for debenzylation (hydrogenation) of (aS / aR,2S,2'S)-1,1'-{4,4',5,5'- tetrakis(benzyloxy)-[1,1'-biphenyl]-2,2'-diyl}bis(propan-2-ol) [20 on Scheme 18] Pd / C catalyst (250 mg, 10 w / w%, 0.23 equiv.) was disperged in THF (15 ml) and it was stirred at room temperature for 20 minutes under hydrogen atmosphere. (aS / aR,2S,2'S)-1,1'-{4,4',5,5'-tetrakis(benzyloxy)-[1,1'- biphenyl]-2,2'-diyl}bis(propan-2-ol) (640 mg, 0.92 mmol, 1.0 equiv.) was added to the suspension, and the reaction mixture was stirred further under H2atmosphere at room temperature until the end of hydrogen lessening. After that, the Pd / C catalyst was filtered out from the mixture through a glass filter. The filter was washed three times with THF and the solvent was evaporated in vacuo. The crude product was purified by trituration with CH2Cl2to yield the desired bis-pyrocatechol derivative. (aS / aR)-6,6'-bis[(S)-2-hydroxypropyl]-[1,1'-biphenyl]-3,3',4,4'-tetraol [21 on Scheme 18] CZ-228: 280 mg (yield: 91%) white solid. Rf= 0.32 (CH2Cl2 / MeOH 8.5:1.5). 1H NMR (400 MHz, MeOH-d4) δ = 6.70, 6.69, 6.51, 6.50 [4s, 4 × 2H, (aR), (aS) H-6, H-9, H-6', H-9'], 3.75 – 3.66 [m, 4H, (aR), (aS) H-2, H-2'], 2.53 [dd, J = 13.5, 6.2 Hz, 2H, (aR) or (aS) H-1-a or H-1'-a], 2.48 [dd, J = 13.4, 6.7 Hz, 2H, (aR) or (aS) H-1-a or H-1'-a], 2.30 – 2.17 [m, 2H, (aR) or (aS) H-1-b, H-1'-b], 1.88 – 1.80 [m, 4H, (aR) or (aS) H-1, H-1']), 0.98 [d, J = 6.2 Hz, 2 × 3H, (aR) or (aS) H-3, H-3'], 0.90 (d, J = 6.2 Hz, 2 × 3H, (aR) or (aS) H-3, H-3'];13C NMR (100 MHz, MeOD-d4) δ = 145.0, 144.0, 134.3, 134.2, 129.9, 129.4 [16C, (aR), (aS) C-4, C-5, C-7, C-8, C-4', C-5', C-7', C-8'] 118.8, 118.7, 118.1, 117.6 [8C, (aR), (aS) C-6, C-9, C-6', C-9'], 69.6, 68.9 [4C, (aR), (aS) C-2, C-2'], 43.5, 43.1 [4C, (aR), (aS) C-1, C-1'], 23.1, 23.0 [4C, (aR), (aS) C-3, C-3']. IR (KBr): 3357, 2673, 2359, 1607, 1509, 1451, 1372, 1272, 1233, 1086, 1063, 943, 750, 725, 691 cm−1. HRMS (ESI) calcd. for C18H22NaO6[M+Na]+357.1309, found 357.1304. 5.2.4.3. -6,6’-bis[(2R)-2-hydroxypropyl]biphenyl-3,3’,4,4’-tetrol [23 on Scheme 18] (reference example in Table 1 Compound 55 (reference example) 5.2.4.4. - (aR / aS,3R,3’R)-3,3’-dimethyl-[5,5’-bis-isochroman]-7,7’,8,8’-tetraol [ ≈ 1:1] [25 on Scheme 18] Compound 47 5.2.5. General procedure for Brønsted-acid catalyzed oxa-Pictet-Spengler ring-closing reaction of biaryl derivatives Scheme 19: Brønsted-acid catalyzed oxa-Pictet-Spengler ring-closing reaction of biaryl derivatives. Scheme 20: Brønsted-acid catalyzed oxa-Pictet-Spengler ring-closing reaction 5.2.5.1. - Brønsted-acid catalyzed oxa-Pictet-Spengler reaction of (aS / aR)-6,6'-bis[(S)-2- hydroxypropyl]-[1,1'-biphenyl]-3,3',4,4'-tetraol with 4-fluorobenzaldehyde [21 on Scheme 20]. To the solution of (aS / aR)-6,6'-bis[(S)-2-hydroxypropyl]-[1,1'-biphenyl]-3,3',4,4'-tetraol (200 mg, 0.598 mmol, 1.0 equiv.) in 20 ml MeOH 4-fluorobenzaldehyde (2.1 equiv.), (R)-3,3′-bis[3,5-bis(trifluoromethyl)phenyl]- 1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (10 mg, 0.0129 mmol, 0.0216 equiv.) and (1S)-(+)-10-camphorsulfonic acid (20 mg, 0.0861 mmol, 0.14 equiv.) were added under argon atmosphere. The reaction mixture was stirred in 70 °C oil bath until the starting material and the monocyclized intermediate products were consumed (ca.15-20 heating hours of 48 hours stirring) on the basis of TLC monitoring. During this time, depending on the progress of reaction additional amount of 4-fluorobenzaldeyde (up to 4.0 equiv.) and (1S)-(+)-10-camphorsulfonic acid (up to 1.0 equiv.) can be added. Due to the stereoisomers presence in different ratios, a lower polarity eluent (CH2Cl2 / MeOH 10:0.2- 1.0) can be used for better detection. After that, the reaction concentrated in vacuo. The suspension was diluted with EtOAc and the mixture was extracted with water. The aqueous phase was washed three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the 5,5'-linked bis-isochroman derivative. The (aS) and (aR) atropisomers could be detected by chiral HPLC. (aS / aR,1R,1'R,3S,3'S)-1,1'-bis(4-fluorophenyl)-3,3'-dimethyl-[5,5'-biisochroman]-7,7',8,8'-tetraol [mixture of atropdiastereomers (29 and 30) on Scheme 20] F . . . V TFA). CZ-238 / 4: 58 mg (yield: 18%) brown-beige solid. Rf = 0.70 and 0.78 (CH2Cl2 / MeOH 10:1). −148, (c = 0.23; CH2Cl2). 1H NMR (700 MHz, acetone-d6) δ = 7.41 – 7.34 [m, 2 × 4H, (aR), (aS) H-11, H-15, H-11', H-15'], 7.04 – 7.00 [m, 4H, (aR) H-12, H-14, H-12', H-14'], 7.04 – 6.99 [m, 4H, (aS) H-12, H-14, H-12', H-14'], 6.72 [s, 2H, (aS) H-6, H-6'], 6.63 [s, 2H, (aR) H-6, H-6'], 5.96 [s, 2H, (aR) H-1, H-1'], 5.94 [s, 2H, (aS) H-1, H-1'], 3.73 – 3.67 [m, 4H, (aR), (aS) H-3, H-3'], 2.53 [ddd, J = 15.6, 10.6, 1.4 Hz, 2H, (aR) H-4ax, H-4'ax], 2.47 [ddd, J = 15.8, 10.8, 1.4 Hz, 2H, (aS) H-4ax, H-4'ax), 2.37 [ddd, J = 15.5, 2.1, 1.0 Hz, 2H, (aR) H-4eq, H-4'eq], 2.20 [ddd, J = 15.8, 2.2, 1.1 Hz, 2H, (aS) H- 4eq, H-4'eq], 1.20 [d, J = 6.1 Hz, 6H, (aR) H-9, H-9'], 1.17 [d, J = 6.1 Hz, 6H, (aS) H-9, H-9'];13C NMR (175 MHz, acetone-d6) δ = 162.7 [d, JC-F = 242.5 Hz, 2 × 2C, (aR), (aS) C-13, C-13'], 142.9, 141.8 [4C, (aR) C-7, C-8, C-7', C- 8'], 142.7, 141.8 [4C, (aS) C-7, C-8, C-7', C-8'], 141.3 [d, JC-F= 2.9 Hz, 2C, (aR) C-10, C-10', JC-F= 2.9 Hz, 2C, (aS) C-10, C-10'], 131.9 [2C, (aR) C-5, C-5'], 131.5 [2C, (aS) C-5, C-5'], 131.1 [d, JC-F = 7.6 Hz, 2 × 4C, (aR), (aS) C-11, C-15, C-11', C-15'], 127.0 [2C, (aR) C-4a, C-4a'], 126.1 [2C, (aS) C-4a, C-4a'], 125.5 [2C, (aS) C-8a, C-8a'], 125.3 [2C, (aR) C-8a, C-8a'], 116.8 [2C, (aS) C-6, C-6'], 115.8 [2C, (aR) C-6, C-6'], 115.0 [d, JC-F= 21.4 Hz, 4C, (aR) C- 12, C-14, C-12', C-14', d, JC-F = 21.4 Hz, 4C, (aS) C-12, C-14, C-12', C-14'], 77.4 [2C, (aS) C-1, C-1'], 77.2 [2C, (aR) C-1, C-1'], 71.2 [2C, (aS) C-3, C-3'], 71.1 [2C, (aR) C-3, C-3'], 36.8 [2C, (aS) C-4, C-4'], 35.8 [2C, (aR) C-4, C-4'], 22.1 [2C, (aS) C-9, C-9'], 22.0 [2C, (aR) C-9, C-9']. IR (KBr): 3275, 2972, 2930, 2349, 2309, 1688, 1603, 1507, 1474, 1275, 1218, 1155, 1040, 947, 826, 794, 751 cm−1. HRMS (ESI) calcd. for C32H28F2NaO6[M+Na]+569.1746, found 569.1741. 5.2.5.2. - (aS,1S,3R,1’S,3’R)-1,1’-bis(4-fluorophenyl)-3,3’-dimethyl-[5,5’-bis-isochroman]-7,7’,8,8’- tetraol [aS,1S,1’S,3R,3’R)-27 on Scheme 19] tetraol [aR,1S, 1’S,3R,3’R-28 on Scheme 19] fluorophenyl)-3,3’-dimethyl-[5,5’-bis-isochroman]-7,7’,8,8’- tetraol [aS,1R, 1’R,3S,3’S-29 on Scheme 20]

[0048] Compound 50 5.2.5.5. - (aR,1R,3S,1’R,3’S)-1,1’-bis(4-fluorophenyl)-3,3’-dimethyl-[5,5’-bis-isochroman]-7,7’,8,8’- tetraol Scheme 20] ompound 51 5.2.6. Procedure for Miyaura borylation, Suzuki biaryl coupling reaction and deacetylation with 3,4-dimethoxy substitution Scheme 21: Miyaura borylation, Suzuki biaryl coupling reaction and deacetylation with 3,4-dimethoxy substitution. i) anhydrous DMF, 1. PPh3, 2. (PPh3)2PdCl2, 3. anhydrous NaOAc, 4. B2Pin2[Bis(pinacolato)diborone], 150°C; ii) anhydrous DMF, rt, 120°C, SPhos, Pd(OAc)2, CsF. 5.2.6.1. - (aS,3R,3’R)-1,1’-7,7’,8,8’–tetramethoxy-3,3’-dimethyl-[5,5’-bis-isochroman] [37 on Scheme 21] Compound 52 5.2.6.2. - (aR,3R,3’R)-1,1’-7,7’,8,8’–tetramethoxy-3,3’-dimethyl-[5,5’-bis-isochroman] [38 on Scheme 21] Compound 53 EXAMPLE 6: Synthesis of stereoisomeric isochroman-tetrahydroisoquinoline heterodimers 6.1. Syntheses and characterization of the compounds 6.1.1. General procedure for oxa-Pictet-Spengler reactions of chiral non-racemic 1-arylpropan-2-ol derivatives The 1-arylpropan-2-ol derivative MK-90 (on Scheme 22) (1.0 equiv.) was dissolved in anhydrous Et2O (5 ml) or anhydrous toluene (3 ml), and dimethoxymethane (15.0 equiv.) or ethyl-3,3-diethoxypropionate (90%, technical grade, 2.0 equiv.) was added to the solution. The solution was cooled to 0 °C and BF3.Et2O (0.3-0.6 equiv.) was added. The reaction mixture was allowed to warm up to room temperature. When the starting material was consumed (3-24 hours) on the basis of TLC monitoring, the reaction was quenched with a saturated solution of NaHCO3and stirred for 10 minutes. EtOAc was added to the mixture and the layers were separated. The organic layer was extracted twice with a saturated solution of NaHCO3 and once with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the chiral non-racemic N-Cbz protected biaryl isochroman-tetrahydroisoquinoline heterodimer target derivatives. (See Scheme 22, R1= H or -CH2COOEt, R2= Cbz) Scheme 22 MK-90 6.1.2. - The mixture of (aS,1R,3S)-benzyl 5-[(3’S)-7’,8’-dimethoxy-3’-methylisochroman-5’-yl]-1-(4- fluorophenyl)-6,7,8-trimethoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate and (aR,1R,3S)-benzyl 5- [(3’S)-7’,8’-dimethoxy-3’-methylisochroman-5’-yl]-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methyl-3,4-

[0049] [(aS,1R,3S,3’S) isomer of Compound 20] [(aR,1R,3S,3’S) isomer of Compound 20] Starting from the mixture of (aS,1R,3S,2’S) isomer and (aR,1R,3S,2’S) isomer of MK-90 (131 mg, 0.20 mmol, 1.0 equiv.): anhydrous Et2O (5 ml), dimethoxymethane (263 µl, 226 mg, 2.97 mmol, 15.0 equiv.), BF3.Et2O (17 µl, 15 mg, 0.12 mmol, 0.6 equiv.), reaction time: 24 hours. the mixture of (aS,1R,3S,3’S) isomer and (aR,1R,3S,3’S) isomer of MK-94 (Compound 20): 129 mg (yield: 97%) white amorphous solid foam; dr = 83:17. Flash chromatography (hexanes / EtOAc 85:15 → 8:2 → 75:25 → 7:3); Rf = 0.27 (hexanes / EtOAc 8:2);1H NMR (400 MHz, 318 K, CDCl3) δ = 7.45 – 7.25 [m, 2 × 5H, (aS), (aR) H-22, H-23, H-24, H-25, H-26], 7.21 – 7.07 [m, 2 × 2H, (aS), (aR) H-14, H-18], 6.99 – 6.89 [m, 2 × 3H, (aS), (aR) H-1, H-15, H-17], 6.64, 6.50 [2s, 2 × 1H, (aS), (aR) H-6’], 5.26, 5.25 [q, J = 12.6 Hz, 2H, q, J = 12.4 Hz, 2H, (aS), (aR) H-20], 5.04, 4.98 [d, J = 15.8 Hz, 1H, d, J = 15.8 Hz, 1H, (aS), (aR) H-1’-a], 4.74, 4.73 [d, J = 15.8 Hz, 1H, d, J = 15.9 Hz, 1H, (aS), (aR) H-1’-b], 3.98, 3.97, 3.87, 3.86, 3.81, 3.77, 3.67, 3.63 [8s, 10 × 3H, (aS), (aR), H-9, H-10, H-11, H-9’, H-10’], 3.79 – 3.73, 3.68 – 3.62 [2m, 4 × 1H, (aS), (aR), H-3, H-3’], 2.42 – 2.27, 2.22 – 2.10, 2.04 – 1.88 [3m, 8 × 1H, (aS), (aR), H-4ax, H-4eq, H-4’ax, H-4’eq], 1.24, 1.21, 1.14, 1.10 [d, J = 6.1 Hz, 3H, d, J = 6.2 Hz, 3H, d, J = 5.6 Hz, 3H, d, J = 5.9 Hz, 3H (aS), (aR) H-12, H-11’];13C NMR (100 MHz, 318 K, CDCl3) δ = 162.0 [d, JC-F = 245.5 Hz, 1C, (aS), C-16], 151.5, 149.7, 149.5, 144.4, 144.1, 136.8, 131.0, 130.9, 130.6, 129.6, 128.7, 126.4, 126.2, 126.0 [26C, (aS), (aR), C-4a, C-5, C-6, C-7, C-8, C-8a, C-19, C-21, C-4a’, C-5’, C-7’, C-8’, C-8a’], 137.2 [d, JC-F= 2.7 Hz, (aS) C-13], 128.5, 128.4, 128.1, 128.0 [14C, (aS), (aR), C-14, C-18, C-22, C-23, C-24, C-25, C-26], 115.1 [2d, JC-F = 21.4 Hz, 4C, (aS), (aR) C-15, C-17], 113.8, 112.7 [2C, (aS), (aR) C-6’], 70.6, 70.5, 61.4, 61.3, 61.0, 61.0, 60.2, 56.2, 56.0, 52.6, 52.4, 50.2 [16C, (aS), (aR) C-1, C-3, C-9, C-10, C-11, C-3’, C-9’, C-10’], 67.5, 65.0, 64.7 [4C, (aS), (aR) C-20, C-1’], 33.6, 32.6 [4C, (aS), (aR) C-4, C-4’], 21.5 [4C, (aS), (aR) C-12, C-11’]; ESI-TOF-HRMS: m / z calculated for C39H43FNO8[M+H]+672.2967, found 672.2963. 6.1.3. - The mixture of (aS,1R,3S)-benzyl 5-[(1’R,3’S)-1’-(2-ethoxy-2-oxoethyl)-7’,8’-dimethoxy-3’- methylisochroman-5’-yl]-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)- carboxylate and (aR,1R,3S)-benzyl 5-[(1’R,3’S)-1’-(2-ethoxy-2-oxoethyl)-7’,8’-dimethoxy-3’- methylisochroman-5’-yl]-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)- carboxylate [the mixture of (aS,1R,3S,1’R,3’S) isomer (MK-102 / F) (Compound 22 / I) and (aR,1R,3S,1’R,3’S) isomer (MK-102 / K) (Compound 22 / II)]

[0050] Compound 22 / I Compound 22 / II Starting from the mixture of (aS,1R,3S,2’S) isomer and (aR,1R,3S,2’S) isomer of MK-90 (138 mg, 0.21 mmol, 1.0 equiv.): anhydrous PhMe (3 ml), ethyl-3,3-diethoxypropionate (90%, technical grade, 90 µl = 81 µl, 79 mg, 0.42 mmol, 2.0 equiv.), BF3.Et2O (8 µl, 9 mg, 0.06 mmol, 0.3 equiv.), reaction time: 3 hours. (aS,1R,3S,1’R,3’S) isomer MK-102 / F (Compound 22 / I): 97 mg (yield: 61%) off-white amorphous solid foam; the mixture of (aS,1R,3S,1’R,3’S) isomer (Compound 22 / I) and (aR,1R,3S,1’R,3’S) isomer (Compound 22 / II) MK-102 / K: 53 mg (yield: 34%) off-white amorphous solid foam. Flash chromatography (hexanes / EtOAc 85:15 → 8:2 → 6:4). (aS,1R,3S,1’R,3’S) isomer MK-102 / F (Compound 22 / I): Rf= 0.35 (hexanes / EtOAc 75:25); [α]^^^: +46 (c = 0.47; CHCl3);1H NMR (500 MHz, 318 K, CDCl3) δ = 7.43 – 7.27 (m, 5H, H-22, H-23, H-24, H-25, H-26), 7.20 – 7.12 (m, 2H, H-14, H-18), 7.00 – 6.92 (m, 2H, H-15, H-17), 6.90, 6.51 (bs, 1H, s, 1H, H-1, H-6’), 5.41 (dd, J = 7.9, 2.7 Hz, 1H, H-1’), 5.24 (q, J = 12.3 Hz, 2H, H-20’), 4.17 (q, J = 7.1 Hz, 2H, H-14’), 3.96, 3.87, 3.77, 3.61 (4s, 5 × 3H, H-9, H-10, H-11, H-9’, H-10’), 3.76 – 3.67, 3.59 – 3.51 (2m, 2 × 1H, H-3, H-3’), 3.23 (dd, J = 15.1, 3.2 Hz, 1H, or H-4’ax), 2.28 (dd, J = 15.4, 11.8 Hz, 1H, H-4ax H-12’, H-11’);13C NMR (125 MHz, CDCl3) δ = 171.8 (1C, C-13’), 162.1 (d, JC-F = 245.4 Hz, 1C, C-16), 151.7, 150.1, 149.6, 145.0, 144.5, 137.2, 136.8, 130.5, 130.3, 129.6, 128.7, 128.6 (13C, C-4a, C-5, C-6, C-7, C-8, C-8a, C-19, C-21, C-4a’, C-5’, C-7’, C-8’, C-8a’), 128.5 (d, JC-F= 7.5 Hz, 2C, C-14, C-18), 128.1, 128.0, 126.4 (5C, C-22, C-23, C-24, C-25, C-26), 115.2 (d, JC-F= 21.3 Hz, 2C, C-15, C-17), 114.2 (1C, C-6’), 71.6, 70.0, 61.4, 61.1, 61.0, 60.3, 56.2, 52.7 (9C, C-1, C-3, C- 9, C-10, C-11, C-1’, C-3’, C-9’, C-10’), 67.6, 60.2 (2C, C-4, C-4’, C-12’),42.2, 34.7, 32.7 (3C, C-4, C-4’, C-12’), 21.7, 14.4 (3C, C-12, C-11’, C-15’); ESI-TOF-HRMS: m / z calculated for C43H49FNO10 [M+H]+758.3335, found 758.3330. The mixture of (aS,1R,3S,1’R,3’S) isomer and (aR,1R,3S,1’R,3’S) isomer MK-102 / K: Rf= 0.35 and 0.28 (hexanes / EtOAc 75:25); ESI-TOF-HRMS: m / z calculated for C43H48FNNaO10[M+Na]+780.3154, found 780.3152. 6.1.4. - General procedure for catalytic hydrogenation of isochroman-tetrahydroisoquinoline heterodimers Pd / C catalyst (10 w / w%, 0.20 equiv.) was disperged in THF (12-18 ml) under Ar atmosphere and it was stirred at room temperature for 30 minutes under hydrogen atmosphere. The corresponding N-Cbz protected biaryl derivative (1.0 equiv.) was added to the suspension, and the reaction mixture was stirred further under H2atmosphere at room temperature until the starting material was consumed (3-4 hours) on the basis of TLC monitoring. After that, the mixture was filtered through a short pad of Celite®. The Celite®was washed with THF, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography to yield the isochroman-tetrahydroisoquinoline heterodimer target derivatives. 6.1.5. - (aS)-(1R,3S)-5-[(3’S)-7’,8’-dimethoxy-3’-methylisochroman-5’-yl]-1-(4-fluorophenyl)-6,7,8- trimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline [(aS,1R,3S,1’R,3’S) isomer] MK-101 / F (Compound 21 / I) and (aR)-(1R,3S)-5-[(3S)-7’,8’-dimethoxy-3’-methylisochroman-5’-yl]-1-(4-fluorophenyl)-6,7,8-trimethoxy-3- methyl-1,2,3,4-tetrahydroisoquinoline and [(aR,1R,3S,1’R,3’S) isomer] MK-101 / A (Compound 21 / II) Compound 21 / I Compound 21 / II Starting from (S) isomer of MK-94 (60 mg, 0.09 mmol, 1.0 equiv.): THF (13 ml), Pd / C (10 w , 19 mg, 0.18 mmol, 0.20 equiv.), reaction time: 4 hours. (aS,1R,3S,3’S) isomer MK-101 / F (Compound 21 / I): 32 mg (yield: 67%) off-white amorphous solid foam; (aR,1R,3S,3’S) isomer MK-101 / A (Compound 21 / II): 7 mg (yield: 14%) off- white amorphous solid foam; the mixture of (aS,1R,3S,3’S) isomer and (aR,1R,3S,3’S) isomer MK-101 / K: 9 mg (yield: 19%, dr aS:aR = 4:6) off-white amorphous solid foam. Flash chromatography (CH2Cl2 / MeOH 100:1 → 100:3). (aS,1R,3S,3’S) isomer MK-101 / F (Compound 21 / I): Rf= 0.29 (CH2Cl2 / MeOH 100:3); [α]^^^: −30 (c = 0.41; CHCl3);1H NMR (500 MHz, CDCl3) δ = 7.34 – 7.29 (m, 2H, H-14, H-18), 7.06 – 7.00 (m, 2H, H-15, H-17), 6.67 (s, 1H, H-6’), 5.26 (s, 1H, H-1), 5.08 (d, J = 15.7 Hz, 1H, H-1’ax), 4.79 (d, J = 15.7 Hz, 1H, H-1’eq), 3.91 (s, 3H, H-10’), 3.88 (s, 3H, H-9’), 3.80 (s, 3H, H-10), 3.72 – 3.61 (m, 1H, H-3’), 3.58 (s, 3H, H-9), 3.15 (s, 3H, H-11), 2.93 – 2.85 (m, 1H, H-3), 2.41 (dd, J = 16.4, 10.8 Hz, 1H, H-4’ax), 2.23 (ddd, J = 16.2, 10.8, 1.1 Hz, 1H, H-4ax), 2.04 (ddd, J = 16.2, 2.9, 1.0 Hz, 1H, H-4eq); 2.00 (ddd, J = 16.4, 3.1, 0.8 Hz, 1H, H-4’eq), 1.75 (s, 1H, NH), 1.27 (d, J = 6.1 Hz, 3H, H-11’), 1.11 (d, J = 6.3 Hz, 3H, H-12);13C NMR (125 MHz, CDCl3) δ = 161.8 (d, JC-F = 244.2 Hz, 1C, C-16), 150.7 (1C, C-6), 150.5 (1C, C-8), 149.8 (1C, C-7’), 144.5 (1C, C-7), 143.7 (1C, C-8’), 143.1 (1C, C-13), 131.8 (1C, C-5’), 130.7 (1C, C-4a), 129.5 (d, JC-F = 7.8 Hz, 2C, C-14, C-18), 128.6 (1C, C-8a’), 128.5 (1C, C-5), 127.4 (1C, C-8a), 125.8 (1C, C-4a’), 115.2 (d, JC-F = 21.2 Hz, 2C, C-15, C-17), 113.0 (1C, C-6’), 70.8 (1C, C-3’), 65.0 (1C, C-1’), 61.0 (1C, C-9), 60.6 (1C, C-10), 60.3 (1C, C-10’), 59.7 (1C, C-1), 59.3 (1C, C-11), 56.1 (1C, C-9’), 49.3 (1C, C-3), 37.6 (1C, C-4), 33.6 (1C, C-4’), 22.4 (1C, C-12), 21.7 (1C, C-11’); ESI-TOF-HRMS: m / z calculated for C31H37FNO6[M+H]+538.2599, found 538.2591. (aR,1R,3S,3’S) isomer MK-101 / A (Compound 21 / II): Rf= 0.24 (CH2Cl2 / MeOH 100:3); [α]^^^: −33 (c = 0.45; CHCl3);1H NMR (500 MHz, CDCl3) δ = 7.25 – 7.19 (m, 2H, H-14, H-18), 7.04 – 6.98 (m, 2H, H-15, H-17), 6.60 (s, 1H, H-6’), 5.26 (s, 1H, H-1), 5.08 (d, J = 15.7 Hz, 1H, H-1’ax), 4.79 (d, J = 15.7 Hz, 1H, H-1’eq), 3.89 (s, 3H, H-10’), 3.84 (s, 3H, H-9’), 3.81 (s, 3H, H-10), 3.75 – 3.68 (m, 1H, H-3’), 3.60 (s, 3H, H-9), 3.16 (s, 3H, H-11), 2.95 – 2.87 (m, 1H, H-3), 2.34 – 2.26 (m, 3H, H-4eq, H-4’ax, H-4’eq), 2.06 (dd, J = 15.6, 10.8 Hz, 1H, H-4ax), 1.31 (d, J = 6.1 Hz, 3H, H-11’), 1.08 (d, J = 6.2 Hz, 3H, H-12);13C NMR (125 MHz, CDCl3) δ = 161.9 (d, JC-F = 244.2 Hz, 1C, C-16), 150.4 (1C, C-8), 150.1 (1C, C-6), 150.0 (1C, C-7’), 144.6 (1C, C-7), 143.8 (1C, C-8’), 142.9 (1C, C-13), 131.8 (1C, C-5’), 131.6 (1C, C-4a), 129.4 (d, JC-F= 7.5 Hz, 2C, C-14, C-18), 128.8 (2C, C-8a, C-8a’), 127.5 (1C, C-5), 125.6 (1C, C-4a’), 115.3 (d, JC-F= 21.3 Hz, 2C, C-15, C-17), 112.7 (1C, C-6’), 70.7 (1C, C-3’), 65.1 (1C, C-1’), 60.9 (1C, C-9), 60.7 (1C, C-10), 60.3 (1C, C-10’), 59.3 (2C, C-1, C-11), 56.0 (1C, C-9’), 49.0 (1C, C-3), 36.2 (1C, C-4), 33.6 (1C, C-4’), 22.3 (1C, C-12), 21.8 (1C, C-11’); ESI-TOF-HRMS: m / z calculated for C31H37FNO6 [M+H]+538.2599, found 538.2594. 6.1.6. - (aS)-ethyl 2’-{(1’R,3’S)-5’-[(1R,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methyl-1,2,3,4- tetrahydroisoquinolin-5-yl]-7’,8’-dimethoxy-3’-methylisochroman-1’-yl}acetate (aS,1R,3S,1’R,3’S) isomer MK-107 (Compound 23) (Compound 23 / I) Starting from (aS,1R,3S,1’R,3’S) isomer MK-102 / F (70 mg, 0.09 mmol, 1.0 equiv.): THF (18 ml), Pd / C (10 w / w%, 20 mg, 0.02 mmol, 0.20 equiv.), reaction time: 3 hours. (aS,1R,3S,1’R,3’S) isomer MK-107 (Compound 23 / I): 50 mg (yield: 88%) off-white amorphous solid foam. Flash chromatography (CH2Cl2 / MeOH 100:1 → 100:2). (aS,1R,3S,1’R,3’S) isomer MK-107 (Compound 23 / I): Rf= 0.35 (CH2Cl2 / MeOH 100:3); [α]^^^: −34 (c = 0.47; CHCl3);1H NMR (500 MHz, CDCl3) δ = 7.33 – 7.28 (m, 2H, H-14, H-18), 7.05 – 6.98 (m, 2H, H-15, H-17), 6.68 (s, 1H, H-6’), 5.44 (dd, J = 8.3, 3.0 Hz, 1H, H-1’), 5.24 (s, 1H, H-1), 4.19 (qd, J = 7.1, 1.9 Hz, 1H, H-14’), 3.91 (s, 3H, H-10’), 3.86 (s, 3H, H-9’), 3.79 (s, 3H, H-10), 3.62 – 3.52 (m, 1H, H-3’), 3.54 (s, 3H, H-9), 3.28 (dd, J = 15.1, 3.3 Hz, 1H, H-12’-a), 3.13 (s, 3H, H-11), 2.90 – 2.82 (m, 1H, H-3), 2.63 (dd, J = 15.1, 8.4 Hz, 1H, H-12’-b), 2.40 (dd, J = 15.9, 11.0 Hz, 1H, H-4’ax), 2.23 (dd, J = 16.1, 10.9 Hz, 1H, H-4ax), 1.96 (dd, J = 16.2, 2.5 Hz, 1H, H-4eq), 1.96 – 1.88 (m, 1H, H-4’eq), 1.57 (s, 1H, NH), 1.28 (t, J = 7.1 Hz, 3H, H-15’), 1.19 (d, J = 6.1 Hz, 3H, H-11’), 1.10 (d, J = 6.3 Hz, 3H, H-12);13C NMR (125 MHz, CDCl3) δ = 172.1 (1C, C-13’), 161.8 (d, JC-F = 244.3 Hz, 1C, C-16), 150.8 (1C, C-6), 150.5 (1C, C-8), 150.1 (1C, C-7’), 144.5 (2C, C-8’, C-7), 143.1 (1C, C-13), 131.2 (1C, C-5’), 130.7 (1C, C-4a), 130.3 (1C, C-8a’), 129.5 (d, JC-F = 7.6 Hz, 2C, C-14, C-18), 128.6 (1C, C-5), 127.6 (1C, C-4a’), 127.4 (1C, C-8a), 115.2 (d, JC-F = 21.2 Hz, 2C, C-15, C-17), 113.4 (1C, C-6’), 71.7 (1C, C-1’), 70.0 (1C, C-3’), 60.9 (1C, C-9), 60.7 (1C, C-10), 60.4 (1C, C-10’), 60.3 (1C, C-14’), 59.7 (1C, C-1), 59.3 (1C, C-11), 56.1 (1C, C-9’), 49.2 (1C, C- 3), 42.2 (1C, C-12’), 37.8 (1C, C-4), 34.6 (1C, C-4’), 22.4 (1C, C-12), 21.7 (1C, C-11’), 14.4 (1C, C-15’); ESI-TOF- HRMS: m / z calculated for C35H43FNO8 [M+H]+624.2967, found 624.2967. 6.1.7. - (aS)-ethyl 2’-{(1’R,3’S)-5’-[(1R,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methyl-1,2,3,4- tetrahydroisoquinolin-5-yl]-7’,8’-dimethoxy-3’-methylisochroman-1’-yl}acetate (aS,1R,3S,1’R,3’S) isomer MK-113 / F = MK-107 and (aR)-ethyl 2’-{(1’R,3’S)-5’-[(1R,3S)-1-(4-fluorophenyl)-6,7,8-trimethoxy-3-methyl- 1,2,3,4-tetrahydroisoquinolin-5-yl]-7’,8’-dimethoxy-3’-methylisochroman-1’-yl}acetate (aR,1R,3S,1’R,3’S) isomer MK-113 / A Compound 23 / I Compound 23 / II Starting from the mixture of (aS,1R,3S,1’R,3’S) isomer and (aR,1R,3S,1’R,3’S) isomer MK-102 / K (42 mg, 0.06 mmol, 1.0 equiv.): THF (12 ml), Pd / C (10 w / w%, 12 mg, 0.11 mmol, 0.20 equiv.), reaction time: 4 hours. (aS,1R,3S,1’R,3’S) isomer MK-113 / F (Compound 23 / I): 11 mg (yield: 32%) off-white amorphous solid foam; (aR,1R,3S,1’R,3’S) isomer MK-113 / A (Compound 23 / II): 14 mg (yield: 40%) off-white amorphous solid foam; the mixture of (aS,1R,3S,1’R,3’S) isomer and (aR,1R,3S,1’R,3’S) isomer MK-113 / K: 5 mg (yield: 14%, dr aS:aR = 34:66) off-white amorphous solid foam. Flash chromatography (hexanes / THF 8:2 → 75:25 → 1:1), then (CH2Cl2 / MeOH 100:1 → 100:2) to remove BHT (stabilizator of THF). (aS,1R,3S,1’R,3’S)-xx MK-113 / F = MK-107 (Compound 23 / I): Rf= 0.54 (hexanes / THF 1:1). Characterization is disclosed elsewhere. (aR,1R,3S,1’R,3’S)-xx MK-113 / A (Compound 23 / II): Rf= 0.44 (hexanes / THF 1:1); [α]^^^: −12 (c = 0.52; CHCl3);1H NMR (500 MHz, CDCl3) δ = 7.25 – 7.19 (m, 2H, H-14, H-18), 7.04 – 6.98 (m, 2H, H-15, H-17), 6.64 (s, 1H, H-6’), 5.44 (dd, J = 8.0, 3.1 Hz, 1H, H-1’), 5.28 (s, 1H, H-1), 4.18 (q, J = 7.1 Hz, 1H, H-14’), 3.90 (s, 3H, H- 10’), 3.84 (s, 3H, H-9’), 3.81 (s, 3H, H-10), 3.68 – 3.61 (m, 1H, H-3’), 3.57 (s, 3H, H-9), 3.29 (dd, J = 15.2, 3.3 Hz, 1H, H-12’-a), 3.17 (s, 3H, H-11), 2.94 – 2.87 (m, 1H, H-3), 2.66 (dd, J = 15.2, 8.1 Hz, 1H, H-12’-b), 2.34 (dd, J = 15.2, 10.6 Hz, 1H, H-4’ax), 2.28 (dd, J = 16.2, 2.4 Hz, 1H, H-4eq), 2.22 (dd, J = 15.5, 1.3 Hz, 1H, H-4’eq), 2.10 (dd, J = 16.3, 11.1 Hz, 1H, H-4ax), 1.27 (t, J = 7.2 Hz, 3H, H-15’), 1.26 (d, J = 5.9 Hz, 3H, H-11’), 1.09 (d, J = 6.3 Hz, 3H, H-12);13C NMR (125 MHz, CDCl3) δ = 171.9 (1C, C-13’), 161.9 (d, JC-F= 245.0 Hz, 1C, C-16), 150.4 (1C, C-8), 150.3 (1C, C-7’), 150.1 (1C, C-6), 144.6 (2C, C-7, C-8’), 142.8 (1C, C-13), 131.8 (1C, C-4a), 131.2 (1C, C-5’), 130.5 (1C, C-8a’), 129.4 (d, JC-F = 7.5 Hz, 2C, C-14, C-18), 128.8 (1C, C-5), 127.4 (2C, C-8a, C-4a’), 115.3 (d, JC-F = 21.3 Hz, 2C, C-15, C-17), 113.0 (1C, C-6’), 71.7 (1C, C-1’), 69.9 (1C, C-3’), 60.7 (2C, C-9, C-10), 60.4 (1C, C-10’), 60.3 (1C, C-14’), 59.3 (1C, C-11), 59.1 (1C, C-1), 56.0 (1C, C-9’), 49.0 (1C, C-3), 42.1 (1C, C-12’), 36.1 (1C, C-4), 34.5 (1C, C-4’), 22.2 (1C, C-12), 21.7 (1C, C-11’), 14.5 (1C, C-15’); IR; ESI-TOF-HRMS: m / z calculated for C35H43FNO8 [M+H]+624.2967, found 624.2964. EXAMPLE 7: Antimicrobial activity Some compounds were evaluated for their antibacterial activities toward six indicator strains Staphyloccocus aureus ATCC 29213, Bacillus subtilis 1064, Methicillin-resistant Staphylococcus aureus MRSA ATCC 43300 and Micrococcus luteus SCSIO ML01, Ciprofloxacin was used as a positive control. Later, the antimicrobial activity of further bis-isochroman compounds were also evaluated. Thus, in total 43 compounds were tested. The evaluated compounds are shown in Table 1. Table 1. Axially chiral bis-isochroman samples for antibacterial studies

[0051]

[0052]

[0053] Table 1a. Additional axially chiral bis-isochromans

[0054] 4.1 Determining antimicrobial activity The efficacy of the prepared compounds was determined using the broth microdilution method in accordance with the reccommendation of European Committee on Antimicrobial Susceptibility Testing (EUCAST) (1). EUCAST recommends testing according to the International Standard ISO 20776-1 (EUCAST reading guide for broth microdilution Version 5.0 January 2024 https: / / www.eucast.org / ast_of_bacteria / mic_determination). Briefly, the Minimal Inhibitory Concentrations (MICs) of the compounds were measured against four Gram- positive and one Gram-negative bacterial strain (Bacillus subtilis ATCC6633, Methicillin sensitive Staphylococcus aureus (MSSA) ATCC29213, Methicillin resistant Staphylococcus aureus (MRSA) ATCC 33591, Enterococcus faecalis ATCC51299 and Acinetobacter baumannii ATCC BAA1605). Bacterial strains were grown on Mueller- Hinton (MH) agar plates at 35 °C overnight. Appropriate numbers of colonies were suspended in physiological saline to reach the density of 0.5 McFarland for inoculation. The given preparations of the compounds were two-fold serially diluted from 64 to 0.125 μg / mL in MH broth, and then 100 μL of each dilution was transferred into microplate holes. Inoculation was carried out with 10 μL of each bacterial suspension. Incubation was performed at 35.5 °C for 18 h, and the determination of the MIC was made with the naked eye. Antimicrobial activity with further strains of bacteria and of further bis-isochroman compounds were also determined. Results are shown in Table 2. Table 2. Antibacterial activity of bis-isochromans

[0055] REFERENCES Bara, R., I. Zerfass, A. H. Aly, H. Goldbach-Gecke, V. Raghavan, P. Sass, A. Mándi, V. Wray, P. L. Polavarapu, A. Pretsch, W. Lin, T. Kurtán, A. Debbab, H. Brötz-Oesterhelt and P. Proksch, Atropisomeric Dihydroanthracenones as Inhibitors of Multiresistant Staphylococcus aureus, J. Med. Chem., 2013, 56, 3257-3272. Bianco, A., F. Coccioli, M. Guiso and C. Marra, The occurrence in olive oil of a new class of phenolic compounds: hydroxy-isochromans, Food Chem., 2002, 77, 405-411. Chai, J-D. and Head-Gordon, M., Systematic optimization of long-range corrected hybrid density functionals, J. Chem. Phys., 2008, 128, 084106, https: / / doi.org / 10.1063 / 1.2834918. Clayden, J., W. J. Moran, P. J. Edwards and S. R. LaPlante, The Challenge of Atropisomerism in Drug Discovery, Angew. Chem., Int. Ed., 2009, 48, 6398-6401. Csupor, D., T. Kurtán, M. Vollár, N. Kúsz, K. E. Kövér, A. Mándi, P. Szűcs, M. Marschall, S. A. Senobar Tahaei, I. Zupkó and J. Hohmann, Pigments of the Moss Paraleucobryum longifolium: Isolation and Structure Elucidation of Prenyl-Substituted 8,8′-Linked 9,10-Phenanthrenequinone Dimers, J. Nat. Prod., 2020, 83, 268-276. EUCAST. MIC determination of non-fastidious and fastidious organisms - EUCAST reading guide for broth microdilution Version 5.0 January 2024; https: / / www.eucast.org / ast_of_bacteria / mic_determination Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, V., Barone, G., Mennucci, B., Petersson, G. A., et al. Gaussian 09 (Revisions C.01); Gaussian, Inc.: Wallingford, CT, USA, 2010. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, V.; Barone, G.; Mennucci, B.; Petersson, G. A., et al. Gaussian 09 Revisions E.01; Gaussian, Inc.: Wallingford, CT, USA, 2013. González-Liste, P. J., F. León, I. Arribas, M. Rubio, S. E. García-Garrido, V. Cadierno and A. Pizzano, Highly Stereoselective Synthesis and Hydrogenation of (Z)-1-Alkyl-2-arylvinyl Acetates: a Wide Scope Procedure for the Preparation of Chiral Homobenzylic Esters, ACS Catal., 2016, 6, 3056-3060. He, G., H. Matsuura, T. Takushi, S. Kawano and T. Yoshihara, A New Antifungal Metabolite from Penicillium expansum, J. Nat. Prod., 2004, 67, 1084-1087. Inoue, K., Y. Makino and N. Itoh, Production of (R)-chiral alcohols by a hydrogen-transfer bioreduction with NADH- dependent Leifsonia alcohol dehydrogenase (LSADH), Tetrahedron: Asymmetry, 2005, 16, 2539-2549. Kerti, G., T. Kurtán, T.-Z. Illyés, K. E. Kövér, S. Sólyom, G. Pescitelli, N. Fujioka, N. Berova and S. Antus, Enantioselective Synthesis of 3-Methylisochromans and Determination of Their Absolute Configurations by Circular Dichroism, Eur. J. Org. Chem., 2007, 296-305. Kock, I., S. Draeger, B. Schulz, B. Elsässer, T. Kurtán, Á. Kenéz, S. Antus, G. Pescitelli, P. Salvadori, J.-B. Speakman, J. Rheinheimer and K. Krohn, Pseudoanguillosporin A and B: Two New Isochromans Isolated from the Endophytic Fungus Pseudoanguillospora sp., Eur. J. Org. Chem., 2009, 1427-1434. Li, W., C. Lee, S. H. Bang, J. Y. Ma, S. Kim, Y.-S. Koh and S. H. Shim, Isochromans and Related Constituents from the Endophytic Fungus Annulohypoxylon truncatum of Zizania caduciflora and Their Anti-Inflammatory Effects, J. Nat. Prod., 2017, 80, 205-209. Li, X. L., T. Kurtán, J. C. Hu, A. Mándi, J. Li, X. W. Li and Y. A.-O. Guo, Structural and Stereochemical Studies of Laurokamurols A-C, Uncommon Bis-sesquiterpenoids from the Chinese Red Alga Laurencia okamurai Yamada, J. Agric. Food Chem., 2017, 65, 1550–1555. Lorenz, P., M. Zeh, J. Martens-Lobenhoffer, H. Schmidt, G. Wolf and T. F. W. Horn, Natural and newly synthesized hydroxy-1-aryl-isochromans: A class of potential antioxidants and radical scavengers, Free Radical Res., 2005, 39, 535-545. MacroModel; Schrödinger LLC, 2015, https: / / newsite.schrodinger.com / platform / products / macromodel (accessed on 12 July 2024). Ola, A. R. B., A. Debbab, A. H. Aly, A. Mandi, I. Zerfass, A. Hamacher, M. U. Kassack, H. Brötz-Oesterhelt, T. Kurtan and P. Proksch, Absolute configuration and antibiotic activity of neosartorin from the endophytic fungus Aspergillus fumigatiaffinis, Tetrahedron Lett., 2014, 55, 1020-1023. Patel, S., K. Sandha, A. Waingankar, P. Jain and A. Abhyankar, Atropisomerism transforming anti-cancer drug discovery, Chem. Biol. Drug Des., 2023, 101, 138-157. Perreault, S., J. Chandrasekhar and L. Patel, Atropisomerism in Drug Discovery: A Medicinal Chemistry Perspective Inspired by Atropisomeric Class I PI3K Inhibitors, Acc. Chem. Res., 2022, 55, 2581-2593. Polavarapu, P. L., N. Jeirath, T. Kurtán, G. Pescitelli and K. Krohn, Determination of the absolute configurations at stereogenic centers in the presence of axial chirality, Chirality, 2009, 21, E202-E207. Ren, X., X. She, K. Peng, Y. Su, X. Xie, X. Pan and H. Zhang, First Enantioselective Synthesis of the Neolignans Rhaphidecursinol A and Virolongin B, J. Chin. Chem. Soc., 2004, 51, 969-974. Rönsberg, D., A. Debbab, A. Mándi, V. Vasylyeva, P. Böhler, B. Stork, L. Engelke, A. Hamacher, R. Sawadogo, M. Diederich, V. Wray, W. Lin, M. U. Kassack, C. Janiak, S. Scheu, S. Wesselborg, T. Kurtán, A. H. Aly and P. Proksch, Pro-Apoptotic and Immunostimulatory Tetrahydroxanthone Dimers from the Endophytic Fungus Phomopsis longicolla, J. Org. Chem., 2013, 78, 12409-12425. Sayed, A. M., A. H. Ibrahim, N. Tajuddeen, J. Seibel, J. Bodem, N. Geiger, K. Striffler, G. Bringmann and U. R. Abdelmohsen, Korupensamine A, but not its atropisomer, korupensamine B, inhibits SARS-CoV-2 in vitro by targeting its main protease (Mpro), Eur. J. Med. Chem., 2023, 251, 115226. Smyth, J. E., N. M. Butler and P. A. Keller, A twist of nature – the significance of atropisomers in biological systems, Nat. Prod. Rep., 2015, 32, 1562-1583. Stephens, P. J. and N. Harada, ECD cotton effect approximated by the Gaussian curve and other methods, Chirality, 2010, 22, 229-233, https: / / doi.org / 10.1002 / chir.20733. Togna, A. R., V. Latina, G. Trefiletti, M. Guiso, S. Moschini and G. I. Togna, 1-Phenil-6,7-dihydroxy-isochroman inhibits inflammatory activation of microglia, Brain Res. Bull., 2013, 95, 33-39. Varetto, U., MOLEKEL 5.4; Swiss National Supercomputing Centre: Manno, Switzerland, 2009. Wu, Z.-J., M.-A. Ouyang and Q.-W. Tan, New asperxanthone and asperbiphenyl from the marine fungus Aspergillus sp, Pest Manag. Sci., 2009, 65, 60-65. Wu, G., G. Yu, T. Kurtán, A. Mándi, J. Peng, X. Mo, M. Liu, H. Li, X. Sun, J. Li, T. Zhu, Q. Gu and D. Li, Versixanthones A–F, Cytotoxic Xanthone–Chromanone Dimers from the Marine-Derived Fungus Aspergillus versicolor HDN1009, J. Nat. Prod., 2015, 78, 2691-2698. Wu, X.-Z., W.-J. Huang, W. Liu, A. Mándi, Q. Zhang, L. Zhang, W. Zhang, T. Kurtán, C.-S. Yuan and C. Zhang, Penicisteckins A–F, Isochroman-Derived Atropisomeric Dimers from Penicillium steckii HNNU-5B18, J. Nat. Prod., 2021, 84, 2953-2960. Wuts, P. G. M. and Greene, T. W., Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, 2006. nov. 10. (4th Edition).Yang, Y. D., B. B. Yang and L. A.-O. Li, A nonneglectable stereochemical factor in drug development: Atropisomerism, Chirality, 2022, 34, 1355-1370. Zhang, Q., A. Mándi, S. Li, Y. Chen, W. Zhang, X. Tian, H. Zhang, H. Li, W. Zhang, S. Zhang, J. Ju, T. Kurtán and C. Zhang, N–N-Coupled Indolo-sesquiterpene Atropo-Diastereomers from a Marine-Derived Actinomycete, Eur. J. Org. Chem., 2012, 5256-5262. Zhu, Q., C. Tang, A. A.-O. Mándi, T. A.-O. Kurtán and Y. A.-O. Ye, Trigonostemons G and H, dinorditerpenoid dimers with axially chiral biaryl linkage from Trigonostemon chinensis, Chirality, 2020, 32, 265-272.

Claims

CLAIMS 1. A chiral biaryl-type heterocyclic compound of general formula (I)Formula (I) wherein X is O, NH or N-PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group A is a heteroatom, preferably O, R1ais selected from H,wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R1bis selected from H, (C1-6)alkyl-O-C(O), (C1-6)alkyl-O-C(O)-CH2-, preferably H, -CH2COOEt and -COOEt,wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, more preferably (1-4)alkyl or (1- 4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H,R4ais H, OH, O-alkyl, O-PGAr or =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAror =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAr is a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl, O-PGAr or =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPhor =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

2. The compound according to claim 1, said compound having general Formula (I), wherein X is O, NH or NCbz, in particular O or NH, preferably O, R1aand R1bare, independently, as defined in claim 1, R2aand R2bare, independently, H or an alkyl, preferably methyl, R3ais H, an alkyl or O-alkyl, preferably OCH3, R3bis H or alkyl, preferably H, R4a, R4b, R5a, R5bare, independently H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when R4band R5bis both =O, is a single bond.

3. The compound according to claim 1, said compound having general Formula (I), wherein X is O, NH or NCbz, preferably O or NH, in particular O, A is a heteroatom, preferably O, R1ais selected from H,wherein Y1is halogen, preferably F or Br, R1bis selected from H, (1-4)alkyl-O-C(O), (1-4)alkyl-O-C(O)-CH2-,preferably H, -CH2COOEt and -COOEt,wherein Y1is halogen, preferably F or Br, R2aand R2bare, independently, (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably H or OCH3, R3bis H, R4ais H, OH or (1-4)alkyloxy, preferably H, OH or OCH3, preferably OCH3, R4bis OH, (1-4)alkyloxy, OPGAr, preferably benzyloxy (BnO) or =O, preferably OH, OCH3, BnO or =O, in particular OH, OCH3or =O, R5ais H, OH, O-alkyl or =O, preferably OH, (1-4)alkyloxy or =O, in particular H, OH or OCH3, , R5bis H, OH, (1-4)alkyloxy, OPGAr, preferably BnO, or =O, preferably H, OH, OCH3, BnO or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

4. The compound according to claim 3, wherein said compound ha formula (I.2)R1aand R1bare, independently, selected from the group consisting of H,wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, in particular methyl,R2bis (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably OCH3, R3bis H, R4ais H, R4bis (1-4)alkyloxy, BnO, preferably OH, R5ais H, or (1-4)alkyloxy, preferably H or OCH3, in particular OCH3, R5bis OH, or BzO, in particular OH.

5. A compound according to formula (I.2),wherein said compounds have antimicrobial activity, and R1aand R1bare, independently, selected from the group consisting of H,wherein Y1is halogen, preferably F or Br, wherein Y1is halogen, preferably F or Br, R2aand R2bare methyl, R3ais H or OH or OCH3, R3bis H R4ais H, OH, OCH3or =O, preferably H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, OCH3or =O, preferably H, OH or =O, R5ais OH or OCH3, preferably OH or =O, more preferably OH, R5bis OH, OCH3or =O, preferably OH or =O, more preferably OH, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

6. The compound according to claim 5, wherein said compounds have antimicrobial activity, andR2aand R2bare methyl, R3ais H or OH or OCH3, R3bis H R4ais H, OH, OCH3, preferably H or OH or OCH3, preferably OH or OCH3, R4bis H, OH, OCH3, preferably H or OH, R5ais OH or OCH3, preferably OH, R5bis OH, OCH3O, preferably OH; preferably, wherein said compound is selected from the group consisting of compounds 2, 4, 6, 9, 10, 18, 24, 25, 26, 27, 37, 41, 43.

7. The compound according to any of the previous claims wherein the compound has axial chirality, preferably around the 5,5’ axis.

8. A pharmaceutical composition comprising a compound of any of the previous claims, preferably according to claim 5 or 6, for use as an antimicrobial agent, said pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

9. The pharmaceutical composition for use according to claim 8, wherein said compound has an antibacterial activity and is for use as an antibacterial agent, preferably against any of the following bacteria: Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii.

10. A use of a compound according to any of the previous claims, preferably according to claim 5 or 6, as an antimicrobial agent in vitro, wherein the compound has antimicrobial activity.

11. The use according to claim 8, wherein said compound ha an antibacterial activity and is used as an antibacterial agent, preferably against any of the following bacteria: Staphyloccocus aureus, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Micrococcus luteus, Enterococcus faecalis or Acinetobacter baumannii.

12. A method for synthesis of 5,5’-linked biaryl-type heterocyclic compounds of general Formula I.1 (general synthesis method 1),said method comprising the steps of cross-coupling of a 5-halogen compound (preferably an isochroman) of general Formula (III)with the pinacolatoboronate ester derivative of general Formula (IV.1)by a Suzuki-Miyaura biaryl cross-coupling reaction in the presence of a Pd catalysator and if desired in the presence of a phosphine ligand, to obtain a compound of general Formula (II.1),removal of the protecting groups, an oxa-Pictet-Spengler cyclization of said compound of general Formula (II.1) with an aldehyde having the formula R1b-CHOto produce general Formula (Ia), optionally as a mixture of stereoisomers, e.g. diastereoisomers or atropodiastereomers, wherein in the formulae X is O, NH or N-PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group PGO is a hydroxyl-protecting group, preferably acetyl, R1ais selected from H,wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R1bis selected from H, (1-6)alkyl-O-C(O), (1-6)alkyl-O-C(O)-CH2-, preferably H, -CH2COOEt and -COOEt,wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, more preferably (1-4)alkyl or (1- 4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, more preferably (1-4)alkyl, in particular H, R4ais H, OH, O-alkyl or =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAror =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAris a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl or =O, preferably OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPhor =O, preferably H, OH, (1-6)alkyloxy, more preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

13. The method according to claim 12, wherein the pinacolatoboronate ester derivative of general Formula (IV) is a compound of Formula (IVH)whereas the compound of general Formula (III) is selected from the group of compounds consisting of: cis-(1R,3S)-J, trans-(1S,3S)-J cis-(1S,3R)-J and trans-(1R,3R)-Jto give, after Suzuki-Miyaura biaryl cross-coupling and oxa-Pictet-Spengler cyclization(1R,3S)-(I.1) (1S,3S)-(I.1)the respective (1R,3S), (1S,3S), (1S,3R) and (1R,3R) derivatives of the biaryl compounds, whereas each may be present in the form of aR and / or aS stereomer(s), and wherein X is O, R1aand R1bare, independently, selected is selected from H,, and , in particular wherein Y1is halogen, preferably F or Br, R2ais (1-4)alkyl, in particular methyl, R2bis (1-4)alkyl, in particular methyl, R3ais H or (1-4)alkyloxy, preferably H or OCH3, R3bis H, R4ais H, OH or (1-4)alkyloxy, preferably H, OH or OCH3, preferably OCH3, R4bis OH, (1-4)alkyloxy, O-PGAr (preferably BnO) or =O, preferably OH, OCH3, BnO or =O, in particular OH, OCH3or =O, R5ais H, OH, O-alkyl or =O, preferably OH, (1-4)alkyloxy or =O, in particular H, OH or OCH3, , R5bis H, OH, (1-4)alkyloxy, O-PGAr(preferably BnO) or =O, preferably H, OH, OCH3, BnO or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

14. A method for synthesis of 5,5’-linked biaryl-type heterocyclic compounds of general Formula (I.2), (general synthesis method 2),said method comprising the steps of coupling the pinacolatoboronate ester derivative of general Formula (IV.2)with a halogen compound of general formula (III.2)by a Suzuki-Miyaura biaryl cross-coupling reaction in the presence of a Pd catalyst and if desired in the presence of a phosphine ligand, to obtain a compound of general Formula (II.2)removal of the protecting groups, an oxa-Pictet-Spengler cyclization of said compound of general Formula (II.2) with an aldehyde having the formulaR1b-CHO, preferably two equivalents of aldehydes, to produce general Formula (I.2), optionally as a mixture of stereoisomers, e.g. diastereoisomers or atropodiastereomers, wherein in the formulae X is O, NH or N-PGN, preferably O or NH, in particular O, wherein PGNis an amino protecting group PGOis a hydroxyl-protecting group, preferably acetyl, R1ais selected from H,wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R1bis selected from H, (C1-6)alkyl-O-C(O), (C1-6)alkyl-O-C(O)-CH2-, preferably H, -CH2COOEt and -COOEt,wherein Y1is halogen or pseudohalogen, preferably halogen, more preferably F or Br, R2ais H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H or methyl, R2bis H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H or methyl, R3ais H, an alkyl or O-alkyl, preferably (1-6)alkyl or (1-6)alkyloxy, in particular (1-4)alkyl or (1-4)alkyloxy, preferably H, methyl or OCH3, preferably OCH3, R3bis H or an alkyl, preferably (1-6)alkyl, in particular (1-4)alkyl, in particular H, R4ais H, OH, O-alkyl or =O, preferably H, OH, (1-6)alkyloxy, preferably (1-4)alkyloxy or =O, in particular H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, O-alkyl, O-PGAror =O, preferably OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular OH, OCH3, or =O, wherein PGAris a phenolic hydroxyl protecting group, R5ais H, OH, O-alkyl or =O, preferably OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular H, OH or OCH3, , R5bis H, OH, O-alkyl, O-PGPhor =O, preferably H, OH, (1-6)alkyloxy, preferably (1-4)alkyloxy, or =O, in particular H, OH, OCH3or =O, and each is independently a single bond or a double bond,wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

15. The method according to any of claims 12 to 14, wherein X is O, , R1aand R1bare, independently, selected from H,wherein Y1is halogen, preferably F or Br, R2aand R2bare methyl, R3ais H or OH or OCH3, R3bis H R4ais H, OH, OCH3or =O, preferably H, OH or OCH3, preferably OH or OCH3, R4bis H, OH, OCH3or =O, preferably H, OH or =O, R5ais OH or OCH3, preferably OH or =O, more preferably OH, R5bis OH, OCH3or =O, preferably OH or =O, more preferably OH, and each is independently a single bond or a double bond, wherein preferably when R4aand R5ais both =O, is a single bond, or when (preferably) R4band R5bis both =O, is a single bond.

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