Chiral spiro compounds, methods of making and using the same

Abstract

The present application provides a chiral spiro compound, a preparation method thereof and application thereof. The chiral spiro compound is represented by the following formula: the chiral spiro compound can be used as a skeleton or a support of many chiral catalysts, and has a new chiral framework.

Description

TECHNICAL FIELD

[0001] The present invention relates to a novel chiral spiro compound (in particular, a chiral spiro diol structure-SPHENOL), a method for preparing the same and the use thereof. Due to the special molecular shape and three-dimensional orientation, the chiral spiro compound can be used as a chiral scaffold for designing novel chiral ligands and catalysts for asymmetric synthesis. BACKGROUND

[0002] Enantioselective catalysis is a key pillar of modern organic chemistry. Over the past few decades, multifunctional chiral catalysts have been reported, which have facilitated the development of catalytic asymmetric synthesis. However, most practically useful enantioselective reactions are rooted in a small number of privileged core structures, which are known as "privileged chiral catalysts". The essential feature that makes a catalyst "privileged" is its scaffold structure (core structure). Some representative examples, such as BINOL, TADDOL and SPINOL, and their derivatives have been widely used as chiral scaffolds and ligands of metal complexes of various organic catalysts, which are very effective in various mechanically unrelated reactions. However, a large number of reactions still lack effective chiral ligands, and the enantioselectivity in many reactions is dependent on the substrate.

[0003] The development of new effective chiral catalysts, especially the development of new chiral scaffolds on which these catalysts are based, remains an important task in the field of asymmetric catalysis. SUMMARY

[0004] To this end, the present invention provides a novel chiral spiro compound, a method for preparing the same and the use thereof. The chiral spiro compound can be used as a scaffold or a support for many chiral catalysts and has a new chiral framework.

[0005] In particular, the present invention provides:

[0006] A chiral spiro compound represented by the following formula:

[0007]

[0008] SPHENOL represents a structure represented by the following formula I,

[0009]

[0010] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R10 Each independently represents the optional substitution of C. 1-100 Alkyl, optionally substituted aryl, optionally substituted polycyclic aromatic ring groups, or optionally substituted heterocyclic aryl,

[0011] n is an integer selected from 0 to 5.

[0012] D represents a C atom or a Si atom.

[0013] X represents C or a heteroatom selected from N, O, S, and P.

[0014] A and B each independently represent at least one of -OH, -SO3H, -P, -O-, C1-C6 alkylene, heteroaryl, amino, and -SO2-, wherein A and B may optionally be substituted by at least one substituent;

[0015] m1 and m2 are either 0 or 1;

[0016] Z represents -PN(R) 15 )2, -PR2', optional phenylene substituted with R2', B - N + , At least one of imino and amino groups, wherein Tf represents trifluoromethanesulfonyl and O(S) represents O or S;

[0017] SPHENOL-A represents the enantiomer of SPHENOL;

[0018] m3 and m4 represent 0 or 1.

[0019] m represents 0 or 1;

[0020] * indicates that it does not exist or represents a connection point with Z;

[0021] R2' represents hydrogen, an optionally substituted aryl group, an optionally substituted polycyclic aromatic ring group, an optionally substituted heterocyclic aryl group, or an optionally substituted C1-C6 alkyl group.

[0022] R 15 Indicates unsubstituted C1-C6 alkylene groups or C1-C6 alkylene groups substituted with aryl groups;

[0023] This indicates a single key or that the key does not exist.

[0024] A method for preparing a chiral spirocyclic compound includes the following steps: converting a ketone compound represented by Formula II into a bisnaphthol compound represented by Formula I in the presence of a chiral acid catalyst and a solvent.

[0025]

[0026] and

[0027] optionally converting the bisnaphthol compound represented by Formula I into other chiral spiro compounds other than Formula I,

[0028] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 each independently represent a C 1-100 alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic ring group, or an optionally substituted heterocyclic aryl group,

[0029] n is selected from an integer from 0 to 5,

[0030] D represents a C atom or a Si atom,

[0031] A and B each represent -OH;

[0032] m1 and m2 are 1;

[0033] * represents the absence; and

[0034] X represents C or a heteroatom selected from N, O, S and P.

[0035] Use of any one of the compounds as described above in an asymmetric catalytic reaction, an intermolecular hydroacylation reaction, an enantioselective spiro compound synthesis reaction, or an intramolecular desymmetrization reaction.

[0036] Use of the compounds as described above as chiral catalysts or chiral ligands.

[0037] The chiral spiro compounds of the present application also have good conformational rigidity and electronic properties, combining the advantages of existing chiral catalysts, and can serve as an excellent platform for developing new chiral ligands and catalysts. In addition, the design of the core catalyst of the present application is new and significantly different from existing chiral catalyst skeletons in terms of structural rigidity, dihedral angle, and pKa, etc., which is crucial for achieving better performance.

[0038] In addition, this new chiral spiro compound is characterized by easy synthesis (3 steps), and is cheaper than SPINOL on the market, which is very expensive due to a cumbersome synthesis process (7-step synthesis and the need for chiral resolution).

[0039] In addition, since the compound of the present application contains a naphthalene structure, it leads to a simplified route for its synthesis, which greatly reduces the cost of synthesis, thus promising to lead to wide application. In contrast, the existing SPINOL is too expensive, and despite its good performance, it still cannot be truly applied. DETAILED DESCRIPTION

[0040] Embodiments of the present application are described in detail below. The embodiments described below are examples only and are not intended to limit the present application, which can be embodied in various ways without being limited to any particular embodiments described below. Unless otherwise specified, technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which the present application pertains. Unless otherwise specified, all patents and publications mentioned in the present application are incorporated by reference in their entirety.

[0041] Definitions and General Terminology

[0042] Certain embodiments of the present application are now described in detail by referring to the following examples and the accompanying structural and chemical formulas. The present application is intended to cover all alternatives, modifications and equivalents of the embodiments included within the scope of the present application as defined by the claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many methods and materials similar or equivalent to those described herein. The present application is not intended to be limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts with the present application, including but not limited to defined terms, term application, described techniques, etc., the present application controls.

[0043] It should be further recognized that certain of the described features of the present application, while individually disclosed above, can be provided in combination in a single embodiment. Conversely, various features of the present application, which are, for brevity, described in a specific context, can also be provided separately or in any appropriate subcombination.

[0044] Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as commonly understood by one of ordinary skill in the art to which the present application pertains. All patents and publications mentioned in the present application are incorporated by reference in their entirety.

[0045] The following definitions shall apply unless otherwise indicated. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the "Handbook of Chemistry and Physics" 75thEd., 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5thEd., Ed.: Smith, Michael B., and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0046] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "at least one") of the enumerated items, unless otherwise indicated by context. The use of the terms "first", "second", and "third" with

[0047] The term "comprising", used in the disclosure, is a transitional term which is to be interpreted in an open, non-limiting sense, i.e. it does not exclude other elements or steps.

[0048] Also, it is to be noted that the descriptive terms "each independently" and "independently" are used interchangeably in the present application, unless otherwise explicitly indicated, and should be interpreted in a broad sense, i.e. it can mean that the specific options expressed by the same symbols in different groups do not influence each other, or that the specific options expressed by the same symbols in the same group do not influence each other.

[0049] Throughout the specification, substituents of compounds disclosed herein are presented according to group type or range. It is specifically intended that the present application include each and every independent combination of the members of these group types and ranges. For example, the term "C1-C8alkyl" is specifically intended to individually and separately recite "C1alkyl", "C2alkyl", "C3alkyl", "C4alkyl", "C5alkyl", "C6alkyl", "C7alkyl", "C8alkyl", and so on. 1-18 "Alkyl" includes methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0050] Throughout the specification, substituents of compounds disclosed herein are presented according to group type or range. It is specifically intended that the present application include each and every independent combination of the members of these group types and ranges. For example, the term "C1-C8alkyl" is specifically intended to individually and separately recite "C1alkyl", "C2alkyl", "C3alkyl", "C4alkyl", "C5alkyl", "C6alkyl", "C7alkyl", "C8alkyl", and so on.

[0051] The term "alkyl" as used herein includes aliphatic saturated hydrocarbon groups. The alkyl group can be optionally substituted with one or more substituents as described herein. In one embodiment of the application, the alkyl group has 1 to 100 carbon atoms (i.e., Ci-100alkyl), preferably 1 to 18 carbon atoms (i.e., Ci-18alkyl). In another embodiment, the alkyl group has 1 to 12 carbon atoms (i.e., Ci-12alkyl); in yet another embodiment, the alkyl group has 1 to 6 carbon atoms (i.e., Ci-6alkyl); in still another embodiment, the alkyl group has 1 to 4 carbon atoms (i.e., Ci-4alkyl); and in yet another embodiment, the alkyl group has 1 to 3 carbon atoms (i.e., Ci-3alkyl).

[0052] Examples of alkyl groups include, but are not limited to, Ci-12alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-l-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like.

[0053] The terms "halogen" and "halo" mean fluorine (F), chlorine (CI), bromine (Br), or iodine (I).

[0054] The term "aryl" includes groups in which a direct link is made to the remainder of the molecule through one or two hydrogen atoms of an aromatic ring. Aryl groups include monocyclic aryl or arylene groups in which the ring system is aromatic and contains 3-6 atoms in the ring. The aryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring system". Examples of aryl groups can include phenyl and biphenyl groups, and the like. The aryl group is optionally substituted with one or more substituents as described herein.

[0055] The term "heteroaryl" means a group in which at least one ring atom, for example N, O or S, is replaced in an aryl group.

[0056] The term "polycyclic aromatic ring group" includes bicyclic, tricyclic, or higher ring aryl groups in which at least one ring system is aromatic, wherein each ring system contains 5-18 atoms in the ring. Examples of polycyclic aromatic ring groups can include naphthyl and anthracene groups, and the like. The polycyclic aromatic ring group is optionally substituted with one or more substituents as described herein.

[0057] In the present invention, the term "optionally substituted" means that the modified group can be free of substituents or substituted with at least one substituent group.

[0058] The substituents can be selected from at least one of a halogen atom, a hydroxyl group, an aldehyde group, a carboxyl group, an amino group, a C1-C18 alkyl group optionally substituted with one or more C6-C18 aryl groups or a heterocyclic aryl group of ring-forming carbon atoms 5-18, a halogen atom (particularly F), an aryl group of ring-forming carbon atoms 6-18, a heterocyclic aryl group of ring-forming carbon atoms 5-18, a mercapto group, a cyano group, and a nitro group.

[0059] Examples of the aryl group, the heterocyclic aryl group, and the polycyclic aromatic hydrocarbon ring group include, for example, a phenyl group substituted with -CF3, a phenyl group, a naphthyl group, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a naphthacene group, a pyrenyl group, a benzo[c]phenanthryl group, a benzophenanthryl group, a fluorenyl group, a benzofluorenyl group, a dibenzofluorenyl group, a biphenyl group, a terphenyl group, a quaterphenyl group, a fluoranthenyl group, a pyrrolyl group, a pyrazinyl group, a pyridyl group, a pyrimidinyl group, a triazinyl group, an indolyl group, an isoindolyl group, an imidazolyl group, a furanyl group, a benzofuranyl group, an isobenzofuranyl group, a dibenzofuranyl group, a dibenzothiophenyl group, a quinolyl group, an isoquinolyl group, a quinoxalyl group, a carbazolyl group, a phenanthridinyl group, an acridinyl group, a phenanthrolinyl group, a phenoxazinyl group, a phenothiazinyl group, a phenoxazinyl group, an oxazolyl group, an oxadiazolyl group, a furazanyl group, a thiophenyl group, a benzothiophenyl group, a dihydroacridinyl group, an azacarbazolyl group, a quinazolinyl group, and the like.

[0060] It remains an important task in the field of asymmetric catalysis to develop efficient chiral catalysts, especially ligands with novel chiral skeletons. BINOL has slightly higher acidity due to the large naphthalene conjugated system, but the SPINOL skeleton often shows better asymmetric induction ability due to its greater structural rigidity. In this case, the present invention proposes a new structure (which is sometimes referred to as SPHENOL). This new structure is expected to inherit the excellent conformational rigidity and chemical stability of SPINOL, while having comparable electronic properties (acidity) to BINOL. The latter is sometimes very important in Brønsted acid catalysis. In addition, similar to BINOL and SPINOL, the introduction of two substituents at the 3,3'-position of SPHENOL is expected to allow the chirality of the C2-symmetric skeleton to be adjusted. Combining the advantages of these two special structures, SPHENOL can serve as an excellent platform for developing new chiral ligands and catalysts. Such a new framework has superior performance in mechanically unrelated reactions, thus demonstrating the potential of SPHENOL as a privileged framework for asymmetric synthesis.

[0061] The main difference between SPHENOL and the previous related inventions SPINOL and modified SPINOL is that the conjugated system is extended to naphthalene in structure. SPHENOL has fundamental differences and advantages in function and synthesis. SPHENOL of the present invention has better performance as a catalyst skeleton, and is cheaper due to clever design. The nucleophilicity and selectivity of naphthol in the cyclization process are much higher than that of phenol, which makes the synthesis only 3 steps and the yield is very high. However, the existing method of manufacturing SPINOL does not allow cheap and scalable production. This makes SPINOL unable to be used on a large scale, and our invention will fill this gap and is expected to become a new generation of catalyst.

[0062] In one aspect, a chiral spiro compound is provided, represented by the following formula:

[0063]

[0064] SPHENOL represents the structure of the following formula I,

[0065]

[0066] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 each independently represents an optionally substituted C 1-100 alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic ring group, or an optionally substituted heterocyclic aryl group,

[0067] n is selected from an integer from 0 to 5,

[0068] D represents a C atom or a Si atom,

[0069] X represents C or a heteroatom selected from N, O, S and P,

[0070] A and B each independently represent at least one of -OH, -SO3H, -P, -O-, C1-C6 alkylene, heteroaryl, amino, and -SO2-, wherein A and B can be optionally substituted with at least one substituent;

[0071] m1 and m2 are 0 or 1;

[0072] Z represents -PN(R 15 )2, -PR2’, phenylene optionally substituted with R2’, B- , N + 、 at least one of imino and amino, wherein Tf represents trifluoromethylsulfonyl group, O(S) represents O or S;

[0073] SPHENOL-A represents an enantiomer of SPHENOL;

[0074] m3 and m4 represent 0 or 1,

[0075] m represents 0 or 1;

[0076] * represents nothing or a point of attachment to Z;

[0077] R2' represents hydrogen, optionally substituted aryl, optionally substituted polycyclic aromatic ring group, optionally substituted heteroaromatic group, or optionally substituted C1-C6 alkyl,

[0078] R 15 represents unsubstituted C1-C6 alkylene or C1-C6 alkylene substituted with aryl;

[0079] represents a single bond or nothing.

[0080] In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently located at ortho, meta or para position on the respective aromatic ring.

[0081] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently -OR, -OH, -NH2, -NHR, -NR 11 R 12 , -F, -Cl, -Br, -I, -SR, -PR 13 R 14 or -SeR, wherein R 11 , R 12 are each independently hydrogen or C1-6 alkyl, R 13 and R14 each independently carbonyl, hydroxyl, hydrogen, or C1-6alkyl.

[0082] Preferably, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each hydrogen, and R 9 and R 10 are each independently phenyl substituted with -CF3or

[0083] In particular, the chiral spiro compound can be selected from at least one of the following:

[0084]

[0085] wherein R and R' each independently represent C 1-100 alkyl, optionally substituted aryl, optionally substituted polycyclic aromatic ring group, optionally substituted heterocyclic aryl, or a substituent having a heteroatom, X, n and O(S) are as defined above, Ar represents aryl, and P represents phosphorus.

[0086] Preferably, both R 15 are each C1-C6alkylene substituted with aryl, and are enantiomers of each other.

[0087] Preferably, when each group is substituted, the substituent is selected from aryl, -NR 2 ', polycyclic aromatic ring group, optionally substituted heterocyclic aryl, or C1-C6alkyl.

[0088] Preferably, the compound is selected from any one of the following:

[0089]

[0090] In another aspect, the present application provides a method of preparing a chiral spiro compound, comprising the steps of:

[0091] (I) converting a ketone compound represented by the following formula II into a bisnaphthol compound represented by formula I in the presence of a chiral acid catalyst and a solvent:

[0092]

[0093] and

[0094] (II) optionally, converting the bisnaphthol compound represented by formula I into another chiral spiro compound other than formula I,

[0095] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 each independently represent a C 1-100 alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic ring group, or an optionally substituted heterocyclic aryl group,

[0096] n is selected from an integer from 0 to 5,

[0097] D represents a C atom or a Si atom,

[0098] A and B both represent -OH;

[0099] m1 and m2 are 1 ;

[0100] * represents the absence; and

[0101] X represents C or a heteroatom selected from N, O, S and P.

[0102] The chiral acid catalyst can be selected from at least one of the following:

[0103]

[0104] wherein R represents a C 1-100 alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic ring group, an optionally substituted heterocyclic aryl group hydrogen or a substituent having a heteroatom.

[0105] The chiral acid catalyst is preferably a (S)-type chiral phosphoric acid which catalyzes the reaction to provide a chiral spirodiol having an inverted configuration.

[0106] Preferably, the catalyst can be a chiral phosphoric acid having BINOL (III), 8H-BINOL (IV) or SPINOL (V) as a backbone, wherein the 3,3'-substituent R represents a polycyclic aromatic hydrocarbon such as a substituted benzene, naphthalene, fluorene, pyrene, anthracene phenanthrene or triaryl.

[0107] The temperature of the conversion reaction of step (I) can be from -20 °C to 120 °C.

[0108] The solvent can be selected from at least one of chlorobenzene, PhCF3, PhF, CCl4, DCM, CHCl3, PhMe, DCE.

[0109] In one embodiment, the chiral spiro compound is a chiral ligand compound, and the method comprises converting the compound of Formula I in the presence of a ligand to a chiral ligand compound represented by the following formula:

[0110]

[0111] SPHENOL represents the following structure represented by Formula I,

[0112]

[0113] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 each independently represent an optionally substituted C 1-100 alkyl group, an optionally substituted aryl group, an optionally substituted polycyclic aromatic hydrocarbon ring group, or an optionally substituted heterocyclic aryl group,

[0114] n is selected from an integer from 0 to 5,

[0115] D represents a C atom or a Si atom,

[0116] X represents C or a heteroatom selected from N, O, S and P,

[0117] A and B each independently represent at least one of -SO3H, -P, -O-, C1-C6 alkylene, heteroaryl, amino and -SO2- wherein A and B can be optionally substituted with at least one substituent;

[0118] m1 and m2 are 0 or 1;

[0119] Z represents -PN(R 15 )2, -PR2’, phenylene optionally substituted with R2’, B - , N + 、

[0120] imino and amino wherein Tf represents trifluoromethylsulfonyl group, O(S) represents O or S;

[0121] SPHENOL-A represents an enantiomer of SPHENOL;

[0122] m3 and m4 represent 0 or 1,

[0123] m represents 0 or 1;

[0124] * represents the absence or the point of attachment to Z;

[0125] R2' represents hydrogen, optionally substituted aryl, optionally substituted polycyclic aromatic ring group, optionally substituted heteroaromatic group, or optionally substituted C1-C6 alkyl,

[0126] R 15 represents unsubstituted C1-C6 alkylene or C1-C6 alkylene substituted with aryl;

[0127] represents a single bond or the absence.

[0128] In a third aspect, there is also provided the use of the above-mentioned compound in an asymmetric catalytic reaction, an intermolecular hydroacylation reaction, an enantioselective spirocyclisation synthesis reaction, or an intramolecular desymmetrisation reaction.

[0129] Preferably, the asymmetric catalytic reaction comprises asymmetric hydrogenation of one of the following:

[0130]

[0131]

[0132] The intermolecular hydroacylation reaction is selected from one of the following:

[0133] and

[0134]

[0135] The enantioselective spirocyclisation synthesis reaction is selected from:

[0136]

[0137] The intramolecular desymmetrisation reaction is selected from:

[0138]

[0139] Accordingly, the present application provides a process for the synthesis of a range of chiral spiro compounds. These compounds can also be converted to other useful compounds, such as chiral ligands and chiral catalysts, by simple chemical procedures. Enantioselectivity is generally maintained unaffected.

[0140] This process represents the first catalytic enantioselective synthesis of this class of structures.

[0141] The following examples are provided to illustratively describe, and to aid in the understanding of, the present application, by those of ordinary skill in the art, without being construed to unduly limit the present application. Changes and modifications to the examples discussed can be made by those of ordinary skill in the art without departing from the scope of the present application.

[0142] 1. General procedure

[0143] 1.1 Materials, conditions and instruments

[0144] Flash column chromatography was performed on silica gel (200-300 mesh) purchased from Qingdao Puk Chemical Technology Co. Ltd. All reactions sensitive to air or moisture were performed in oven-dried glassware under nitrogen using anhydrous solvents. Anhydrous solvents were purified by solvent purification system. Chemicals were purchased from commercial suppliers and used without further purification unless otherwise stated.

[0145] 1 H, 13 C, 19 F and 31 P nuclear magnetic resonance spectra were collected on a Bruker AV 400 megahertz nuclear magnetic resonance spectrometer using residual solvent peaks as internal standards (H NMR: CDCl3 at 7.26 ppm, acetone-D6 at 2.05 ppm, MeOD-d4 at 3.31 ppm; C NMR: CDCl3 at 77.00 ppm, and acetone-D6 at 29.84 ppm, MeOD-d4 at 49.00 ppm). 1 H NMR: CDCl3 at 7.26 ppm, acetone-D6 at 2.05 ppm, MeOD-d4 at 3.31 ppm; 13 C NMR: CDCl3 at 77.00 ppm, and acetone-D6 at 29.84 ppm, MeOD-d4 at 49.00 ppm). 1 Data for H NMR are reported as follows: chemical shift (delta, ppm), multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; p = pentet; sept = septet; m = multiplet; br = broad), coupling constants (Hz), integration. Mass spectra were collected on an Agilent GC / MS 5975C system, a MALDI Micro MX mass spectrometer, or an API QSTAR XL system. Infrared spectra were recorded on a Bruker TENSOR 27 spectrometer and reported in units of absorption frequency (cm-1). Optical rotations were measured on a JASCO P-2000 polarimeter, and [a]D values are reported in degrees; concentrations (c) are in units of 10 milligrams per milliliter. Enantiomeric excess values were determined by chiral HPLC using an Agilent 1200 LC instrument and Daicel Chiralpak® IC-HAS-OD-H columns. AD-H,

[0146] IC-HAS- OD-H column.

[0147] 1.2 Synthesis of chiral diols I ​

[0148]

[0149] General procedure. Ketone II (5.0 mmol) and (S)-SPINOL-3,5-(CF3)2C6H2-OH (1-10 mol%) were dissolved in toluene (50 mL) and stirred at 50 °C for 12 h. Progress was monitored by thin layer chromatography. Upon completion (time specified for each case), the solvent was removed by evaporation. The crude product was concentrated and the residue was filtered through a short pad of silica gel with dichloromethane as eluent to give the pure silica gel product.

[0150] Preparation of (R)-Ia

[0151]

[0152] (R)-Ia, also known as (R)-SPHENOL, was prepared from Ila (1.85 g, 5.0 mmol) and (S)-SPINOL-3,5-(CF3)2C6H2-OH (74 mg, 0.1 mmol) as catalyst following the general procedure as a white solid in 89% yield (1.57 g, 90% ee). 1.39 g of (R)-Ia (90% ee) was recrystallized from hexane / dichloromethane (v / v = 10:1) to give optically pure (R)-Ia as a white solid in 89% yield (1.24 g, >99% ee).

[0153] [α]D 23 : +268.3 (c = 1.0, CH2Cl2). The product was analyzed by HPLC: Daicel CHIRALPAK AD-H column; 20% i-PrOH in hexane; 1.0 mL / min; retention time. 9.0 min (major peak), 13.8 min (minor peak).

[0154] 1 H NMR (400 MHz, CDC13) δ 7.78 (d, J = 8.9 Hz, 2H), 7.76 - 7.65 (m, 2H), 7.42 - 7.30 (m, 4H), 7.12 - 7.00 (m, 2H), 5.13 (s, 2H), 3.41 - 3.23 (m, 2H), 3.17 - 3.04 (m, 2H), 2.53 - 2.41 (m, 2H), 2.38 - 2.19 (m, 2H).

[0155] 13 C NMR (101 MHz, CDC13) δ 151.8, 133.1, 130.2, 130.0, 129.7, 126.8, 125.7, 123.5, 119.0, 118.2, 39.0, 30.4, 26.2.

[0156] IR (thin film) 3466, 3051, 2936, 1601, 1512, 1449, 1363, 1264, 1208, 1140, 943, 825, 754 cm -1 .

[0157] HRMS (CI+) C 25 H 20 O2(M + ) 352.1458, found 352.1453.

[0158] 2. Preparation of II-2

[0159]

[0160] To a solution of 2-naphthol (28.8 g, 200 mmol) and pyridine (24 mL, 300 mmol) in anhydrous dichloromethane (150 mL) was added triflic anhydride (48 mL, 300 mmol) dropwise at 0 °C under nitrogen. The mixture was allowed to warm to room temperature and stirred at the same temperature. After completion (about 2 h), the resulting mixture was added hydrochloric acid aqueous solution (2.0 M, 200 mL) dropwise at 0 °C. The mixture was phase separated, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a red liquid. The red liquid was used directly for the next step without further purification.

[0161]

[0162] To a solution of 1,1-dichloro dimethyl ether (34.2 g, 300 mmol) in dry dichloromethane (120 mL) was added dropwise TiCl4(75.8 g, 400 mmol) at 0 °C under nitrogen. The mixture was then stirred at the same temperature for 15 min before the addition of a solution of crude II-1 in dry dichloromethane (30 mL) dropwise. The mixture was allowed to warm to room temperature and stirred at the same temperature. Upon completion (ca. 2 h), the mixture was carefully poured into 0 °C aqueous hydrochloric acid solution (1.0 M, 300 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (200 mL x 3) and brine (200 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a red liquid. The red oil was dissolved in dry ethanol (200 mL) and cooled to 0 °C, to which was added potassium hydroxide (28.6 g, 500 mmol) portionwise. The mixture was then allowed to warm to 65 °C and stirred vigorously. Upon completion (ca. 3 h), the mixture was carefully poured into 0 °C aqueous hydrochloric acid solution (1.0 M, 500 mL). Next, the layers were separated and the aqueous layer was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (200 mL x 3) and brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to ca. 80 mL and the mixture was then filtered through a glass frit. The filter cake was washed with acetone (150 mL x 3) to give the desired product II-2 as a light yellow solid (12.5 g, 36% over two steps).

[0163] 1 H NMR (400 MHz, Methanol-d4) δ 10.25 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.99 (dd, J = 7.1, 1.3 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.45 (dd, J = 8.1, 7.1 Hz, 1H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H).

[0164] 13 C NMR (101 MHz, Methanol-d4) δ 195.6, 160.0, 139.4, 136.5, 133.6, 131.4, 131.2, 130.2, 123.0, 120.1, 107.9.

[0165] Synthesis of IIa

[0166] To a solution of potassium hydroxide (22.4 g, 400 mmol) in absolute ethanol (100 mL) at 0 °C was slowly added 7-hydroxy-l-naphthaldehyde II-2 (17.2 g, 100.0 mmol) to form an orange suspension. The mixture was stirred at 0 °C for another 30 min. Next, a solution of acetone (3.7 mL, 50 mmol) in absolute ethanol (20 mL) was added dropwise via a dropping funnel over 30 min. The mixture was allowed to warm to room temperature and stirred at the same temperature. Upon completion (ca. 12 h), the dark red mixture was carefully poured into a 0 °C aqueous hydrochloric acid solution (3.0 M, 200 mL). The mixture was then stirred vigorously for 10 min, and then allowed to stand in an ice bath for 20 min. The mixture was then filtered through a glass frit, and the red filter cake was washed with water (100 mL x 2) and absolute ethanol / water (100 mL x 2, v / v = 1 :2). The red solid was dried under vacuum at 60 °C to give dienone II-3 (16.7 g, 91% yield). The orange solid was used directly in the next step without further purification.

[0167] Next, dienone II-3 (6.0 g, 16.4 mmol) was dissolved in tetrahydrofuran (60 mL) and palladium on carbon (600 mg, 10 wt%) was added to it. The mixture was transferred to a Parr bomb, flushed with hydrogen gas three times, and finally pressurized to 3 bar. The mixture was stirred at room temperature for 1.5 h, and the hydrogen gas was carefully released in a fume hood. The mixture was filtered through a fritted disc, and the filter cake was washed with ethyl acetate (30 mL x 3). The filtrate was concentrated, and the crude product was purified by flash chromatography on silica gel (eluent: hexanes / acetone = 5:1 → 2:1) to give ketone Ila as a light yellow solid, which was further purified by recrystallization from acetone / dichloromethane / hexanes (v / v / v = 1 : 1 : 10) to give pure Ila as a white solid (3.90 g, 65% yield).

[0168]

[0169] 1 H NMR (400 MHz, Methanol-d4) δ 7.66 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 7.6 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.16 - 6.98 (m, 6H), 3.22 - 3.05 (m, 4H), 2.85 - 2.66 (m, 4H).

[0170] 13 C NMR (101 MHz, Methanol-d4) δ 212.2, 156.7, 136.2, 134.4, 131.5, 130.2, 127.7, 127.2, 123.6, 118.8, 106.2, 44.1, 28.0.

[0171] IR (thin film) 2925, 2698, 1625, 1515, 1457, 1377, 1257, 1201, 1100, 830, 739 cm"1.

[0172] HRMS (ES+) C 25 H 22 NaO3: 393.1461, found: 393.1466.

[0173] 3. Synthesis of chiral monophosphoramidite ligands

[0174]

[0175] General procedure. In a dry flask equipped with a stir bar, the chiral diol I (352 mg, 1.0 mmol) was dissolved in dry tetrahydrofuran (5.0 mL) at 0 °C. Triethylamine (1.01 g, 10.0 mmol) was added. Then dimethyl phosphoramidite chloride (3.0 mmol) was added to the solution. After that, the reaction mixture was allowed to warm to room temperature. The progress was monitored by thin layer chromatography. Upon completion, the mixture was diluted with diethyl ether (20 mL), washed with distilled water and brine, dried over sodium sulfate and concentrated. The residue was flash chromatographed on silica gel to give the pure product VI.

[0176]

[0177] (Prepared according to the general procedure (eluent: hexane / diethyl ether = 15:1) from (R)-la (>99% ee, 352.0 mg, 1.0 mmol) and dimethyl phosphoramidite chloride (435 mg, 3.0 mmol) as a white foam in 83% yield (354 mg).

[0178] [α]D 23 : +654.6 (c = 1.0, CH2Cl2).

[0179] 1 H NMR (400 MHz, CDC13) δ 7.83 - 7.67 (m, 4H), 7.44 - 7.27 (m, 5H), 6.97 (d, J = 8.8 Hz, 1H), 3.54 - 3.35 (m, 2H), 3.16 - 2.96 (m, 2H), 2.48 - 1.98 (m, 10H).

[0180] 13C NMR (101 MHz, CDC13) δ 145.7 (d, J = 3.7 Hz), 142.2 (d, J = 4.5 Hz), 136.2 (d, J = 5.8 Hz), 134.4 (d, J = 2.0 Hz), 134.2, 133.8, 132.3 (d, J = 1.5 Hz), 132.1, 130.5, 130.4 (d, J = 2.3 Hz), 128.5, 127.8, 126.7, 126.6, 125.4, 125.4, 125.2, 124.3 (d, J = 5.7 Hz), 124.2, 123.9, 42.8, 34.1, 34.0, 27.3, 27.1.

[0181] 31 P NMR (162 MHz, CDC13) δ 115.20.

[0182] IR (thin film) 3049, 2924, 2357, 1596, 1446, 1366, 1313, 1266, 1197, 950, 830, 743, 685, 643, 557 cm -1 .

[0183] HRMS (CI+) C 27 H 25 NO2P (M+H + ): 426.1617, found: 426.1617.

[0184] (R)-VIb was prepared from (R)-la (>99% ee, 352.0 mg, 1.0 mmol) and dimethyl phosphoramidic chloride (516 mg, 3.0 mmol) as a white foam in 80% yield (362.0 mg) following the general procedure (eluent: hexanes / ethyl acetate = 15:1).

[0185] [α]D 23 : +551.2 (c = 1.0, CH2CI2).

[0186] 1 H NMR (400 MHz, CDC13) δ 7.77 (d, J = 8.7 Hz, 1 H), 7.75-7.69 (m, 2H), 7.66 (d, J = 8.7 Hz, 1H), 7.42-7.24 (m, 5H), 7.07 (d, J = 8.7 Hz, 1H), 3.56-3.30 (M, 2H), 3.17-2.98 (M, 2H), 2.88-2.31 (M, 5H), 2.29-2.18 (M, 1H), 2.17-1.99 (M, 2H), 1.00 (s, 6H).

[0187] 13 C NMR (101 MHz, CDC13) δ 146.2 (d, J = 4.1 Hz), 142.5 (d, J = 4.8 Hz), 136.1 (d, J = 5.9 Hz), 134.2, 134.2, 133.9, 132.3, 132.0, 130.5 (d, J = 2.5 Hz), 130.3, 128.4, 127.4, 126.6, 126.6, 125.6, 125.4, 125.3, 124.7 (d, J = 5.9 Hz), 124.2, 123.8, 42.8, 34.1, 33.9, 27.3, 27.2, 14.9.

[0188] 31 P NMR (162 MHz, CDC13) δ 118.86.

[0189] IR (thin film) 3051, 2968, 2927, 2358, 1596, 1504, 1449, 1264, 1198, 1024, 940, 830, 744, 679, 642 cm -1 .

[0190] HRMS (CI+) C 29 H 29 NO2P: 454.1930, found: 454.1929.

[0191]

[0192] (R,RN,RN)-Vlc was prepared from (R)-la (>99% ee, 352.0 mg, 1.0 mmol) and 1,1-dichloro-N,N-bis((R)-1-phenylethyl)phosphoramine (975 mg, 3.0 mmol) as a white foam in 80% yield (485 mg) following the general procedure (eluent: hexanes / ethyl acetate = 15: 1 to 10: 1).

[0193] [α]D 23 : +462.2 (c = 1.0, CH2CI2).

[0194] 1 H NMR (400 MHz, CDC13) δ 7.80 - 7.53 (m, 4H), 7.46 - 6.61 (m, 16H), 4.31 (s, 2H), 3.47 - 3.23 (m, 2H), 3.11 - 3.01 (m, 1H), 2.95 - 2.86 (m, 1H), 2.61 - 2.48 (m, 1H), 2.18 - 0.97 (m, 9H).

[0195] 13 C NMR (101 MHz, CDC13) δ 146.6 (d, J = 5.5 Hz), 143.2 (d, J = 5.8 Hz), 135.3 (d, J = 6.2 Hz), 134.1, 133.7, 133.6 (d, J = 1.8 Hz), 132.2, 132.1, 130.8, 130.20 (d, J = 2.4 Hz), 128.5, 127.9, 127.7, 126.5 (d, J = 15.6 Hz), 125.8, 125.71, 125.2, 124.5 (d, J = 6.7 Hz), 124.1, 123.9, 52.3, 43.2, 34.4, 34.0, 31.5, 27.5, 26.9, 22.6, 14.1.

[0196] 31 P NMR (162 MHz, CDC13) δ 120.59.

[0197] IR (thin film) 3050, 2968, 2930, 2356, 1598, 1500, 1447, 1371, 1321, 1196, 939, 831, 743 cm -1 .

[0198] HRMS (ES+) C 41 H 37 NO2P (M+) found: 606.2556, required: 606.2562.

[0199] (R,SN,SN)-VId was prepared from (R)-la (>99% ee, 352.0 mg, 1.0 mmol) and 1,1-dichloro-N,N-bis((S)-1-phenylethyl)phosphoramine (975 mg, 3.0 mmol) as a white foam in 76% yield (456 mg) following the general procedure (eluent: hexane / ether = 15:1 to 10:1).

[0200] [α]D 23 : +226.7 (c = 1.0, CH2CI2).

[0201] 1 H NMR (400 MHz, CDC13) δ 7.80 - 7.53 (m, 4H), 7.46 - 6.61 (m, 16H), 4.31 (s, 2H), 3.47 - 3.23 (m, 2H), 3.11 - 3.01 (m, 1H), 2.95 - 2.86 (m, 1H), 2.61 - 2.48 (m, 1H), 2.18 - 0.97 (m, 9H).

[0202] 13 C NMR (101 MHz, CDC13) δ 146.6 (d, J = 5.5 Hz), 143.2 (d, J = 5.8 Hz), 135.3 (d, J = 6.2 Hz), 134.1, 133.7, 133.6 (d, J = 1.8 Hz), 132.2, 132.1, 130.8, 130.20 (d, J = 2.4 Hz), 128.5, 127.9, 127.7, 126.5 (d, J = 15.6 Hz), 125.8, 125.71, 125.2, 124.5 (d, J = 6.7 Hz), 124.1, 123.9, 52.3, 43.2, 34.4, 34.0, 31.5, 27.5, 26.9, 22.6, 14.1.

[0203] 31 P NMR (162 MHz, CDC13) δ 120.59.

[0204] IR (thin film) 3052, 2969, 2929, 2361, 2165, 1597, 1448, 1265, 1198, 947, 830, 744, 698 cm -1 .

[0205] HRMS (ES+) C 41 H 37 NO2P found (M+): 606.2556, 606.2567.

[0206] 4. Synthesis of chiral phosphoric acids

[0207]

[0208] 5.1 Synthesis of (R)-VII-1

[0209]

[0210] To a suspension of sodium hydride (60% dispersion in mineral oil, 430 mg, 18 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere at 0 °C, a solution of (R)-Ia (>99% ee, 2.70 g, 7.7 mmol) in anhydrous tetrahydrofuran (50 mL) was added slowly. The mixture was stirred at room temperature for 2 h, then bromomethyl methyl ether (1.7 mL, 18 mmol) was added in one portion at 0 °C. The mixture was stirred at room temperature for another 1 h. Subsequently, the reaction mixture was cooled to 0 °C and quenched by dropwise addition of saturated aqueous ammonium chloride (20 mL) and water (20 mL). The resulting mixture was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane / ethyl acetate = 40:1) to give the product (R)-VII-1 as a white solid in 94% yield (3.20 g, 7.2 mmol).

[0211] [α]D 23 : +232.1 (c = 1.0, CH2Cl2).

[0212] 1 H NMR (400 MHz, CDCl3) δ 7.75 - 7.66 (m, 4H), 7.39 - 7.28 (m, 6H), 4.50 (d, J = 6.7 Hz, 2H), 4.34 (d, J = 6.7 Hz, 2H), 3.44 - 3.31 (m, 2H), 3.15 - 3.04 (m, 2H), 2.93 (s, 6H), 2.66 - 2.54 (m, 2H), 2.51 - 2.42 (m, 2H).

[0213] 13 C NMR (101 MHz, CDCl3) δ 150.6, 134.7, 130.9, 130.5, 129.9, 126.7, 125.9, 123.9, 123.1, 116.5, 94.8, 55.4, 40.5, 30.5, 26.8.

[0214] IR (thin film) 3048, 2939, 2839, 2359, 1594, 1506 1449, 1351, 1246, 1193, 1147, 1012, 920, 822, 742, 611, 552 cm -1 .

[0215] HRMS (ES+) C 29 H 28 NaO4 + (M+Na +Theoretical value of (R)-VII-2: 463.1880, found: 463.1882.

[0216] 5.2 Synthesis of (R)-VII-2

[0217]

[0218] To a solution of (R)-VII-1 (3.0 g, 6.7 mmol), distilled N,N,N',N'- tetramethylethylenediamine (2.6 mL, 17.7 mmol) and dry diethyl ether (100 mL) was added dropwise n-butyllithium (2.4 M in hexanes, 7.1 mL, 17.7 mmol) at 0 °C under nitrogen. After stirring for 0.5 h, the reaction was slowly warmed to room temperature and stirred for an additional 12 h. The reaction mixture was cooled to -78 °C and a solution of iodine (5.46 g, 21.5 mmol) in dry tetrahydrofuran (10 mL) was added in one portion. The reaction mixture was slowly warmed to 0 °C, stirred for 1 h, then quenched with a saturated aqueous solution of sodium sulfite (20 mL) and water (20 mL). The resulting mixture was extracted with diethyl ether (15 mL x 3), and the combined organic layers were dried over sodium sulfate and concentrated. The crude product (620 mg) was used in the next step without further purification.

[0219] To a solution of the above crude in 1,4-dioxane (80 mL) was added aqueous hydrochloric acid (6.0 M, 30 mL). The mixture was stirred at 80 °C for 4 h, then cooled to room temperature and water (100 mL) was added. The resulting mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexanes / ethyl acetate = 40:1) to give the product (R)-VII-2 as a white solid in 60% yield over two steps (2.4 g, 3.98 mmol).

[0220] [α]D 23 : +261.6 (c = 1.0, CH2Cl2).

[0221] 1 H NMR (400 MHz, CDC13) δ 8.30 (s, 2H), 7.62-7.55 (m, 2H), 7.37-7.30 (m, 4H), 5.31 (s, 2H), 3.35-3.21 (m, 2H), 3.13-3.02 (m, 2H), 2.49-2.34 (m, 4H).

[0222] 13C NMR (101 MHz, CDC13) δ 147.7, 138.1, 133.4, 131.0, 130.0, 125.6, 125.4, 124.0, 122.0, 89.4, 41.1, 29.8, 26.1.

[0223] IR (thin film) 3459, 2937, 1571, 1485, 1418, 1358, 1263, 1195, 869, 753 cm-1 .

[0224] HRMS (ES-) C 25 H 17 I2O2 - (M-H+): 602.9323, found: 602.9323.

[0225] 5.3 Synthesis of (R)-VII-3

[0226]

[0227] To a 25 mL round bottom flask equipped with a stir bar was added (R)-VII-2 (188 mg, 0.3 mmol), potassium carbonate (219 mg, 1.6 mmol), 3,5-bis(trifluoromethyl)benzoic acid (771 mg, 3.0 mmol), palladium acetate (1.6 mg, 7 μmol), diamantylbutylphosphine (3.2 mg, 9 μmol), dimethoxyethane (2.0 mL), and water (2.0 mL) at room temperature. The flask was evacuated and backfilled with nitrogen 5 times. The mixture was then stirred at 90 °C under nitrogen for 24 h. After cooling to room temperature, a saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexanes / ethyl acetate = 40:1) to give the product (R)-VII-3 as a white solid in 99% yield (230 mg).

[0228] [α]D 23 : +159.0 (c = 1.0, CH2Cl2).

[0229] 1H NMR (400 MHz, Acetone-d6) δ 8.12 (d, J = 1.7 Hz, 4H), 7.98 (s, 2H), 7.94 (s, 2H), 8.85 - 7.75 (m, 2H), 7.44 - 7.30 (M, 4H), 6.57 (S, 2H), 3.50 - 3.30 (M, 2H), 3.11 (Dt, J = 16.3, 3.5 Hz, 2H), 2.68 - 2.47 (M, 4H).

[0230] 13 C NMR (101 MHz, Acetone-de) δ 148.4, 142.1, 134.7, 131.9 (q, J = 33.2 Hz), 131.4, 130.7, 130.2, 129.7, 127.7, 126.4, 126.2, 124.7, 124.6 (q, J = 273.1 Hz), 121.6 (q, J = 3.4 Hz), 41.5, 31.1, 26.9.

[0231] 19 F NMR (376 MHz, Acetone-de) δ -63.3.

[0232] IR (thin film) 3465, 1426, 1368, 1271, 1178, 1131, 896, 755, 700 cm"1.

[0233] HRMS (ES-) C 41 H 23 F 12 O2 - Theoretical value (M-H+): 775.1511, found: 775.1509.

[0234] 5.4 Synthesis of (R)-VII-4

[0235]

[0236] To a 25 mL round bottom flask equipped with a stir bar was added (R)-VII-2 (132 mg, 0.22 mmol), potassium carbonate (161 mg, 1.2 mmol), 1-pyrenylboronic acid (541 mg, 2.2 mmol), palladium acetate (1.1 mg, 4.7 μmol), diamantylbutylphosphine (2.1 mg, 6.0 μmol), dimethoxyethane (2.0 mL), and water (2.0 mL) at room temperature. The flask was evacuated and backfilled with nitrogen 5 times. The mixture was then stirred at 90 °C under nitrogen for 24 h. After cooling to room temperature, saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture, which was then extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexanes / ethyl acetate = 40:1) to give the product (R)-VII-4 as a white solid in 99% yield (175 mg) as a mixture of diastereomers due to axial chirality.

[0237] [α]D 23 : +40.9 (c = 1.0, CH2Cl2).

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 62.1, 7.7 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 8.26 - 8.05 (m, 8H), 8.04 - 7.87 (m, 3H), 7.87 - 7.76 (m, 2H), 7.76 - 7.62 (M, 2H), 7.56 - 7.35 (M, 5H), 7.26 - 6.75 (M, 5H), 5.69 (S, 1H), 3.36 - 3.16 (M, 2H), 3.13 - 2.86 (M, 2H), 2.79 - 2.31 (M, 4H).

[0239] 13 C NMR (101 MHz, DMSO-d6) δ 148.7, 133.9, 133.87, 133.82, 133.7, 133.5, 130.93, 130.87, 130.8, 130.6, 130.5, 130.3, 130.2, 130.19, 130.13, 129.6, 129.5, 129.2, 128.84, 128.75, 128.6, 128.5, 128.3, 127.7, 127.6, 127.5, 127.3, 127.2, 126.4, 126.2, 126.1, 125.9, 125.7, 125.5, 125.3, 125.2, 125.0, 124.7, 124.4, 124.2, 124.1, 124.08, 124.00, 122.5, 55.0, 30.0, 26.3.

[0240] IR (thin film) 3452, 3040, 2929, 2351, 1923, 1671, 1600. 1424, 1365, 1250, 1187, 1030, 841, 746 cm -1 .

[0241] HRMS (ES+) C 57 H 36 NaO2 + Theoretical value (M+Na+): 775.2608, found: 775.2617.

[0242] 5.5 Synthesis of (R)-VIIa

[0243]

[0244] Phosphorus oxychloride (7.5 mmol) was added to a solution of (R)-VII-3 (260 mg, 0.33 mmol) in pyridine (2.5 mL) at 0 °C under nitrogen atmosphere. The mixture was heated to 90 °C and stirred at the same temperature for 24 h. Then, the mixture was cooled to 0 °C, followed by slow addition of water (1.0 mL) and 1,4-dioxane (2.0 mL). Next, the mixture was heated to 90 °C and stirred at the same temperature for 48 h, then cooled to room temperature, diluted with dichloromethane (10 mL) and washed with aqueous hydrochloric acid (1.0 M, 20 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40:1). The obtained product was re-dissolved in dichloromethane (4.0 mL) and treated with aqueous hydrochloric acid (3.0 M, 2.0 mL). The organic layer was separated, dried over sodium sulfate, and evaporated to give the desired chiral phosphoric acid (R)-VIIa as a white solid in 91% yield (255 mg).

[0245] [α]D 23 : +456.0 (c = 1.0, CH2Cl2).

[0246] 1 H NMR (400 MHz, Acetone-d6) δ 8.24 (s, 4H), 8.14 (s, 2H), 8.05 - 7.89 (m, 4H), 7.60 - 7.39 (m, 4H), 3.60 - 3.40 (m, 2H), 3.15 (dd, J = 17.5, 3.0 Hz, 2H), 2.49 (td, J = 14.1, 4.9 Hz, 2H), 2.25 - 2.14 (m, 2H).

[0247] 13 C NMR (101 MHz, Acetone-d6) δ 142.2, 141.4, 141.3, 137.1, 137.0, 135.1, 134.28, 134.25, 133.68, 133.67, 131.7 (q, J = 33.2 Hz), 131.5, 131.4, 131.03, 131.01, 130.7, 128.2, 127.5, 126.7, 124.6 (q, J = 273.1 Hz), 121.5 (q, J = 3.8 Hz), 45.89, 45.87, 35.4, 27.6.

[0248] 31 P NMR (162 MHz, acetone-d6) δ -13.1.

[0249] 19F NMR (376 MHz, Acetone-d6) δ -63.1.

[0250] IR (thin film) 3049, 2356, 1595, 1506, 1452, 1357, 1272, 1185, 1139, 1072, 1012, 921, 822, 744 cm -1

[0251] HRMS (ES+) C 41 H 23 F 12 NaO4P + Theoretical value (M+Na+): 861.1035, found: 861.1037.

[0252] 5.6 Synthesis of (R)-VIIb

[0253]

[0254] Phosphorus oxychloride (7.5 mmol) was added to a solution of (R)-VII-4 (250 mg, 0.33 mmol) in pyridine (2.5 mL) at 0 °C under nitrogen atmosphere. The mixture was heated to 90 °C and stirred at the same temperature for 24 h. Then, the mixture was cooled to 0 °C, followed by slow addition of water (1.0 mL) and 1,4-dioxane (2.0 mL). The mixture was then heated to 90 °C and stirred at the same temperature for 48 h, then cooled to room temperature, diluted with dichloromethane (10 mL) and washed with aqueous hydrochloric acid (1.0 M, 20 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (10 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40:1). The obtained product was re-dissolved in dichloromethane (4.0 mL) and treated with aqueous hydrochloric acid (3.0 M, 2.0 mL). The organic layer was separated, dried over sodium sulfate and evaporated to give the desired chiral phosphoric acid (R)-VIIb as a white solid in 74% yield (200 mg), which was a mixture of diastereomers due to axial chirality.

[0255] [α]D 23 : +378.3 (c = 0.5, CH2Cl2).

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 - 7.72 (m, 20H), 7.72 - 7.36 (m, 6H), 3.50 - 3.32 (m, 2H), 3.28 - 3.06 (m, 2H), 2.63 - 2.43 (m, 2H), 2.34 - 2.16 (m, 2H).

[0257] 13 C NMR (101 MHz, DMSO-D6) δ 142.2, 135.2, 134.9, 131.2, 133.6, 132.9, 130.5, 130.34, 130.28, 129.9, 129.3, 129.5, 128.8, 128.3, 127.5, 127.3, 126.8, 126.2, 125.8, 125.4, 125.2, 125.1, 124.5, 123.9, 123.7, 123.3, 44.5, 44.3, 35.0, 29.1, 26.7

[0258] 31 P NMR (162 MHz, DMSO-d6) δ -12.80, -13.12, -13.59.

[0259] IR (thin film) 3042, 2921, 2853, 2354, 1594, 1413, 1262, 1169, 1088, 956, 841, 728, 564 cm -1 .

[0260] HRMS (ES+) C 57 H 35 NaO4P + Theoretical value (M+Na+): 837.2166, found: 837.2175.

[0261] 6. Use of chiral monophosphoramidite ligands and chiral phosphoric acids

[0262] 6.1 Use of (R)-VIa

[0263] 6.1.1 Asymmetric hydrogenation of dehydroamino acid derivative VIIIa

[0264]

[0265] To a vial with a magnetic stir bar was added bis(1,5-cyclooctadiene)tetrafluoroborate (3.5 mg, 0.01 mmol), (R)-VIa (8.5 mg, 0.02 mmol) and dry dichloromethane (1.0 mL) under nitrogen. The mixture was stirred for 30 min. Then a solution of the chiral rhodium complex (0.1 mL) was added to dehydroamino acid derivative VIIIa (44.0 mg, 0.2 mmol) in dry toluene (2.0 mL). The reaction mixture was transferred to a pressure vessel, backfilled with H2 gas (<10 bar) three times and finally the pressure vessel was pressurized with H2 at 10 bar. The mixture was stirred at room temperature for 8 h. The solution was concentrated in vacuo and sampled with GC-MS. 1H NMR assay of conversion. The residue was purified by silica gel column chromatography to give the hydrogenated product IXa as a white solid in 99% yield (43.6 mg, 99% ee).

[0266] [α]D 23 -57.2 (c = 1.0, CH2Cl2). The following HPLC analysis was performed on this product: Daicel CHIRALPAK AD-H column; 10% i-PrOH in n-hexane; 1.0 mL / min; retention time. 9.4 min (major peak), 13.0 min (minor peak).

[0267] 1 H NMR (400 MHz, CDC13) δ 7.32 - 7.19 (m, 3H), 7.12 - 7.05 (m, 2H), 6.05 (s, 1H), 4.92 - 4.83 (m, 1H), 3.71 (s, 2H), 3.18 - 3.02 (m, 2H), 1.97 (s, 2H).

[0268] 13 C NMR (101 MHz, CDC13) δ 172.1, 169.6, 135.8, 129.2, 128.5, 127.1, 53.1, 52.2, 37.8, 23.0.

[0269] 6.1.2 Asymmetric hydrogenation of dehydroamino acid derivative VIIIb

[0270]

[0271] To a vial with a magnetic stir bar was added bis(1,5-cyclooctadiene)tetrafluoroborate (3.7 mg, 0.01 mmol), (R)-VIa (8.5 mg, 0.02 mmol) and anhydrous dichloromethane (1.0 mL) under nitrogen. The mixture was stirred for 30 min. Then a solution of the chiral rhodium complex (0.6 mL) was added to dehydroamino acid derivative VIIIb (94.2 mg, 0.6 mmol) in anhydrous Tol (6.0 mL). The reaction mixture was transferred to a pressure vessel, backfilled with H2 gas (<5 bar) three times and finally the pressure vessel was pressurized with 5 bar of H2. The mixture was stirred at room temperature for 12 h. The solution was concentrated in vacuo and sampled with 1 H NMR assay of conversion. The residue was purified by silica gel column chromatography to give the hydrogenated product IXa as a white solid in 99% yield (43.6 mg, 99% ee).

[0272] [α]D 23-5.8 (c = 1.0, CH2Cl2). The product was analyzed by the following HPLC: Daicel CHIRALCEL OD-H column; 5% i-PrOH in n-hexane; 1.0 mL / min; retention time. 13.8 min (major peak), 20.6 min (minor peak).

[0273] 1 H NMR (400 MHz, CDC13) δ 6.16 (s, 1H), 4.61-4.51 (m, 1H), 3.72 (s, 3H), 2.01 (s, 3H), 1.92-1.79 (m, 1H), 1.77-1.62 (m, 1H), 0.88 (t, J = 7.5 Hz, 3H).

[0274] 13 C NMR (101 MHz, CDC13) δ 173.04, 169.79, 53.15, 52.25, 25.55, 23.09, 9.41.

[0275] 6.1.3 Asymmetric hydrogenation of dehydroamino acid derivative VIIIc

[0276]

[0277] To a vial with a magnetic stir bar was added bis(benzene)chromium tricarbonyl 2 (5.0 mg, 0.01 mmol), (R)-VIa (8.5 mg, 0.02 mmol) and anhydrous dichloromethane (1.0 mL) under nitrogen. The mixture was stirred for 30 min. To a solution of dehydroamino acid derivative VIIIc (118 mg, 0.8 mmol) in anhydrous toluene (8.0 mL) was added a solution of the chiral rhodium complex (0.4 mL). The reaction mixture was back-flushed with H2gas three times. The mixture was stirred at room temperature under an atmosphere of H2for 24 h. The solution was concentrated in vacuo and sampled by HPLC. 1 H NMR was used to determine conversion. The residue was purified by silica gel column chromatography to give the hydrogenated product IXc as a colorless oil in 99% yield (116.8 mg, 99% ee).

[0278] [α]D 23 : +28.2 (c = 1.0, CH2Cl2). The product was analyzed by the following HPLC: Daicel CHIRALCEL OD-H column; 5% i-PrOH in n-hexane; 1.0 mL / min; retention time. 13.8 min (major peak), 20.6 min (minor peak).

[0279] 1H NMR (400 MHz, CDC13) δ 6.16 (s, 1H), 4.61-4.51 (m, 1H), 3.72 (s, 3H), 2.01 (s, 3H), 1.92-1.79 (m, 1H), 1.77-1.62 (m, 1H), 0.88 (t, J = 7.5 Hz, 3H).

[0280] 13 C NMR (101 MHz, CDC13) δ 173.04, 169.79, 53.15, 52.25, 25.55, 23.09, 9.41.

[0281] 6.2 Use of (R,R N,R N)-Vlc

[0282] 6.2.1 Rhodium-catalyzed intermolecular hydroacylation

[0283]

[0284] (R,R N,R N)-Vlc (12.1 mg, 0.02 mmol) and 1,5-cyclooctadiene rhodium chloride (4.9 mg, 0.01 mmol) were dissolved in dry dichloromethane (2.0 mL) and the solution was transferred to a Schlenk tube containing potassium phosphate (4.2 mg, 0.02 mmol), salicylaldehyde Xa (22 μί, 0.2 mmol) and homoallylic sulfide Xb (46 μί, 0.3 mmol). The reaction mixture was stirred at 0 °C for 72 h and the reaction mixture was analyzed by H NMR. The branched / linear ratio (bl) was determined to be > 20: 1. The crude product was purified by silica gel column chromatography to give the hydrogenation product XIa as a colorless oil in 91% yield (52.4 mg, 93% ee). 1 H NMR analysis, the branched / linear ratio (bl) was determined to be > 20: 1. The crude product was purified by silica gel column chromatography to give the hydrogenation product XIa as a colorless oil in 91% yield (52.4 mg, 93% ee).

[0285] [α]D 23 : +55.0 (c = 1.0, CH2Cl2). The product was analyzed by HPLC: Daicel CHIRALCEL OD-H column; 1% i-PrOH in n-hexane; 1.0 mL / min; retention time. 9.5 min (major peak), 10.3 min (minor peak).

[0286] 1H NMR (400 MHz, CDC13) δ 12.47 (s, 1H), 7.77-7.70 (m, 1H), 7.50-7.41 (m, 1H), 7.35-7.22 (m, 4H), 7.20-7.11 (m, 1H), 7.02-6.95 (m, 1H), 3.82-3.69 (m, 1H), 3.04-2.88 (m, 2H), 2.28-2.15 (m, 1H), 1.84-1.71 (m, 1H), 1.24 (D, J = 6.9 Hz, 3H).

[0287] 13 C NMR (101 MHz, CDC13) δ 209.7, 163.1, 136.4, 135.8, 129.8, 129.1, 128.9, 126.0, 118.9, 118.7, 118.4, 38.7, 32.5, 31.2, 17.5.

[0288] 6.2.2 Rhodium-catalyzed intermolecular hydroacylation

[0289]

[0290] (R,RN,RN)-Vic (6.1 mg, 0.01 mmol) and 1,5-cyclooctadiene rhodium chloride (2.5 mg, 0.005 mmol) were dissolved in dry dichloromethane (2.0 mL) and the solution was transferred to a Schlenk tube containing potassium phosphate (2.1 mg, 0.01 mmol), 2-hydroxy-1-naphthaldehyde Xc (34.6 mg, 0.2 mmol) and homoallyl sulfide Xb (46 μL, 0.3 mmol). The reaction mixture was stirred at room temperature for 72 h, and the reaction mixture was analyzed by HPLC. The crude product was purified by silica gel column chromatography to give the hydroacylated product XIb as a colorless oil in 95% yield (63.8 mg, 82% ee). 1 H NMR analysis determined the branched / linear ratio (b:l) to be 8.7:1. The crude product was purified by silica gel column chromatography to give the hydroacylated product XIb as a colorless oil in 95% yield (63.8 mg, 82% ee).

[0291] [α]D 23 : +50.1 (c = 1.0, CH2Cl2). The product was analyzed by HPLC: Daicel CHIRALCEL OD-H column; 2% i-PrOH in n-hexane; 1.0 mL / min; retention time. 32.5 min (minor peak), 34.9 min (major peak).

[0292] 1H NMR (400 MHz, CDC13) δ 11.89 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.45 - 7.36 (m, 1H), 7.26 - 7.08 (m, 6H), 4.03 - 3.86 (m, 1H), 2.86 (t, J = 7.4 Hz, 2H), 2.25 - 2.12 (m, 1H), 1.92 - 1.81 (m, 1H), 1.32 (d, J = 6.7 Hz, 3H).

[0293] 13 C NMR (101 MHz, CDC13) δ 211.6, 161.1, 136.5, 135.7, 131.4, 129.2 (2C), 128.8, 128.6, 127.9, 76.0, 124.3, 123.9, 119.3, 115.9, 3.13.

[0294] IR (thin film) 3058, 2972, 2357, 1677, 1512, 1264, 1177, 1091, 825, 738 cm -1 .

[0295] HRMS (ES-) for C 21 H 19 O2S (M-) 335.1111 found 335.1100.

[0296] 6.3 Use of (R)-VIIa

[0297] Enantioselective spirocyclization of ketone substrates Ha catalyzed by (R)-VIIa for the synthesis of (S)-la

[0298]

[0299] Ha (10.05 g, 27.1 mmol), (R)-Vle (22.4 mg, 27 μηιοΐ) and 135 mL of toluene were added to a 250 mL flask with a magnetic stirring bar. After completion of the reaction, the solvent was evaporated and the residue was filtered through a short pad of silica gel (eluent: dichloromethane) to give the product (S)-la as a white solid in 89% yield (8.45 g, 93% ee).

[0300] HPLC analysis of the product: Daicel CHIRALPAK AD-H column; 20% i-PrOH in n-hexane; 1.0 mL / min; retention time: 9.2 min (minor peak), 13.9 min (major peak).

[0301] 6.4 Use of (R)-VIIb

[0302] (R)-VIIb catalyzes the intramolecular desymmetrization of oxirane XII.

[0303]

[0304] A mixture of XII (24.3 mg, 0.1 mmol) and (R)-VIIb (8.2 mg, 0.01 mmol) in toluene (1.0 mL) was stirred at 50 °C for 36 h. Next, the reaction mixture was filtered through a short plug of silica (eluent: hexane / ethyl acetate = 2:1). Concentration of the filtrate gave the desired product XIII as a white solid in 99% yield (62% ee).

[0305] [α]D 23 : +58.4 (c = 1.0, CH2Cl2). The product was analyzed by HPLC: Daicel CHIRALPAK IC column; 30% i-PrOH in n-hexane; 1.0 mL / min; retention time. 5.9 min (major peak), 10.5 min (minor peak).

[0306] 1 H NMR (400 MHz, CDC13) δ 11.74 (s, 1H), 8.21 (d, J = 9.4 Hz, 1H), 7.70 (dd, J = 25.7, 8.1 Hz, 2H), 7.46 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.36 - 7.26 (m, 2H), 4.64 - 4.49 (m, 2H), 4.48 - 4.37 (m, 1H), 4.01 - 3.89 (m, 1H), 3.74 (dd, J = 11.7, 3.4 Hz, 1H), 2.04 (s, 1H).

[0307] 13 C NMR (101 MHz, CDC13) δ 166.5, 155.1, 136.7, 129.9, 128.7, 128.3, 127.0, 126.3, 123.6, 112.5, 110.8, 68.6, 67.2, 63.8.

[0308] IR (thin film) 3384, 3052, 2920, 2729, 2356, 1646, 1521, 1461, 1359, 1306, 1209, 1143, 1045, 957, 872, 745 cm -1 .

[0309] HRMS (ES-) for C14 H 12 Calcd for N03"(M-H+): 242.0822, Found: 242.0816.

[0310] Comparative Example

[0311]

[0312] When (R)-VIa was used as the ligand, the product was obtained with a superior enantiomeric excess (ee).

[0313] Intermolecular hydroacylation reaction:

[0314]

[0315] When (R,RN,RN)-VIc was used as the ligand, the product was obtained with superior yield, ee, and regioselectivity.

[0316] Enantioselective spirocyclization reaction:

[0317]

[0318] In this reaction, when 1 mol% of (R)-VIIa was used as the catalyst, the product was obtained with 95% yield and 95% ee, which is significantly superior to the 83% yield and 90% ee obtained using (R)-SPINOL-3,5-(CF3)2C6H2-OH catalyst. Furthermore, when the amount of (R)-VIIa used was reduced to 0.1 mol%, 89% yield and 93% ee were obtained, which is even superior to the results obtained using 2 mol% of (R)-SPINOL-3,5-(CF3)2C6H2-OH (89% yield and 90% ee), demonstrating the superior catalytic activity and chiral induction ability of the SPHENOL backbone chiral catalyst.

[0319] Intramolecular desymmetrization reaction:

[0320]

[0321] In this reaction, the SPHENOL backbone catalyst (R)-VIIb has both superior catalytic activity and chiral control ability compared to BINOL and SPINOL backbone catalysts, demonstrating that the SPHENOL backbone chiral catalyst has both the advantages of the superior catalytic activity of BINOL catalysts and the superior chiral control ability of SPINOL catalysts.

[0322] It is understood that the above-mentioned embodiments are only illustrative examples for illustrating the principles of the present disclosure, and the present disclosure is not limited thereto. Various modifications and improvements can be made by those of ordinary skill in the art without departing from the spirit and essence of the present disclosure, and these modifications and improvements are also considered to be within the scope of protection of the present disclosure.

Claims

1. A chiral spiro compound having a structure represented by the following Formula I or VI, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 each independently represent H, C 1-18 alkyl, phenyl optionally substituted with -CF3, or R 11 , R 12 each independently is hydrogen, C1-6alkyl or -CH(CH3)Ph, n is selected from an integer from 0 to 5; or The structure of the chiral spiro compound is:

2. The chiral spiro compound according to claim 1, characterized by The compound is selected from any one of the following: where Me represents methyl, Et represents ethyl and Ph represents phenyl.

3. A process for the preparation of a chiral spiro compound according to claim 1, characterized in that comprising the step of converting a ketone compound represented by the following Formula II into a bisnaphthol compound represented by Formula I in the presence of a chiral acid catalyst and a solvent: and, optionally converting the bisnaphthol compound represented by Formula I into other chiral spiro compounds other than Formula I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 each independently represent H, C 1-18 alkyl, phenyl optionally substituted with -CF3, or n is selected from an integer from 0 to 5.

4. The method of claim 3, wherein The chiral acid catalyst is selected from at least one of the following: where R represents a substituted benzene, naphthalene, fluorene, pyrene, anthracene phenanthrene or triaryl, and the substituents are selected from at least one of a halogen atom, a hydroxyl group, an aldehyde group, a carboxyl group, an amino group, a C1-C18 alkyl group substituted with one or more C6-C18 aryl groups or heterocyclic aryl groups of ring-forming carbon atoms 5-18, a halogen atom, an aryl group of ring-forming carbon atoms 6-18, a heterocyclic aryl group of ring-forming carbon atoms 5-18, a mercapto group, a cyano group and a nitro group.

5. The method according to claim 3 or 4, characterized in that, The solvent is selected from at least one of the following solvents: chlorobenzene, PhCF3, PhF, CCl4, DCM, CHCl3, PhMe, DCE.

6. The method according to claim 3 or 4, characterized in that, The chiral acid catalyst is an (S)-type chiral phosphoric acid which catalyzes the reaction to provide a chiral spiro diol having an inverted configuration.

7. Use of the compound according to claim 1 or 2 in an asymmetric catalytic reaction, an intermolecular hydroacylation reaction, an enantioselective spirocyclization reaction or an intramolecular desymmetrization reaction.

8. Use according to claim 7, characterized in that The asymmetric catalytic reaction is one of the following asymmetric hydrogenations:

9. Use according to claim 7, characterized in that The intermolecular hydroacylation reaction is selected from one of the following: and 10. Use according to claim 7, characterized in that The enantioselective spirocyclization reaction is selected from:

11. Use according to claim 7, characterized in that The intramolecular desymmetrization reaction is selected from:

12. Use of the compound according to claim 1 or 2 as a chiral catalyst or a chiral ligand.

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