Collective synthesis of phantomolin family through total synthesis of the sesquiterpene lactone molephantin

Abstract

Disclosed herein are processes to generate an intermediate in the total synthesis of (+)- molephantin or a derivative thereof, and a total synthesis of (+)-molephantin or a derivative thereof. Also disclosed herein are methods of forming a compound of formula XIV and of forming a compound of formula XV, wherein compound of formula XIV and compound of formula XV are as defined in the description.

Description

[0001] COLLECTIVE SYNTHESIS OF PHANTOMOLIN FAMILY THROUGH TOTAL SYNTHESIS OF THE SESQUITERPENE LACTONE MOLEPHANTIN

[0002] Field of Invention

[0003] The present invention generally relates to the synthesis of phantomolin family, and more particularly relates to the processes and methods for collective synthesis of phantomolin family through total synthesis of the sesquiterpene lactone molephantin.

[0004] Background

[0005] The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0006] The diverse family of sesquiterpene lactones (germacranolides), which are plant secondary metabolites, has captured considerable attention from the natural product chemistry, medicinal chemistry, and synthetic chemistry communities over the years. Molephantin (1), a highly oxygenated germacranolide, was first isolated in 1973 from a medicinal herb, Elephantopus mollis, by Lee (K.-H. Lee et al., J. Chem. Soc. Chem. Commun. 1973, 476- 477), and then found in 2012 from Elephantopus tomentosus by Liu and Dai (W.-L. Mei et al., Phytochem. Lett. 2012, 5, 800-803) (Fig. 1A). Molephantin (1) is known to exhibit strong in vivo antitumor activity in Ehrlich and Walker 256 carcinosarcoma tumors (I. H. Hall et al., J. Pharm. Sci. 1978, 67, 1235-1239) as well as anti-inflammatory and leishmanicidal activities (Z.-N. Wu et al., Phytochemistry 2017 , 137, 81-86; and H. Fuchino et al., Planta Med. 2001 ,

[0007] 67, 647-653). The molecular structure of molephantin (1) consists of a 10-membered macrocyclic core with an (E,Z)-dienone moiety (C10-1-4), which is fused with an a-methylene- y-butyrolactone and adorned with four successive stereogenic centers (C5-8). Tomenphantopin F (2), isolated in 2012 from Elephantopus tomentosus by Liu and Dai, is structurally analogous to molephantin (1) (B. Wang et al., Chin. J. Chem. 2012, 30, 1320- 1322). Its structure is based on the same 10-membered macrocyclic core with an a-(S)-methyl- y-butyrolactone moiety and a free hydroxyl group at C8. Other topologically relevant constituents found in Elephantopus mollis and Elephantopus tomentosus include furanogermacranolides such as EM-2 (2-deethoxy-2β-methoxyphantomolin) (3) (S. Banerjee e al., Planta Med. 1986, 52, 29-32), phantomolin (4) (K.-H. Lee et al., J. Pharma. Sci. 1980,

[0008] 68, 1050-1056), 2-O-demethyltomenphantopin C (5) (Z.-N. Wu et al., Phytochemistry 2017 , 137, 81-86), and tomenphantopin C (6) (W.-L. Mei et al., Phytochem. Lett. 2012, 5, 800-803; and M. Bai et al., J. Nat. Prod. 2022, 85, 2433-2444). Notably, EM-2 (3) has been observed to render breast cancer cells more susceptible to epirubicin when both are co-administered, primarily by inhibiting the cells’ protective autophagy pathway (J. Li etal., Phytomedicine 2023, 116, 154878). Their 10-membered macrocyclic core contains a (Z,Z)-skipped diene centered on a C2 (hemi)ketal carbon. While the biosynthetic routes of these highly oxygenated (furano)germacranolides remain unclear, we posited that molephantin (1) could be a biosynthetic precursor of EM-2 (3) and other furanogermacranolides. This hypothesis is based on their intriguing topological similarity, suggesting a potential synthetic route involving E / Z- isomerization of the C1-C10 double bond of molephantin (1) to the (Z,Z)-dienone congener A and its successive (hemi)ketalization with the C5-hydroxyl group.

[0009] Despite the landmark studies in the synthesis of highly oxygenated germacranolides isolated from different plant species such as eremantholide (J. Am. Chem. Soc. 1991 , 113, 9682- 9684), and goyazensolide (ACS Cent. Sci. 2021 , 7, 954-962), to the best of our knowledge, total synthesis of (furano)germacranolides derived from Elephantopus species has not been reported (Fig. 1 B). The exception to this gap is the synthesis of nordeoxyelephantopin, an unnatural analogue of deoxyelephantopin derived from Elephantopus scaber (R. Lagoutte et al., Nat. Commun. 2016, 7, 12470; and R. Lagoutte et al., J. Antibiot. 2018, 71, 248-256).

[0010] Therefore, there exists a need for new synthetic routes allowing the access of sesquiterpene lactones.

[0011] Summary of Invention

[0012] Aspects and embodiments of the invention are provided in the following numbered clauses.

[0013] 1. A process to generate an intermediate in the total synthesis of (+)-molephantin or a derivative thereof, the process comprising:

[0014] (a) providing a compound of formula I:

[0015] where:

[0016] Prot1represents an acid-labile protecting group;

[0017] X represents Cl or, more particularly, Br; and

[0018] (b) reacting the compound of formula I for a period of time with a compound of formula II: where Prot2is selected from a triethylsilyl group, a triisopropylsilyl group, a tert- butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or, more particularly, a tri methylsilyl group, under reaction conditions involving a stoichiometric excess of one or both of a metal salt and a metal relative to the compound of formula I, a solvent and at a temperature of from 0 to 25 °C to provide a compound of formula III: where Prot1is as defined above.

[0019] 2. The process according to Clause 1 , wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p- methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1- (2-chloroethoxy)ethyl ether, 1-methyl-1 -methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1 -methyl- 1 -phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

[0020] 3. The process according to Clause 1 or Clause 2, wherein one or more of the following apply:

[0021] (ai) the metal and / or metal salt is selected from one or more of zinc metal, indium metal, a chromium (III) salt with manganese metal, samarium (II) iodide, tin (II) chloride, and a chromium (II) salt, optionally wherein the metal and / or metal salt is chromium (II) bromide or, more particularly, chromium (II) chloride;

[0022] (bi) the solvent is selected from one or more of the group consisting of tetrahydrofuran, 2- methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,1- dimethoxyethane, dimethylsulfoxide, dimethylacetamide, and, more particularly, dimethyl formamide; and

[0023] (ci) the temperature is about 10 °C.

[0024] 4. A process to generate an intermediate in the total synthesis of (+)-molephantin or a derivative thereof, the process comprising:

[0025] (aii) providing a compound of formula IV: where Prot1represents an acid-labile protecting group; and

[0026] (bii) subjecting the compound of formula IV for a period of time to reaction conditions involving a catalytic amount of a nickel (II) salt or a palladium (II) salt, a stoichiometric excess of one or both of a metal and a metal salt relative to the compound of formula IV, in a solvent, and at a temperature of from 5 to 60 °C to provide a compound of formula V:

[0027] where R is Prot1and Prot1is as defined above.

[0028] 5. The process according to Clause 4, wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p- methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1- (2-chloroethoxy)ethyl ether, 1-methyl-1 -methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1 -methyl- 1 -phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

[0029] 6. The process according to Clause 4 or Clause 5, wherein one or more of the following apply:

[0030] (aiii) the metal and / or metal salt is selected from one or more of a chromium (III) salt with manganese metal, samarium (II) iodide, and a chromium (II) salt, optionally wherein the metal and / or metal salt is chromium (II) bromide or, more particularly, chromium (II) chloride;

[0031] (biii) the solvent is selected from one or more of the group consisting of tetrahydrofuran, 2- methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,1- dimethoxyethane, dimethyl formamide, dimethylacetamide, and, more particularly, dimethyl sulfoxide;

[0032] (ciii) the temperature is about 25 °C; and

[0033] (diii) the catalytic nickel (II) salt or palladium (II) salt is selected from one or more of the group consisting of nickel (II) chloride, nickel (II) bromide, nickel(ll) iodide, nickel(ll) chloride ethylene glycol dimethyl ether complex, 1 ,2-bis(diphenylphosphino)ethane nickel (II) chloride, bis(1,5-cyclooctadiene)nickel(0), 1,3-bis(diphenylphosphino)propane]dichloronickel(ll), tetrakis(triphenylphosphine)nickel, palladium (II) chloride, palladium (II) acetate, and nickel (II) bis(acetylacetonate), optionally wherein the catalytic nickel (II) salt or palladium (II) salt is nickel (II) bis(acetylacetonate).

[0034] 7. A total synthesis of (+)-molephantin or a derivative thereof, the process comprising the synthetic process according to any one of Clauses 1 to 3 and the synthetic process according to any one of Clauses 4 to 6.

[0035] 8. The process according to Clause 7, wherein the compound of formula IV: where Prot1represents an acid-labile protecting group, is prepared by:

[0036] (aiv) providing a compound of formula III: where Prot1is as defined above; and

[0037] (biv) subjecting the compound of formula III to an oxidation reaction to provide the compound of formula IV, optionally wherein the oxidation conditions comprise a stoichiometric excess of manganese dioxide in a solvent (e.g. methylene chloride) and at a temperature of from 5 to 35 °C (e g. about 25 °C), optionally wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

[0038] 9. The process according to Clause 7 or Clause 8, wherein the compound of formula I: where Prot1represents an acid-labile protecting group, is provided by:

[0039] (av) providing a compound of formula la:

[0040] ; and

[0041] (bv) protecting the free hydroxyl of the compound of formula la with an acid-labile protecting group using suitable conditions for a selected protecting group, optionally wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

[0042] 10. The process according to Clause 9, wherein the protecting group is methoxymethyl ether and the reaction conditions involve reaction of the compound of formula la with dimethoxymethane as a solvent and reagent and a catalytic amount of a suitable acidic catalyst (e.g. triflic acid).

[0043] 11 . The process according to Clause 9 or Clause 10, wherein the compound of formula la is provided by reaction of a compound of formula VI: with a stoichiometric excess of hydrobromic acid in a solvent (e.g. ethyl acetate) at a suitable temperature (e.g. about 25 °C). 12. The process according to Clause 11, wherein the compound of formula VI is provided by reaction of a compound of formula VII: with methyl acrylate, a suitable base (e.g. 1 ,4-diazabicyclo[2.2.2]octane), and at a suitable temperature (e.g. about 25 °C).

[0044] 13. The process according to Clause 12, wherein the compound of formula VII is provided by reaction of a compound of formula VIII: with a reducing agent (e.g. diisobutylaluminium hydride), in a suitable solvent (e.g. methylene chloride), and at a suitable temperature (e.g. about -78 °C).

[0045] 14. The process according to Clause 13, wherein the compound of formula VIII is provided by reaction of a compound of formula IX: with (iodomethyl)triphenylphosphonium iodide, and a suitable base (e.g. sodium hexamethyldisilazide) in a suitable solvent (e.g. tetrahydrofuran), and at a suitable temperature (e.g. about -78 °C).

[0046] 15. The process according to Clause 14, wherein the compound of formula IX is provided by reaction of a compound of formula X: with methyl lithium in a suitable solvent (e.g. methylene chloride), and at a suitable temperature (e.g. about -78 °C).

[0047] 16. The process according to any one of Clauses 7 to 15, wherein the compound of formula V:

[0048] where R is Prot1and Prot1is as defined in Clause 8, is subjected to an oxidation reaction to provide a compound of formula XI: where R is as defined above, optionally wherein the oxidation reaction involves a stoichiometric excess of manganese dioxide and a solvent (e.g. methylene chloride) at a suitable temperature (e.g. 25 °C).

[0049] 17. The process according to Clause 16, wherein the compound of formula XI is reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g. triethylamine), a catalytic base (e.g. dimethylaminopyridine) in a suitable solvent (e.g. tetra hydrofuran) and at a suitable temperature (e.g. 25 °C), to provide a compound of formula XII: where R is Prot1and Prot1is as defined in Clause 8 and R’ is H or CH3.

[0050] 18. The process according to Clause 17, wherein the compound of formula XII is reacted with an acid (e.g. trifluoroacetic acid) in a suitable solvent (e.g. methylene chloride) and at a suitable temperature (e.g. 25 °C), to provide a compound of formula XIII: where R’ is H or CH3.

[0051] 19. A method of forming a compound of formula XIV

[0052] where R’ is H or CH3, by a cyclisation reaction of a compound of formula XIII: where R’ is as defined above, through the application of ultraviolet light to the compound of formula XIII in a suitable solvent (e.g. methylene chloride) at a suitable temperature (e.g. about 25 °C), optionally wherein the ultraviolet light is provided at a wavelength of from 200 to 400 nm (e.g. about 370 nm) at a suitable power (e.g. from 10 to 100 Watts, such as about 40 Watts) and using a light source at a suitable distance from a reaction vessel including the compound of formula XIII (e.g. from 1 to 10 cm, such as about 4 cm).

[0053] 20. A method of forming a compound of formula XV:

[0054] where R” is selected from C1to C10alkyl or C2to C10alkenyl, from a compound of formula XIV, where R’ is H or CH3, through reacting the compound of formula XIV with an alcohol of formula

[0055] XVI:

[0056] R”-OH XVI in the presence of an acid catalyst (e.g. the catalyst is para-toluene sulfonic acid).

[0057] Drawings

[0058] Fig. 1 depicts A) germacranolides and furanogermacranolides isolated from Elephantopus mollis and Elephantopus tomentosus. B) Highly oxygenated germacranolides derived from different plants. Fig. 2 depicts1H nuclear magnetic resonance (NMR) spectrum of the crude residue containing aldehyde 12.

[0059] Fig. 3 depicts1H NMR spectrum of the crude residue containing methyl ketone 13.

[0060] Fig. 4 depicts1H NMR spectrum of the purified iodoalkene 14.

[0061] Fig. 5 depicts X-ray crystallographic data of Compound 17 (CCDC-2312148).

[0062] Fig. 6 depicts X-ray crystallographic data of Compound 17’ (CCDC-2312149).

[0063] Fig. 7 depicts1H-1H COSY and HMBC correlations for 18.

[0064] Fig. 8 depicts monitoring of the reaction progress by liquid chromatography-mass spectrometry (LC-MS).

[0065] Fig. 9 depicts X-ray crystallographic data of Compound 20 (CCDC-2312151).

[0066] Fig. 10 depicts origin of the diastereoselectivity in the formation of compound 20.

[0067] Fig. 11 depicts1H-1H COSY and HMBC correlations for molephantin (1).

[0068] Fig. 12 depicts X-ray crystallographic data of Compound 23 (CCDC-2312152).

[0069] Fig. 13 depicts1H-1H COSY and HMBC correlations for tomenphantopin F (2).

[0070] Fig. 14 depicts photochemical reaction setting (the fan was removed from the photo for clarity). The distance between the lamp and the reaction tube was set to 4 cm.

[0071] Fig. 15 depicts ultraviolet-visible (UV-vis) absorption spectrum of molephantin (1) (0.5 mM in CH2CI2).

[0072] Fig. 16 depicts1H NMR monitoring of the photoinduced reaction in CDCI3.

[0073] Fig. 17 depicts1H-1H COSY and HMBC correlations for 25 (photoinduced cycloisomerization of molephantin (1)). Fig. 18 depicts X-ray crystallographic data of EM-2 (3) (CCDC-2324191).

[0074] Fig. 19 depicts1H-1H COSY and HMBC correlations for EM-2 (3).

[0075] Fig. 20 depicts1H-1H COSY and HMBC correlations for phantomolin (4).

[0076] Fig. 21 depicts1H-1H COSY and HMBC correlations for 2-O-demethyltomenphantopin C (5).

[0077] Fig. 22 depicts X-ray crystallographic data of Tomenphantopin C (6) (CCDC-2312153).

[0078] Fig. 23 depicts1H-1H COSY and HMBC correlations for tomenphantopin C (6).

[0079] Fig. 24 depicts retrosynthetic analysis of molephantin (1).

[0080] Fig. 25 depicts A) synthetic route to aldehyde fragment 12. B) Synthetic route to 3- bromomethyl-5H-furan-2-one 17. C) Synthesis of molephantin (1). D) Synthesis of tomenphantopin F (2).

[0081] Fig. 26 depicts collective synthesis of furanogermacranolides.

[0082] Fig. 27 depicts stereoselective synthetic route of (+)-molephantin.

[0083] Fig. 28 depicts the synthetic route of synthon 9.

[0084] Fig. 29 depicts the synthetic route of aldehyde 12.

[0085] Fig. 30 depicts the En route to (+)-molephantin.

[0086] Fig. 31 depicts example with (+ / -)-molephantin.

[0087] Description

[0088] It has been surprisingly found that collective synthesis of (furano)germacranolides may be derived from Elephantopus mollis and Elephantopus tomentosus.

[0089] Thus, in a first aspect of the invention, there is provided a process to generate an intermediate in the total synthesis of (+)-molephantin or a derivative thereof, the process comprising: (a) providing a compound of formula I: where:

[0090] Prot1represents an acid-labile protecting group;

[0091] X represents Cl or, more particularly, Br; and

[0092] (b) reacting the compound of formula I for a period of time with a compound of formula II: where Prot2is selected from a triethylsilyl group, a triisopropylsilyl group, a tert- butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or, more particularly, a tri methylsilyl group, under reaction conditions involving a stoichiometric excess of one or both of a metal salt and a metal relative to the compound of formula I, a solvent and at a temperature of from 0 to 25

[0093] °C to provide a compound of formula III: where Prot1is as defined above.

[0094] The word “comprising” refers herein may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the word “comprising” may also relate to the situation where only the components / features listed are intended to be present (e.g. the word “comprising” may be replaced by the phrases “consists of” or “consists essentially of”). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the word “comprising” and synonyms thereof may be replaced by the phrase “consisting of’ or the phrase “consists essentially of’ or synonyms thereof and vice versa.

[0095] The phrase, “consists essentially of’ and its pseudonyms may be interpreted herein to refer to a material where minor impurities may be present. For example, the material may be greater than or equal to 90% pure, such as greater than 95% pure, such as greater than 97% pure, such as greater than 99% pure, such as greater than 99.9% pure, such as greater than 99.99% pure, such as greater than 99.999% pure, such as 100% pure.

[0096] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a composition” includes mixtures of two or more such compositions, reference to “the catalyst” includes mixtures of two or more such catalysts, and the like.

[0097] The term “halo”, when used herein, includes references to fluoro, chloro, bromo and iodo.

[0098] Any suitable acid-labile protecting group may be used in the first aspect of the present invention.

[0099] In some embodiments of the first aspect of the present invention that may be mentioned herein, the acid-labile protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal. In further embodiments of the first aspect of the present invention that may be mentioned herein, the acid-labile protecting group may be methoxymethyl ether.

[0100] Any suitable period of time may be used in the first aspect of the present invention. For example, the period of time may be 3 hours.

[0101] Any suitable metal and / or metal salt may be used in the first aspect of the present invention.

[0102] In some embodiments of the first aspect of the present invention that may be mentioned herein, the metal and / or metal salt may be selected from one or more of zinc metal, indium metal, a chromium (III) salt with manganese metal, samarium (II) iodide, tin (II) chloride, and a chromium (II) salt (e.g. chromium (II) bromide and chromium (II) chloride).

[0103] In further embodiments of the first aspect of the present invention that may be mentioned herein, the metal and / or metal salt may be chromium (II) chloride.

[0104] Any suitable solvent may be used in the first aspect of the present invention.

[0105] In some embodiments of the first aspect of the present invention that may be mentioned herein, the solvent may be selected from one or more of the group consisting of tetrahydrofuran, 2- methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,1- dimethoxyethane, dimethylsulfoxide, dimethylacetamide, and dimethyl formamide.

[0106] In further embodiments of the first aspect of the present invention that may be mentioned herein, the solvent may be dimethyl formamide.

[0107] In some embodiments of the first aspect of the present invention, the temperature may be about 10 °C.

[0108] Any suitable stoichiometric excess of one or both of a metal salt and a metal relative to the compound of formula I may be used in the first aspect of the present invention.

[0109] In a second aspect of the present invention, there is provided a process to generate an intermediate in the total synthesis of (+)-molephantin or a derivative thereof, the process comprising:

[0110] (aii) providing a compound of formula IV:

[0111] where Prot1represents an acid-labile protecting group; and

[0112] (bii) subjecting the compound of formula IV for a period of time to reaction conditions involving a catalytic amount of a nickel (II) salt or a palladium (II) salt, a stoichiometric excess of one or both of a metal and a metal salt relative to the compound of formula IV, in a solvent, and at a temperature of from 5 to 60 °C to provide a compound of formula V: where R is Prot1and Prot1is as defined above. Any suitable acid-labile protecting group may be used in the second aspect of the present invention.

[0113] In some embodiments of the second aspect of the present invention that may be mentioned herein, the acid-labile protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal.

[0114] In further embodiments of the second aspect of the present invention that may be mentioned herein, the acid-labile protecting group may be methoxymethyl ether.

[0115] Any suitable period of time may be used in the second aspect of the present invention. For example, the period of time may be 16 hours.

[0116] Any suitable catalytic amount of a nickel (II) salt or a palladium (II) salt may be used in the second aspect of the present invention.

[0117] Any suitable stoichiometric excess of one or both of a metal and a metal salt relative to the compound of formula IV may be used in the second aspect of the present invention.

[0118] Any suitable metal and / or metal salt may be used in the second aspect of the present invention.

[0119] In some embodiments of the second aspect of the present invention that may be mentioned herein, the metal and / or metal salt may be selected from one or more of a chromium (III) salt with manganese metal, samarium (II) iodide, and a chromium (II) salt (e.g. chromium (II) bromide and chromium (II) chloride).

[0120] In further embodiments of the second aspect of the present invention that may be mentioned herein, the metal and / or metal salt may be chromium (II) chloride.

[0121] Any suitable solvent may be used in the second aspect of the present invention.

[0122] In some embodiments of the second aspect of the present invention that may be mentioned herein, the solvent may be selected from one or more of the group consisting of tetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1 ,2-dimethoxyethane, 1,1 -dimethoxyethane, dimethyl formamide, dimethylacetamide, and dimethyl sulfoxide. For example, the solvent may be dimethyl sulfoxide.

[0123] In some embodiments of the second aspect of the present invention that may be mentioned herein, the temperature may be about 25 °C. Any suitable catalytic nickel (II) salt or palladium (II) salt may be used in the second aspect of the present invention.

[0124] In some embodiments of the second aspect of the present invention that may be mentioned herein, the catalytic nickel (II) salt or palladium (II) salt may be selected from one or more of the group consisting of nickel (II) chloride, nickel (II) bromide, nickel(ll) iodide, nickel(ll) chloride ethylene glycol dimethyl ether complex, 1 ,2-bis(diphenylphosphino)ethane nickel (II) chloride, bis(1 ,5-cyclooctadiene)nickel(0), 1 ,3- bis(diphenylphosphino)propane]dichloronickel(ll), tetrakis(triphenylphosphine)nickel, palladium (II) chloride, palladium (II) acetate, and nickel (II) bis(acetylacetonate). For example, the catalytic nickel (II) salt or palladium (II) salt may be nickel (II) bis(acetylacetonate).

[0125] In a third aspect of the present invention, there is provided a total synthesis of (+)-molephantin or a derivative thereof, the process comprising the synthetic process according to the first aspect of the present invention and the synthetic process according to the second aspect of the present invention.

[0126] In some embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula IV: where Prot1represents an acid-labile protecting group, may be prepared by:

[0127] (aiv) providing a compound of formula III:

[0128] where Prot1is as defined above; and

[0129] (biv) subjecting the compound of formula III to an oxidation reaction to provide the compound of formula IV.

[0130] In such embodiments of the third aspect of the present invention that may be mentioned herein, the oxidation conditions may comprise a stoichiometric excess of manganese dioxide in a solvent (e.g. methylene chloride) and at a temperature of from 5 to 35 °C (e.g. about 25 °C).

[0131] In such embodiments of the third aspect of the present invention that may be mentioned herein, the acid-labile protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal. For example, the acid-labile protecting group may be methoxymethyl ether.

[0132] In some embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula I: where Prot1represents an acid-labile protecting group, may be provided by: (av) providing a compound of formula la:

[0133] ; and

[0134] (bv) protecting the free hydroxyl of the compound of formula la with an acid-labile protecting group using suitable conditions for a selected protecting group.

[0135] In such embodiments of the third aspect of the present invention that may be mentioned herein, the acid-labile protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal. For example, the acid-labile protecting group may be methoxymethyl ether.

[0136] In such embodiments of the third aspect of the present invention that may be mentioned herein, the protecting group may be methoxymethyl ether and the reaction conditions may involve reaction of the compound of formula la with dimethoxymethane as a solvent and reagent and a catalytic amount of a suitable acidic catalyst (e.g. triflic acid).

[0137] Any suitable catalytic amount of a suitable acidic catalyst may be used in the third aspect of the present invention.

[0138] In some embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula la may be provided by reaction of a compound of formula VI:

[0139] with a stoichiometric excess of hydrobromic acid in a solvent (e.g. ethyl acetate) at a suitable temperature (e.g. about 25 °C).

[0140] In further embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula VI may be provided by reaction of a compound of formula VII: with methyl acrylate, a suitable base (e.g. 1 ,4-diazabicyclo[2.2.2]octane), and at a suitable temperature (e g. about 25 °C).

[0141] Any suitable base may be used in the third aspect of the present invention.

[0142] In further embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula VII may be provided by reaction of a compound of formula VIII: with a reducing agent (e.g. diisobutylaluminium hydride), in a suitable solvent (e.g. methylene chloride), and at a suitable temperature (e.g. about -78 °C).

[0143] Any suitable reducing agent may be used in the third aspect of the present invention.

[0144] In further embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula VIII may be provided by reaction of a compound of formula IX: with (iodomethyl)triphenylphosphonium iodide, and a suitable base (e.g. sodium hexamethyldisilazide) in a suitable solvent (e.g. tetrahydrofuran), and at a suitable temperature (e g. about -78 °C).

[0145] In further embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula IX may be provided by reaction of a compound of formula X: with methyl lithium in a suitable solvent (e.g. methylene chloride), and at a suitable temperature (e.g. about -78 °C).

[0146] In some embodiments of the third aspect of the present invention that may be mentioned herein, the compound of formula V:

[0147] where R is Prot1and Prot1is as defined in the third aspect of the invention, may be subjected to an oxidation reaction to provide a compound of formula XI: where R is as defined above.

[0148] In such embodiments of the third aspect of the present invention, the oxidation reaction may involve a stoichiometric excess of manganese dioxide and a solvent (e.g. methylene chloride) at a suitable temperature (e.g. 25 °C).

[0149] In such embodiments of the third aspect of the present invention, the compound of formula XI may be reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g. triethylamine), a catalytic base (e.g. dimethylaminopyridine) in a suitable solvent (e.g. tetrahydrofuran) and at a suitable temperature (e.g. 25 °C), to provide a compound of formula XII: where R is Prot1and Prot1is as defined in the third aspect of the present invention and R’ is H or CH3. Any suitable catalytic base may be used in the third aspect of the present invention.

[0150] In such embodiments of the third aspect of the present invention, the compound of formula XII may be reacted with an acid (e.g. trifluoroacetic acid) in a suitable solvent (e g. methylene chloride) and at a suitable temperature (e.g. 25 °C), to provide a compound of formula XIII: where R’ is H or CH3.

[0151] Any suitable acid may be used in the third aspect of the present invention.

[0152] In a fourth aspect of the present invention, there is provided a method of forming a compound of formula XIV

[0153] where R’ is H or CH3, by a cyclisation reaction of a compound of formula XIII: where R’ is as defined above, through the application of ultraviolet light to the compound of formula XIII in a suitable solvent (e.g. methylene chloride) at a suitable temperature (e.g. about 25 °C), optionally wherein the ultraviolet light is provided at a wavelength of from 200 to 400 nm (e.g. about 370 nm) at a suitable power (e.g. from 10 to 100 Watts, such as about 40 Watts) and using a light source at a suitable distance from a reaction vessel including the compound of formula XIII (e.g. from 1 to 10 cm, such as about 4 cm).

[0154] The application of ultraviolet light may be provided by any suitable light source. For example, the light source may be a LED light source. In a fifth aspect of the present invention, there is provided a method of forming a compound of formula XV: where R” is selected from C1to C10alkyl or C2 to C10alkenyl, from a compound of formula XIV, where R’ is H or CH3, through reacting the compound of formula XIV with an alcohol of formula

[0155] XVI:

[0156] R”-OH XVI in the presence of an acid catalyst (e.g. the catalyst is para-toluene sulfonic acid).

[0157] Any suitable acid catalyst may be used in the fifth aspect of the present invention.

[0158] Unless otherwise stated, the term “alkyl” refers to a saturated, unbranched or branched, acyclic or cyclic radical, which may be unsubstituted. For example, when the term “alkyl” refers to an acyclic group, it may refer to a C1-10alkyl and, more preferably, C1-6alkyl (such as ethyl, propyl (e.g. n-propyl or isopropyl), butyl (e.g. branched or unbranched butyl), pentyl or, more preferably, methyl). Where the term “alkyl” is a cyclic group, it may be a C3-12cycloalkyl and, more preferably, C5-10(e g. C5-7) cycloalkyl. In embodiments of the invention that may be mentioned herein, the alkyl group may be acyclic.

[0159] Unless otherwise stated, the term “alkenyl” refers to an unsaturated, unbranched or branched, acyclic or cyclic radical, which may be unsubstituted. For example, when the term “alkenyl” refers to an acyclic group, it may refer to a C2-10alkenyl and, more preferably, C2-6alkenyl (such as propenyl), butenyl (e.g. branched or unbranched butenyl), pentenyl or, more preferably, ethenyl). Where the term “alkenyl” is a cyclic group, it may be a C3-12cycloalkenyl and, more preferably, C5-10(e.g. C5-7) cycloalkenyl. In embodiments of the invention that may be mentioned herein, the alkenyl group may be acyclic.

[0160] The compound of formula X and the compound of formula XVI may be known and / or may be commercially available. Other compounds of formula I to IX and XI to XV, as well as certain compounds of formula XVI (e.g. that are not commercially available) may be prepared in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.

[0161] Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisation, column chromatography, preparative HPLC, etc.). In particular, it is noted that compounds with the formula XIII, like molephantin and molephantinin, can be crystallized (or recrystallized) in ethanol (EtOH), methanol (MeOH), diethyl ether (Et2O) or dichloromethane (CH2CI2).

[0162] In the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.

[0163] The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.

[0164] Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds / intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.

[0165] The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Chemistry”, edited by J WF McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis", 3rdedition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).

[0166] As used herein, the term “functional groups” means, in the case of unprotected functional groups, hydroxy-, th io I o- , amino, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, S- acetyl, carboxylic acid ester.

[0167] Derivatives of (+)-molephantin may include, but are not limited to, molephantinin, phantomolin, tomentosuside F, tomentosuside K, tomenphantopin C, tomenphantopin H, 2-0- demethyltomenphantopin C, 2-deethoxy-2|3-methoxyphantomolin-8-O-tiglinate, and 2- deethoxy-2|3-methoxyphantomolin.

[0168] Further aspects and embodiments of the invention will now be discussed by reference to the following non-limiting examples.

[0169] Examples

[0170] Materials n-BuLi (Kanto Chemical-04937-25) was purchased from Kanto Chemical. Trimethylphosphonoacetate (TCI-P1265), 4,4-dimethoxy-2-butanone (TCI-D1157), 1 ,4- diazabicyclo[2.2.2]octane (TCI-D0134), p-toluenesulfonic acid (TCI-T0267), 1 ,4- diazabicyclo[2.2.2]octane (TCI-D0134), dimethoxymethane (TCI-D0637), trifluoromethanesulfonic acid (TCI-T0751), Pyridinium p-toluenesulfonate (P0942) and manganese oxide (TCI-M3448) were purchased from Tokyo Chemical Industry Co., Ltd. (TCI). Diisobutylaluminium hydride (Sigma Aldrich-214949), trimethylsilyl trifluoromethanesulfonate (Sigma Aldrich-225649), 2,6-lutidine (Sigma Aldrich-336106), methyllithium (Sigma Aldrich- 514330), sodium hexamethyldisilazide (Sigma Aldrich-80631), chromium chloride (Sigma Aldrich-450782), triethylamine (Sigma Aldrich-471283), 4-dimethylaminopyridine (Sigma Aldrich-107700), methacrylic anhydride (Sigma Aldrich-276685), trifluoroacetic acid (Sigma Aldrich-T6508), sodium borohydride (Sigma Aldrich-452882), hydrobromic acid (Sigma Aldrich-268003), and methyl acrylate (Sigma Aldrich-M27301) were purchased from Sigma Aldrich. Triphenylphosphine (Fluorochem-037818) was purchased from Fluorochem. Diiodomethane (Alfa Aesar-A15147) was purchased from Alfa Aesar. Nickel(ll) acetylacetonate (Strem Chemicals-28-1130) was purchased from Strem Chemicals.

[0171] Notes The carbon numbers annotated on the compounds correspond to those of molephantin (1).

[0172] Nuclear magnetic resonance (NMR) spectroscopy

[0173] 1H NMR spectra (400 MHz) were recorded on a Jeol-ECA series 400 MHz spectrometer in CDCI3[using TMS (for1H, 6 = 0.00) as an internal standard] or in CD3OD (for1H, δ = 3.31).13C NMR spectra (100 MHz) were recorded on a Jeol-ECA series 400 MHz spectrometer in CDCI3[using CDCI3(for13C, 6 = 77.16) as an internal standard] or in CD3OD (for13C, 5 49.00).

[0174] The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dddd = doublet of doublets of doublets of doublets, qd = quartet of doublets, qt = quartet of triplets, m = multiplet, br s = broad singlet, br m = broad multiplet.

[0175] Mass and infrared (IR) spectroscopy

[0176] High-resolution mass spectroscopy (HRMS) spectra were obtained with a Xevo G2 Tof Premier mass spectrometer (Ionization mode: ESI positive polarity; Mobile phase: MeOH 100 μL / min). IR spectra were recorded on a Shimadzu IR Prestige-21 FT-IR spectrometer.

[0177] Optical rotation

[0178] Optical rotations were recorded on OMNI Lab JASCO P-1030 polarimeter at 589 nm and are recorded as [α]TD(concentration in grams / 100 mL solvent).

[0179] Melting points

[0180] Melting points are uncorrected and were recorded on an MPA 100 Opti Melt Automated Melting Point System.

[0181] Absorption spectroscopy

[0182] Steady-state absorption spectra were recorded using a UV-vis absorption spectrometer (YV3600 Plus, SHIMADZU).

[0183] LED light source

[0184] The Kessil PR160 series (λmax = 370 nm) were used as the LED light source for the photochemical reactions.

[0185] Analytical thin layer chromatography (TLC) and silica gel chromatography TLC was performed using 0.25 mm silica gel 60-F254 plates (Merck), using 254 nm UV light for the visualization and a solution of potassium permanganate as a stain. Flash chromatography was performed Merck silica gel 60 with distilled solvents.

[0186] X-ray diffraction spectroscopy

[0187] The X-ray diffraction data were collected on an Agilent Supernova diffractometer equipped with an ATLAS CCD detector using CuKa (A = 1.54184 A) radiation.

[0188] Liquid chromatography-mass spectrometry (LC-MS)

[0189] LC-MS was performed with Agilent 1260 Infinity Prime LC connected with a mass spectrometer 6475 Triple Quadrupole (ionization mode: ESI positive polarity, column: Agilent Zorbax EclipsePlus C18 RRHD 1.8 pM, 2.1 x 50 mm).

[0190] Gel permeation chromatography (GPC)

[0191] GPC was performed on a GPC LaboACE, column Jaigel-2HR-40 (Chloroform 30 mL / min).

[0192] Example 1. Synthesis of 10 n-BuLi (1.5 M in hexane, 183 mL, 275 mmol) was added dropwise to trimethylphosphonoacetate 7 (50.0 g, 275 mmol) in THF (600 mL) at -20 °C (a dry ice-acetone bath) and the mixture was stirred at the same temperature for 30 min. 4,4-dimethoxy-2- butanone (8) (40 mL, 39.8 g, 301 mmol) was added dropwise to the mixture, and the reaction mixture was allowed to warm up to 4 °C (ice-water bath) and stirred for 4 h. The bath was then removed and the mixture was stirred at 25 °C for additional 16 hours. The mixture was cooled back to 4 °C and quenched with saturated aqueous NH4CI solution (500 mL). The organic materials were extracted twice with Et2O (500 mL x 2) and the combined organic phases were dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / ethyl acetate (EtOAc) = 100:0 to 80:20) to give 7 (41.5 g, 221 mmol) in 80% yield as an E / Z-mixture in the ratio of 71:29 (based on1H NMR analysis). E-10 and Z-10 could be partially separated by flash column chromatography (silica gel, Hexane / EtOAc = 95:5 to 90:10) for characterization. For E- 10

[0193] Aspect: Pale yellow oil.

[0194] TLC: Rf= 0.60 (20% EtOAc / Hexane).

[0195] FTIR (neat, cm’1) 2949 [v(C=C)], 1714 [v(C=O)], 1651 [v(C=C)], 1225 [v(C-O)], 1082 [v(C-O)], 813 [v(C=C)].

[0196] 1H NMR (400 MHz, CDCI3) δ 5.74 (q, J = 1.2 Hz, 1 H, H1), 4.54 (t, J = 5.6 Hz, 1H, H8), 3.68 (s, 3H, CO2Me). 3.33 (s, 6H, OMe), 2.44 (d, J = 5.6 Hz, 2H, Hg), 2.20 (d, J = 1 .2 Hz, 3H, H15).

[0197] 13C NMR (100 MHz, CDCI3) δ 167.1 , 155.1 , 117.9, 102.9, 53.2, 51.0, 44.1 , 19.4.

[0198] HRMS (ESI) calculated for C9H17O5+[M+H]+189.1127; found 189.1126.

[0199] For Z- 10

[0200] Aspect: Pale yellow oil.

[0201] TLC: Rf= 0.62 (20% EtOAc / Hexane).

[0202] FTIR (neat, cm1) 2949 [v(C=C)], 1714 [v(C=O)], 1643 [v(C=C)], 1269 [v(C-O)], 1082 [v(C-O)], 735 [v(C=C)].

[0203] 1H NMR (400 MHz, CDCI3) δ 5.77-5.75 (m, 1H, H1), 4.55 (t, J = 6.0 Hz, 1 H, H8), 3.69 (s, 3H, COaMe), 3.37 (s, 6H, OMe), 2.96 (dd, J = 6.0, 0.8 Hz, 2H, H9), 1 .96 (d, J = 1 .2 Hz, 3H, H15).

[0204] 13C NMR (100 MHz, CDCI3) δ 166.7, 156.3, 117.4, 104.5, 53.8, 51.0, 37.2, 26.6.

[0205] HRMS (ESI) calculated for C9H17O6+[M+H]+189.1127; found 189.1113.

[0206] Example 2. Synthesis of 11

[0207] Diisobutylaluminium hydride (DI BAL, 1 M in cyclohexane, 463 mL, 463 mmol) was added dropwise to a solution of 10 (71:29 E / Z-mixture, 39.5 g, 210 mmol) in CH2CI2(800 mL) at - 50 °C (a dry ice-acetone bath) and the reaction was stirred for 30 minutes. The mixture was allowed to warm up to -20 °C, quenched with EtOAc (30 mL) and diluted with a saturated aqueous solution of the Rochelle salt (500 mL). The mixture was allowed to warm up to 25 °C and stirred for 3 h. The organic materials were extracted from the separated aqueous phase once with CH2CI2(400 mL) and the combined organic phases were washed with brine (500 mL), dried over MgSCU, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 80:20 to 50:50) to give the following four fractions containing 11. Fraction 1 : m = 3.98 g, E / Z = 22:88

[0208] Fraction 2: m = 7.70 g, E / Z = 49:51

[0209] Fraction 3: m = 4.9 g, E / Z = 90:10

[0210] Fraction 4: m = 11.9 g, E / Z = 100:0

[0211] The yield of E-11 could be obtained as 62% yield based on the calculated mass (m = 20.7 g), while that of Z-11 be 24% yield (m = 7.92 g).

[0212] For E-11 :

[0213] Aspect: Colorless oil.

[0214] TLC: Rf= 0.25 (40% EtOAc / Hexane).

[0215] FTIR (neat, cm’1) 3410 [v(O-H)], 2920 [v(C=C)J, 1666 [v(C=C)], 1122 [v(C-O)], 1065 [v(C-O)].1H NMR (400 MHz, CDCI3) δ 5.49 (qt, J = 1.2, 6.8 Hz, 1 H, H1), 4.51 (t, J = 6.0 Hz, 1 H, H8), 4.16 (d, J = 6.8 Hz, 2H, H2), 3.33 (s, 6H, OMe), 2.34 (d, J = 6.0 Hz, 2H, Hg), 1.72 (d, J = 1.2 Hz, 3H, H1s).

[0216] 13C NMR (100 MHz, CDCI3) δ 134.9, 126.7, 103.4, 59.3, 52.9, 42.6, 16.9.

[0217] HRMS (ESI) calculated for C8H17O3+[M+H]+161.1178; found 161.1180.

[0218] For Z-11 (as a mixture with E-11):

[0219] Aspect: Colorless oil.

[0220] TLC: Rf= 0.30 (40% EtOAc / Hexane).

[0221] FTIR (neat, cm1) 3388 [v(O-H)], 2934 [v(C=C)], 1668 [v(C=C)], 1126 [v(C-O)], 1045 [v(C-O)].1H NMR (400 MHz, CDCI3) δ 5.69 (mt, J = 7.6 Hz, 1 H, H1), 4.43 (t, J = 5.6 Hz, 1 H, H8), 4.04 (d, J = 7.6 Hz, 2H, H2), 3.37 (s, 6H, OMe), 2.49 (s, 1H, OH), 2.44 (d, J= 5.6 Hz, 2H, H9), 1.82- 1.80 (m, 3H, H15).

[0222] 13C NMR (100 MHz, CDCI3) δ 135.8, 127.4, 103.0, 58.2, 53.8, 36.0, 24.4.

[0223] HRMS calculated for C8H17O3+[M+H]+161.1178; found 161.1156.

[0224] Example 3. Synthesis of 12 Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 41.6 mL, 228 mmol) was added dropwise to a solution of E-11 (9.15 g, 57.1 mmol) and 2,6-lutidine (39.8 mL, 343 mmol) in CH2CI2(550 mL) at -5 °C (ice-NaCI-water bath), and the reaction mixture was stirred for 15 minutes. The mixture was then quenched by slowly adding water (250 mL), and the organic phase was washed four times with aqueous CuSCU solution (1 M, 4 x 300 mL) to completely remove 2,6- lutidine (insufficient washing at this stage will result in contamination of 2,6-lutidine in aldehyde 12, which hampers the next Barbier allylation), dried over MgSCU and concentrated in vacuo. The resulting crude residue (m = 9.45 g), which contained aldehyde 12 as the major component (see the1H NMR spectrum in Fig. 2), was used forthe coupling with 17 in Example 9 without further purification due to the instability of 12.

[0225] A part of the crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 95:5 to 70:30) for the purpose of the characterization of 12.

[0226] Aspect: Pale yellow oil.

[0227] TLC: Rf= 0.5 (5% EtOAc / Hexane).

[0228] FTIR (neat, cm-1) 2924 [v(C=C)]_ 1720 [v(C=O)j, 1439 [v(C=O)j, 1045 [v(OTMS)].

[0229] 1H NMR (400 MHz, CDCI3) δ 9.64 (t, J = 2.0 Hz, 1H, H8), 5.50 (qt, J = 1.2, 6.4 Hz, 1 H, H1), 4.20 (d, J= 6.4 Hz, 2H, H2), 3.08 (d, J = 2.0 Hz, 2H, H9), 1.71 (d, J= 1.2 Hz, 3H, H15), 0.14 (s, 9H, OSiMe3).

[0230] 13C NMR (100 MHz, CDCI3) δ 200.0, 130.2, 128.9, 59.3, 54.2, 17.3, -0.3.

[0231] HRMS (ESI) calculated for C9H19O2Si+[M+H]+187.1154; found 187.1159.

[0232] Example 4. Synthesis of (Z)-iodoalkene 14

[0233] Methyllithium (MeLi, 3.1 M in diethoxymethane, 75 mL, 232 mmol) was added dropwise to a solution of 9 (38.0 g, 174 mmol) in CH2CI2(380 mL) at -78 °C (a dry ice-acetone bath) and the reaction mixture was stirred for 2 hours before being quenched with saturated aqueous NH4CI solution (150 mL) by maintaining the internal temperature below -65 °C. The solution was allowed to warm up to 25 °C, diluted with water (400 mL), and further stirred for additional 5 minutes. The organic materials were extracted 1 time with CH2CI2(400 mL), and the combined organic phases were washed with water (200 mL), brine (200 mL), dried over MgSO4and concentrated in vacuo. The resulting crude material (m = 25.5 g) containing methyl ketone 13 as the major component was used for the next step without further purification (1H NMR analysis of the crude mixture revealed that it contains 13, 9, and diketone in the molar ratio of 1:0.08:0.07 as shown in Fig. 3).

[0234] Sodium hexamethyldisilazide (NaHMDS, 2 M in THF, 76 mL, 152 mmol) was added dropwise in the dark (by covering the flask with aluminium foils) to a solution of (iodomethyl)triphenylphosphonium iodide [prepared from triphenylphosphine and diiodomethane (Seyferth, D. etal., J. Organomet. Chem. 1966, 5, 267-274), 80.0 g, 151 mmol] in THF (700 mL) at 4 °C (ice-water bath). The solution was stirred for 30 minutes and then cooled to -78 °C (a dry ice-acetone bath). A solution of crude 13 (25.5 g) in THF (75 mL) was added dropwise to the mixture, and the mixture was stirred for 30 minutes at the same temperature before warming up to 0 °C (an ice-water bath). The reaction was quenched with saturated aqueous NH4CI solution (100 mL), and the solid materials were removed via filtration through a Celite pad. The filtrate was diluted with water (600 mL) and Et20 (600 mL), and the aqueous phase was separated. The organic materials were extracted once with Et2O (400 mL) and the combined organic phases were dried over MgSC>4 and concentrated in vacuo. The resulting crude materials were purified by flash chromatography (silica gel, Hexane / EtOAc = 100:0 to 90:10) to give (Z)-iodoalkene 14 (25.8 g, 79.1 mmol, 45% yield in 2 steps).1H NMR analysis of the purified product revealed that the purity of 14 is around 98% (Fig. 4).

[0235] Aspect: Pale yellow oil.

[0236] TLC: Rf= 0.5 (5% EtOAc / Hex).

[0237] [α]” +69.9° (C = 1 , CHCI3).

[0238] FTIR (neat, cm’1) 2989 [v(C=C)], 1759 [v(C=O)], 1207 [v(C-O)], 1103 [v(C-O)], 509 [v(C-l)].1H NMR (400 MHz, CDCI3) δ 6.26 (q, J = 1.2 Hz, 1 H, H3), 5.08 (d, J = 8.4 Hz, 1 H, H5), 4.20 (d, J = 8.4 Hz, 1 H, H6), 3.80 (s, 3H, COsMe), 1.93 (d, J= 1.2 Hz, 3H, H14), 1.53 (s, 3H, Meacetai), 1.52 (s, 3H, Meacetai).

[0239] 13C NMR (100 MHz, CDCI3) δ 170.6, 141.8, 112.2, 82.8, 79.0, 76.5, 52.9, 26.9, 26.0, 19.0. HRMS (ESI) calculated for C10H16IO4+[M+H]+327.0094; found 327.0090.

[0240] Example 5. Synthesis of 15

[0241] Diisobutylaluminium hydride (DIBAL, 1 M in cyclohexane, 91 mL, 91 mmol) was added to a solution of 14 (25.8 g, 79.1 mmol) in CH2CI2(260 mL) at -78 °C (a dry ice-acetone bath), and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was then quenched with ethyl acetate (EtOAc, 30 mL) at -78 °C and diluted with a saturated aqueous solution of the Rochelle salt (500 mL). The mixture was allowed to warm up to 25 °C and stirred for 3 hours. The organic materials were extracted once with CH2CI2(400 mL) and the combined organic phases were washed with brine (300 mL), dried over MgSCu, and concentrated in vacuo. The resulting crude residue containing the corresponding aldehyde (m = 27.2 g) was used for the next step without further purification.

[0242] 1,4-diazabicyclo[2.2.2]octane (DABCO, 22.2 g, 198 mmol) was added to a solution of the crude aldehyde obtained above in methyl acrylate (540 mL, 5.96 mol), and the reaction mixture was stirred in the dark (aluminium foil around the flask) at 25 °C for 40 hours. The reaction was quenched with saturated aqueous NH4CI solution (500 mL) and diluted with CH2CI2(600 mL). The organic materials were extracted twice with CH2CI2(300 mL), and the combined organic extracts were dried over MgSC>4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 90:10 to 80:20) to give 15 (22.6 g, 59.1 mmol, 75% yield in 2 steps) as a mixture of diastereoisomers (51 :49).

[0243] Two diastereomers could partially be separated by flash column chromatography for the characterization. Their stereochemistry at C7 was not determined.

[0244] Major diastereoisomer 15-major

[0245] Aspect: Pale yellow oil.

[0246] TLC: Rf= 0.3 (20% EtOAc / Hexane).

[0247] [a]2D° +5.2° (C = 1 , CHCI3).

[0248] FTIR (neat, cm’1) 3495 [v(O-H)], 2985 [v(C=C)], 1712 [v(C=O)], 1627 [v(C=C)], 1242 [v(C-O)], 1060 [v(C-O)], 509 [v(C-l)].

[0249] 1H NMR (400 MHz, CDCI3) δ 6.37 (dd, J = 0.8, 0.8 Hz, 1 H, H13a), 6.26-6.25 (m, 1 H, H3), 6.02 (dd, J = 0.8, 1.6 Hz, 1 H, H13b), 5.00 (d, J = 8.8 Hz, 1H, H5), 4.56 (d, J = 9.6 Hz, 1 H, H7), 4.05 (dd, J = 8.8, 2.0 Hz, 1 H, H6), 3.76 (s, 3H, CO2Me), 2.84 (d, J = 9.6 Hz, 1 H, OH), 1 .92 (d, J = 1.6 Hz, 3H, H14), 1.50 (s, 3H, Meacetal), 1.46 (s, 3H, Meacetal).

[0250] 13C NMR (100 MHz, CDCI3) δ 166.5, 142.1 , 139.6, 126.8, 110.3, 81.1, 79.6, 79.0, 67.9, 52.1 , 27.4, 27.2, 19.5.

[0251] HRMS (ESI) calculated for CI3H20IO5+[M+H]+383.0355; found 383.0355.

[0252] Minor diastereoisomer 15-minor

[0253] Aspect: Pale yellow oil.

[0254] TLC: Rf= 0.3 (20% EtOAc / Hexane).

[0255] [O]D° +24.6° (C = 1, CHCI3).

[0256] FTIR (neat, cm’1) 3483 [v(O-H)], 2986 [v(C=C)], 1712 [v(C=O)], 1632 [v(C=C)], 1242 [v(C-O)], 1060 [v(C-O)], 509 [v(C-l)].

[0257] 1H NMR (400 MHz, CDCI3) δ 6.30 (s, 1 H, H13a), 6.22 - 6.18 (m, 2H, H13b+H3), 4.79 (d, J = 8.4 Hz, 1H, Hs), 4.74 (dd, J = 4.4, 4.4 Hz, 1H, H7), 4.32 (dd, J = 8.4, 4.4 Hz, 1 H, H6), 3.76 (s, 3H, CO2Me), 3.04 (d, J = 4.4 Hz, 1 H, OH), 1.86 (d, J = 1.2 Hz, 3H, H14), 1.46 (s, 6H, Meacetai).

[0258] 13C NMR (100 MHz, CDCI3) δ 166.7, 141.5, 136.4, 127.7, 109.6, 81.2, 80.4, 79.6, 69.6, 52.1 , 27.3, 27.2, 19.3.

[0259] HRMS (ESI) calculated for CI3H20IO5+[M+H]+383.0355; found 383.0356. as an inseparable mixture precipitation in / -Pr2O

[0260] 15 (14.0 g, 36.6 mmol) was dissolved in hydrobromic acid (HBr 48% in water, Sigma Aldrich- 268003, 125 mL) and EtOAc (125 mL), and the reaction mixture was stirred at 25 °C for 16 hours. After the solution was diluted with water (500 mL) and EtOAc (500 mL), the separated organic phase was washed with H2O, brine, and dried over MgSO4. The solvent was removed under reduced pressure to give the crude mixture, which was purified by flash chromatography (silica gel, Hexane / EtOAc = 90:10 to 70:30) to give an inseparable mixture of 16 and 16’ (8.80 g) in 85:15 molar ratio (16: 55% yield, 16’: 10% yield) based on the1H NMR analysis. 16 could be precipitated by treating the mixture of 16 and 16’ with diisopropyl ether ( / -Pr2O), allowing the isolation of 16 (6.10 g, 16.4 mmol). The structure of 16’ was confirmed via its conversion into the MOM ether 17’ using the mixture of 16 and 16’ obtained from the filtrate (see Example 8).

[0261] Aspect: White solid.

[0262] Melting point: 112 °C.

[0263] TLC: Rf= 0.2 (30% EtOAc / Hexane).

[0264] [a]2D° +77.0° (C = 1 , CHCI3).

[0265] FTIR (neat, cm-1) 3437 [v(O-H)], 2985 [v(C=C)], 1764 [v(C=O)], 1745 [v(C=C)], 1265 [v(C-Br)], 1076 [v(C-O)], 632 [v(C-Br)].

[0266] 1H NMR (400 MHz CDCI3) δ 7.34 (dt, J = 1.6, 1.6 Hz, 1 H, H7), 6.26 (q, J = 1.2 Hz, 1 H, H3), 5.05 (ddt, J = 6.4, 1.6, 1 ,6 Hz, 1 H, H6), 4.65 (d, J = 6.4 Hz, 1H, H5), 4.12 (dd, J = 1.6, 1.6 Hz, 2H, Hn), 2.53 (s, 1 H, OH), 2.00 (d, J = 1.2 Hz, 3H, H14).

[0267] 13C NMR (100 MHz, CDCI3) δ 170.6, 149.3, 144.1 , 132.5, 83.2, 78.4, 77.2, 20.7, 20.2.

[0268] HRMS (ESI) calculated for CgHnBrlOs* [M+ H]+372.8936; found 372.8944.

[0269] Example 7. Synthesis of 17

[0270] 16 17 80% ORTEP of 17

[0271] Trifluoromethanesulfonic acid (TfOH, TCI-T0751 , 740 μL, 8.40 mmol) was added dropwise to a solution of 16 (15.7 g, 42.1 mmol) in dimethoxymethane (700 mL) at 25 °C, and the mixture was stirred for 2 h, before being diluted with water (700 mL) and Et20 (500 mL). After separation of the aqueous phase, the organic materials were extracted twice with Et2<D (500 mL x 2). The combined extracts were dried over MgSC>4, and the solvent was removed in vacuo. The resulting crude material was purified by flash chromatography (silica gel, Hexane / EtOAc = 100:0 to 80:20) to give 17 (14.0 g, 33.6 mmol, 80% yield). Recrystallization of 17 from diisopropyl ether ( / -Pr2O) and diethyl ether (Et2O) afforded a single crystal, which was characterized by X-ray crystallographic analysis to confirm its structure and stereochemistry (CCDC-2312148, Fig. 5).

[0272] Table 1. X-ray crystallographic data of Compound 17 (CCDC-2312148).

[0273] Aspect: Pale yellow solid / colorless crystal when recrystallized.

[0274] Melting point: 114 °C.

[0275] TLC: Rf= 0.4 (30% EtOAc / Hexane). [a]2D° +92.2° (C = 1 , CHCI3).

[0276] FTIR (neat, cm’1) 2924 [v(C=C)], 1755 [v(C=O)], 1616 [v(C=C)], 1280 [v(C-Br)], 1064 [v(C-O)], 621 [v(C-Br)].

[0277] 1H NMR (400 MHz, CDCI3) δ 7.31 (dt, J = 1.2, 1.2 Hz, 1 H, H7), 6.35-6.33 (m, 1H, H3), 5.11 (ddt, J = 6.0, 1.2, 1.2 Hz, 1 H, H6), 4.67 (d, J = 6.0 Hz, 1 H, H5), 4.59 (d, J = 6.8 Hz, 1 H, OCH2OCH3). 4.55 (d. J = 6.8 Hz. 1 H. OCH2OCH34.12 (dd. J= 1.2. 1.2 Hz, 2H, H13), 3.39 (s, 3H, OCH2OCH3), 1.95 (d, J = 1.2 Hz, 3H, H14).13C NMR (100 MHz, CDCI3) δ 170.6, 149.1 , 143.0, 132.7, 94.9, 82.1 , 80.0, 79.8, 56.2, 20.8,

[0278] 20.7.

[0279] HRMS (ESI) calculated for C11H15BrlO4+[M+H]+416.9198; found 416.9196. Example 8. Synthesis of 17’

[0280] 16’ as an inseparable mixture with 16 17' ORTEP separated from 17 of 17 '

[0281] The filtrate containing 16 and 16’ (1.50 g, ca. 1 :1 molar ratio) obtained in Example 6 was treated with TfOH (125 mL) in dimethoxymethane (50 mL) at 25 °C, providing a mixture of MOM ethers 17 and 17’. They could be separated by flash column chromatography (silica gel, Hexane / EtOAc = 95:5 to 70:30) (the yields were not elucidated from this process). Recrystallization of 17’ from diisopropyl ether ( / -Pr20) afforded a single crystal, which was characterized by X-ray crystallographic analysis to confirm its structure and stereochemistry (CCDC-2312149, Fig. 6). Table 2. X-ray crystallographic data of Compound 17’ (CCDC-2312149).

[0282] Aspect: White solid / colorless crystal when recrystallized.

[0283] Melting point: 92 °C.

[0284] TLC: Rf= 0.45 (30% EtOAc / Hexane).

[0285] [a]™ +160. r (C = 1 , CHCI3).

[0286] FTIR (neat, cm1) 2951 [v(C=C)], 1714 [v(C=O)], 1614 [v(C=C)], 1236 [v(C-Br)], 1111 [v(C-O)], 650 [v(C-Br)].

[0287] 1H NMR (400 MHz, CDCI3) δ 7.12 (dt, J = 6.0, 1.2 Hz, 1 H, H7), 6.17 (qd, J = 1.6 Hz, 1H, H3), 5.27 (d, J = 3.2 Hz, 1 H, H5), 4.63 (d, J = 6.8 Hz, 1 H, OCH2OCH3). 4.61 (d, J = 6.8 Hz, 1 H, OCH2OCH3). 4.46 (dd, J = 6.0, 3.2 Hz, 1 H, H6), 4.28 (dd, J = 11.6, 1.2 Hz, 2H, H13a), 4.16 (dd, J = 11.6, 1.2 Hz, 2H, H13b), 3.33 (s, 3H, OCH2OCH3), 2.10 (d, J = 1.6 Hz, 3H, H14).

[0288] 13C NMR (100 MHz, CDCI3) δ 161.9, 143.7, 140.7, 131.7, 96.5, 83.8, 75.8, 66.9, 55.9, 27.4, 22.3.

[0289] HRMS calculated for CnH15BrlO4+[M+H]+416.9198; found 416.9203.

[0290] Example 9. Synthesis of 18

[0291] The crude aldehyde 12 (from Example 3, 9.45 g, ca. 50.7 mmol, ca. 1.95 equiv) was added to a solution of 17 (10.8 g, 26.0 mmol) in DMF (180 mL), followed by a solution of chromium chloride ( CrCI2Sigma Aldrich-450782, 8.95 g, 72.8 mmol) in DMF (110 mL) at 10 °C (an ice- water bath), and the reaction mixture was allowed to warm up to 25 °C and stirred for 3 hours. The mixture was diluted with a saturated aqueous NH4CI solution (600 mL) and p- toluenesulfonic acid (494 mg, 2.60 mmol). The mixture was stirred for 30 minutes until the complete disappearance of the TMS ether intermediate (monitored by TLC: the Rf value of the silyl ether intermediate = 0.35 in 30% EtOAc / Hexane). The organic materials were extracted three times with EtOAc (400 mL x 3), and the combined organic phases were washed with a saturated aqueous NH4CI solution (400 mL), brine (400 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 50:50 to 20:100) to give 18 (9.22 g, 20.4 mmol) in 79% yield (d.r. = >99:1).

[0292] Aspect: Pale yellow oil.

[0293] TLC: Rf= 0.25 (70% EtOAc / Hexane).

[0294] [a]o0+61.5° (C = 1, CHCI3).

[0295] FTIR (neat, cm’1) 3402 [v(O-H)], 2928 [v(C=C)], 1759 [v(C=O)], 1662 [v(C=C)], 1276 [v(C-O)], 1018 [v(C-O)].

[0296] 1H NMR (400 MHz CDCI3) δ 6.38 (d, J = 2.4 Hz, 1 H, Hua), 6.28 (qd, J = 1.6, 0.8 Hz, 1H, H3), 5.76 (d, J = 2.0 Hz, 1 H, Hub), 5.55 (t, J = 6.8 Hz, 1H, H1), 4.62 (dd, J = 4.8, 2.4 Hz, 1 H, Hs), 4.56 (d, J = 6.8 Hz, 1 H, OCH2OCH3), 4.53 (d, J = 4.8 Hz, 1 H, H5), 4.50 (d, J = 6.8 Hz, 1H, OCH2OCH3). 4.18 (d, J = 6.8 Hz, 1 H, H2), 3.91 - 3.81 (m, 1 H, Hs), 3.39 (s, 3H, OCH2OCH3), 3.14 - 3.06 (m, 1 H, H7), 2.29 (dd, 13.6, 3.2 Hz, 1 H, H9b), 2.20 - 2.10 (dd, 13.6, 3.2, 1 H, H9a), 2.12 (br s, 1 H, OH), 1.94 (d, J = 1.6 Hz, 3H, H14), 1.70 (s, 3H, H15).

[0297] 13C NMR (100 MHz, CDCI3) δ 170.4, 144.2, 135.3, 135.1 , 128.0, 124.2, 94.9, 81.6, 80.5, 79.6, 70.4, 59.0, 56.4, 47.0, 43.3, 21.0, 16.4.

[0298] HRMS (ESI) calculated for C17H26IO6+[M+H]+453.0774; found 453.0775. (Fig. 7)

[0299] Example 10. Synthesis of 19

[0300] Manganese oxide (MnO2, 21.1 g, 243 mmol) was added to a solution of 18 (11.0 g, 24.3 mmol) in CH2CI2(380 mL) was added, and the suspension was stirred at 25 °C for 3 hours. The solid materials were removed via filtration through a Celite pad, and the filtrate was concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 70:30 to 30:70) to give 19 (9.32 g, 20.7 mmol) in 85% yield. Aspect: Pale yellow oil.

[0301] TLC: Rf= 0.25 (50% EtOAc / Hexane).

[0302] [a]™ +130.6° (C = 1 , CHCb).

[0303] FTIR (neat, cm1) 3441 [v(O-H)], 2947 [v(C=C)], 1766 [v(C=O)], 1666 [v(C=O)], 1273 [v(C-O)], 1122 [v(C-O)].

[0304] 1H NMR (400 MHz CDCI3) δ 9.98 (d, J = 8.0 Hz, 1 H, H2), 6.41 (d, J = 2.0 Hz, 1 H, H13a), 6.29 (s, 1 H, H3), 5.97 (d, J = 8.0 Hz, 1H, H1), 5.78 (d, J = 2.0 Hz, 1 H, H13b), 4.61 (dd, J = 4.4, 2.0 Hz, 1H, H6), 4.55 (d, J = 6.8 Hz, 1 H, OCH2OCH3. 4.53 (d, J= 4.4 Hz, 1H, H5), 4.49 (d, J = 6.8 Hz, 1 H, OCH2OCH3). 4.00 - 3.92 (m, 1 H, H8), 3.38 (s, 3H, OCH2OCH3), 3.09 (dddd, J = 2.0, 2.0, 2.0, 2.0 Hz, 1 H, H7), 2.57 (d, J = 4.4 Hz, 1H, OH), 2.45 (dd, J = 14.0, 3.2 Hz, 1 H, H9a), 2.37 (dd, J = 14.0, 10.0 Hz, 1 H, H9b), 2.23 (s, 3H, H15), 1 94 (d, J = 1.6 Hz, 3H, H14).

[0305] 13C NMR (100 MHz, CDCI3) δ 191.0, 169.9, 159.3, 144.3, 135.1, 129.7, 124.6, 95.0, 81.5, 80.5, 79.7, 70.9, 56.5, 47.8, 44.0, 21.1 , 18.2.

[0306] HRMS (ESI) calculated for C17H24IO6+[M+H]+451.0618; found 451.0617.

[0307] Example 11. Synthesis of 20

[0308] Anhydrous chromium chloride (CrCI2, 2.46 g, 20.0 mmol) was slowly dissolved in anhydrous DMSO (950 mL, degassed by blowing in Ar gas for 30 minutes before use) at 4 °C (an ice- water bath) to avoid strong exotherm. A solution of 19 (2.25 g, 5.00 mmol) in degassed anhydrous DMSO (40 mL) was added, which was followed by the addition of a solution of nickel(ll) acetylacetonate (Ni(acac)2, 25.7 mg, 0.04 mmol) in degassed anhydrous DMSO (10 mL). The mixture was stirred at 25 °C for 16 hours (the reaction progress was monitored by LC-MS, see Note 3, Fig. 8 and Table 3). The reaction mixture was diluted with a saturated aqueous NH4CI solution (1 L), brine (1 L), and the mixture was stirred at 25 °C for 30 minutes. The organic materials were extracted from the separated aqueous phase seven times with EtOAc (500 mL x 7), and the combined organic phases were washed with brine (1 L). The residual organic material in the brine phase was extracted one time with EtOAc (500 mL x 1) and the combined organic phases were dried over MgSO4and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, CH2CI2 / EtOAc = 50:50 to 0:100) to give 20 (820 mg, 2.55 mmol) in 51% yield (d.r. = >99:1). Recrystallization of 20 from diethyl ether (Et2O) and dichloromethane (CH2CI2) afforded a single crystal, which was analyzed by the X-ray crystallographic analysis (CCDC-2312151 , Fig. 9).

[0309] Note 1: Several anhydrous CrCI2from different suppliers (Sigma Aldrich-450782, TCI-C3788, and Fluorochem-101514) have been tested, revealing that no significant reactivity differences could be observed (see Table 4 for the optimization of the reaction conditions).

[0310] Note 2. The addition of brine in the aqueous phase facilitated the extraction of 20.

[0311] Note 3'. Monitoring of the reaction progress by LC-MS showed the formation of the organochromium species, which could be protonated through the LC column to become the reduced alkene intermediate 19-H detected as [M+Na]+= 347.1 by the mass spectrometry (Fig. 8). 19-H was gradually converted to the cyclized product 20 along with the formation of by-products. Based on the mass spectrometry ([M+Na]+= 671.3), we assumed that the by- products could be dimers (19-dimer) derived from the intermolecular NHK reaction.

[0312] Table 3. Monitoring of the reaction progress by LC-MS.

[0313] Table 4. Optimization of the reaction conditions. aReactions were conducted using 0.067-0.111 mmol (30-50 mg) of 19.bReaction in 5 mmol scale.

[0314] Table 5. X-ray crystallographic data of Compound 20 (CCDC-2312151).

[0315] Aspect: White solid / colorless crystal when recrystallized.

[0316] Melting point: 124 °C.

[0317] TLC: Rf= 0.25 (70% EtOAc / CH2CI2).

[0318] [a]o° +132.6° (C = 1 , CHCI3).

[0319] FTIR (neat, cm’1) 3381 [v(O-H)], 2914 [v(C=C)]> 1728 [v(C=O)]> 1651 [v(C=C)], 1267[v(C-O)], 1020 [v(C-O)].

[0320] 1H NMR (400 MHz CDCI3) δ 6.40 (dd, J = 2.4, 0.8 Hz, 1 H, H13a), 5.91 (dd, J =2.4, 0.8 Hz, 1 H, Hnb), 5.81 (d, J = 7.2 Hz, 1 H, H1), 5.74 (qd, J = 1.2, 6.8 Hz, 1 H, H3), 5.17 (s, 1 H, H5), 4.91- 4.86 (br m, 1 H, H2), 4.51 (s, 2H, OCH2OCH3). 3.93 (d, J = 2.8 Hz, 1 H, Hs), 3.77 (dddd, J = 10.8, 10.0, 5.2, 4.0 Hz, 1 H, H8), 3.30 (s, 3H, OCH2OCH3), 2.91 (dddd, J = 10.0, 2.8, 2.4, 2.4 Hz, 1 H, H7), 2.67 (dd, J = 12.4, 4.0 Hz, 1 H, H9b), 2.40 (dd, J = 12.4, 10.8 Hz, 1H, H9a), 2.21 (d, J = 4.4 Hz, 1H, OH), 1.97 (d, J = 5.2 Hz, 1H, OH), 1.79 (d, J = 1.2 Hz, 3H, H14), 1.63 (s, 3H, H15).

[0321] 13C NMR (100 MHz, CDCI3) δ 170.5, 142.1 , 136.1 , 135.1 , 129.4, 127.5, 126.3, 94.7, 82.2, 76.1 , 71.1, 67.1 , 56.2, 52.4, 49.3, 19.0, 18.2.

[0322] HRMS (ESI) calculated for C17H25O6+[M+H]+325.1651 ; found 325.1644.

[0323] The origin of the diastereoselectivity: Alkenylchromium species 19-Cr could have two conformations 19-Cr major and 19-Cr minor, through C7-8 bond rotation as shown in Fig. 10. 19-Cr major has the C8 tether facing opposite to the a-ethylene-y-butyrolactone moiety, resulting in nucleophilic attack of alkenylchromium species from the top face of the C2 carbonyl group to give 20. On the other hand, 19-Cr minor, which could potentially lead to another stereoisomer of 20, has serious steric crush between the C8 tether and the a- ethylene-y-butyrolactone moiety, thus being energetically unfavored.

[0324] Example 12. Synthesis of 21

[0325]

[0326] Manganese oxide (MnO2, 3.36 g, 38.7 mmol) at 25 °C was added to a solution of 20 (1 .25 g, 3.87 mmol) in CH2CI2(40 mL), and the suspension was stirred for 3 hours. The solid materials were removed by the filtration through a Celite pad, and the filtrate was concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, CH2CI2 / EtOAc = 80:20 to 50:50) to give 21 (1.01 g, 3.14 mmol) in 81% yield.

[0327] Aspect: Pale yellow oil.

[0328] TLC: Rf= 0.3 (50% EtOAc / CH2CI2).

[0329] [a]2D° +136.5° (C = 1 , CHCI3).

[0330] FTIR (neat, cm1) 3518 [v(O-H)], 2945 [v(C=C)], 1755 [v(C=O)]> 1643 [v(C=O)], 1633 [v(C=C)]> 1070 [v(C-O)].

[0331] 1H NMR (400 MHz, CDCI3) δ 6.45 (d, J = 2.8 Hz, 1 H, H13a), 6.20 (s, 1 H, H1), 6.06 (s, 1H, H3),

[0332] 5.98 (d, J = 2.8 Hz, 1 H, H13b), 5.39 (s, 1 H, H5), 4.53 (d, J = 6.8 Hz, 1H, OCH2OCH3), 4.48 (d, J = 6.8 Hz, 1 H, OCH2OCH3). 4.16 (d, J = 2.8 Hz, 1 H, H6), 3.93 (dddd, J = 10.8, 10.8, 4.2, 3.8 Hz, 1 H, H8), 3.31 (s, 3H, OCH2OCH3). 3.02 (dddd, J = 10.8, 2.8, 2.8, 2.8 Hz, 1H, H7), 2.79 (dd, J = 12.4, 3.8 Hz, 1 H, H9b), 2.47 (dd, J = 12.4, 10.8 Hz, 1H, H9a), 2.29 (d, J = 4.2 Hz, 1 H, OH),

[0333] 1.99 (d, J = 1.6 Hz, 3H, H14), 1.73 (s, 3H, H15).

[0334] 13C NMR (100 MHz, CDCI3) δ 195.8, 170.0, 158.1 , 137.5, 134.6, 133.2, 131.0, 126.9, 95.2, 81.4, 76.8, 71.2, 56.6, 52.8, 48.5, 20.7, 19.5.

[0335] HRMS (ESI) calculated for C17H22O6Na+[M+Na]+345.1314; found 345.1310.

[0336] Example 13. Synthesis of 22

[0337]

[0338] Methacrylic anhydride (560 μL, 3.74 mmol) was added to a solution of 21 (1.00 g, 3.11 mmol), triethylamine (Et3N, 1.3 mL, 9.3 mmol), 4-dimethylaminopyridine (DMAP, 75.9 mg, 0.62 mmol) in THF (30 mL), and the reaction mixture was stirred at 25 °C for 16 hours. The mixture was diluted with CH2CI2(80 mL) and aqueous HCI solution (0.1 M, 80 mL). The organic materials were extracted from the separated aqueous phase twice with CH2CI2(40 mL x 2) and the combined organic phases were dried over MgSCU, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 70:30 to 50:50) to give 22 (1.02 g, 2.62 mmol) in 84% yield.

[0339] Aspect: Pale yellow oil.

[0340] TLC: Rf= 0.3 (50% EtOAc / Hexane).

[0341] [a]™ +162.9° (C = 1 , CHCb).

[0342] FTIR (neat, cm1) 2954 [v(C=C)], 1769 [v(C=O)], 1717 [v(C=O)], 1643 [v(C=C)], 1269 [v(C-O)], 1155 [v(C-O)].

[0343] 1H NMR (400 MHz, CDCI3) δ 6.36 (d, J = 2.4 Hz, 1 H, H13a), 6.23 (s, 1 H, H1), 6.16 (qd, J= 1.2,

[0344] 1.2 Hz, 1H, H18a), 6.08 (q, J = 1.2 Hz, 1 H, H3), 5.78 (d, J = 2.4 Hz, 1 H, H13b), 5.67 (qd, J = 1.2,

[0345] 1.2 Hz, 1 H, H18b), 5.41 (s, 1 H, H5), 5.23 (ddd, J = 10.8, 10.8, 4.0 Hz, 1H, H8), 4.55 (d, J = 6.8 Hz, 1H, OCH2OCH3), 4.49 (d, J= 6.8 Hz, 1 H, OCH2OCH3), 4.25 (d, J = 3.2 Hz, 1 H, H6), 3.32 (s, 3H, OCH2OCH3), 3.28 (dddd, J = 10.8, 3.2, 2.4, 2.4 Hz, 1 H, H7), 2.78 (dd, J = 12.4, 4.0 Hz, 1H, H9b), 2.53 (dd, J = 12.4, 10.8 Hz, 1 H, H9a), 2.01 (d, J= 1.2 Hz, 3H, H14), 1.96 (dd, J = 1.2,

[0346] 1.2 Hz, 3H, H19), 1.79 (s, 3H, H15).

[0347] 13C NMR (100 MHz, CDCI3) δ 195.5, 169.4, 165.7, 158.1 , 137.0, 135.9, 133.8, 133.5, 131.0, 127.0, 126.6, 95.3, 81.2, 77.0, 72.4, 56.7, 50.2, 45.6, 20.8, 19.2, 18.5.

[0348] HRMS (ESI) calculated for C21H27O7+[M+H]+391.1757; found 391.1759.

[0349] Example 14. Synthesis of molephantin (1)

[0350] MOM ether 22 (1.02 g, 2.62 mmol) was treated in trifluoroacetic acid (CF3CO2H) and CH2CI2(1 :1 v / v, 30 mL), and the mixture was stirred at 25 °C for 4 h. The reaction was slowly quenched with saturated aqueous NaHCO3solution (150 mL) and the organic materials were extracted from the separated aqueous phase three times with CH2CI2(50 mL x 3). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 80:20 to 40:60) to give molephantin 1 (690 mg, 1.99 mmol) in 76% yield.

[0351] Aspect: White solid.

[0352] Melting point: 217 °C.

[0353] TLC: Rf= 0.2 (50% EtOAc / Hexane).

[0354] [a]2D° +158.2° (C = 1, CHCI3).

[0355] FTIR (neat, cm-1) 3437 [v(O-H)], 2924 [v(C=C)], 1759 [v(C=O)], 1730 [v(C=O)], 1697 [v(C=O)], 1639 [v(C=C)], 1263 [v(C-O)].

[0356] 1H NMR (400 MHz, CDCI3) δ 6.38 (d, J = 2.8 Hz, 1 H, H13a), 6.22 (s, 1 H, H1), 6.15 (s, 1 H, H18a), 6.02 (s, 1H, H3), 5.84 (d, J = 2.0 Hz, 1 H, H13b), 5.68 (s, 1 H, Hwb), 5.46 (d, J = 12.0 Hz, 1H, H5), 5.24 (ddd, J = 10.8, 10.8, 4.0 Hz 1 H, H8), 4.25 (d, J = 4.0 Hz, 1H, H6), 3.40 (dddd, J = 10.8, 4.0, 2.4, 2.0 Hz, 1 H, H7), 2.78 (dd, J = 12.0, 4.0 Hz, 1 H, H9a), 2.51 (dd, J = 12.0, 10.8 Hz, 1 H, H9b), 2.39 (d, J = 12.0 Hz, 1 H, OH), 2.02 (s, 3H, H14), 1.96 (s, 3H H19), 1.80 (s, 3H, H15).

[0357] 13C NMR (100 MHz, CDCI3) δ 195.3 (C2), 169.5 (C12), 165.7 (C16), 159.2 (C4), 137.0 (C10), 135.8 (C17), 133.5 (C1), 133.2 (011), 129.3 (C3), 128.3 (C13), 126.7 (C18), 81.4 (C6), 73.8 (05), 72.5 (C8), 49.6 (C7), 45.5 (C9), 20.2 (014), 19.0 (015), 18.4 (C19).

[0358] HRMS calculated for CwHaOe* [M+H]+347.1495; found 347.1490.

[0359] (Fig. 11)

[0360] Example 15. Synthesis of 23

[0361]

[0362] Sodium borohydride (NaBH4, 585 μL, 0.155 mmol, solution of 10 mg / mL in MeOH) was added to a solution of 20 (50 mg, 0.154 mmol) in MeOH (2 mL) at 0 °C (ice-bath water), and the reaction mixture was stirred at the same temperature for 0.5 hour. The mixture was quenched with a saturated aqueous NH4CI solution (2 mL) and diluted with brine (20 mL). The organic materials were extracted from the aqueous phase three times with EtOAc (20 mL x 3). The combined organic phases were dried over MgSO4and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, CH2CI2 / EtOAc = 50:50 to 0:100) to give 23 (37 mg, 0.113 mmol) in 73% yield. Spontaneous crystallization of 23 from deuterated chloroform (CDCI3) afforded a colorless single crystal, which was analyzed by the X-ray crystallographic analysis (CCDC-2312152, Fig. 12).

[0363] Table 6. X-ray crystallographic data of Compound 23 (CCDC-2312152).

[0364] Aspect: White solid / colorless crystal when recrystallized.

[0365] Melting point: 158 °C.

[0366] TLC: Rf= 0.25 (70% EtOAc / CH2CI2).

[0367] [a]2D° +38.5° (C = 1, CHCI3).

[0368] FTIR (neat, cm1) 3439 [v(O-H)], 2918 [v(C=C)], 1755 [v(C=O)], 1643 [v(C=C)], 1273 [v(C-O)], 1018 [v(C-O)].

[0369] 1H NMR (400 MHz, CDCI3) δ 5.80 (d, J = 7.6 Hz, 1 H, H1), 5.73 (d, J = 6.8 Hz, 1 H, H3), 5.29 (s, 1H, Hs), 4.91-4.83 (br m, 1 H, H2), 4.60 (d, J = 6.8 Hz, 1H, OCH2OCH34.56 (d, J = 6.8 Hz, 1H, OCH2OCH3). 3.91 - 3.82 (m, 1 H, H8), 3.84 (d, J = 5.2 Hz, 1 H, H6), 3.44 (s, 3H, OCH2OCH3), 2.72 (qd, J= 7.2, 7.2 Hz, 1 H, H11), 2.62 (dd, J = 12.0, 3.2 Hz, 1 H, H9b), 2.37 (dd, J= 12.0, 12.0 Hz, 1 H, H9a), 2.06 (ddd, J = 5.2, 7.2, 10.0 Hz, 1 H, H7), 1.89 (d, J = 6.4 Hz, OH), 1.77 (s, 3H, H14), 1.62 (s, 3H, H15), 1.41 (d, J = 7.2 Hz, 3H, H13).

[0370] 13C NMR (100 MHz, CDCI3) δ 179.7, 141.4, 136.5, 128.6, 128.4, 95.0, 82.0, 76.2, 74.3, 67.3, 56.7, 56.0, 50.4, 39.3, 18.8, 18.2, 17.9.

[0371] HRMS calculated for C17H26O6Na+[M+Na]+349.1627; found 349.1630.

[0372] Example 16. Synthesis of 24

[0373] MnO2(80 mg, 0.92 mmol) was added to a solution of 23 (30 mg, 0.092 mmol) in CH2CI2(2 mL) at 25 °C, and the reaction suspension was stirred for 3 hours. The solid materials were removed by filtration through a Celite pad, and the filtrate was concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, CH2CI2 / EtOAc = 80:20 to 50:50) to give 24 (23 mg, 0.071 mmol) in 77% yield.

[0374] Aspect: Colorless oil.

[0375] TLC Rf= 0.3 (50% EtOAc / CH2CI2).

[0376] [a]2D° +84.6° (C = 1 , CHCI3).

[0377] FTIR (neat, cm-1) 3458 [v(O-H)], 2938 [v(C=C)], 1768 [v(C=O)]_ 1643 [v(C=O)], 1633 [v(C=C)], 1238 [v(C-O)], 1192 [v(C-O)], 1018 [v(C-O)].

[0378] 1H NMR (400 MHz, CDCI3) δ6.18 (s, 1 H, H1), 6.06 (s, J = 1 H, H3), 5.53 (s, 1 H, H5), 4.63 (d, J = 6.8 Hz, 1H, OCH2OCH3), 4.52 (d, J = 6.8 Hz, 1 H, OCH2OCH3). 4.04 (d, J = 5.6 Hz, 1H, H6), 4.05 - 3.96 (m, 1 H, H8), 3.45 (s, 3H, OCHyQCH3). 2.78 - 2.70 (m, 2H, H11+H9b), 2.45 (dd, J = 12.0, 11.2 Hz, 1 H, H9a), 2.18 (ddd, J = 10.4, 6.8, 5.6 Hz, 1H, H7), 2.11 (d, J = 5.2 Hz, 1 H, OH), 1.99 (d, J = 1.6 Hz, 3H, H14), 1.71 (s, 3H, H15), 1.43 (d, J = 7.6 Hz, 3H, H13).

[0379] 13C NMR (100 MHz, CDCI3) δ 195.7, 179.2, 158.8, 136.6, 133.3, 131.6, 95.7, 81.4, 77.1 , 74.2, 57.0, 56.2, 49.2, 39.6, 20.6, 19.0, 18.0.

[0380] HRMS calculated for C17H24O6Na+[M+H]+347.1471; found 347.1472.

[0381] Example 17. Synthesis of tomenphantopin F (2) 4%

[0382] MOM ether 24 (20 mg, 0.062 mmol) was dissolved in CF3CO2H and CH2CI2(1 :1 v / v, 2 mL), and the mixture was stirred at 25 °C for 3 hours. The reaction was quenched with saturated aqueous NaHCO3solution (50 mL), and the organic materials were extracted from the separated aqueous phase three times with EtOAc (20 mL x 3). The combined organic phases were dried over MgSO4and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, CH2CI2 / EtOAc = 70:30 to 10:90) to give tomenphantopin F (2) (13 mg, 0.046 mmol) in 74% yield.

[0383] Aspect: White solid.

[0384] Melting point: 184 °C. TLC: Rf= 0.3 (70% EtOAc / CH2CI2).

[0385] [a]2D° +34.8° (C = 1 , MeOH).

[0386] FTIR (neat, cm’1) 3388 [v(O-H)], 2949 [v(C=C)], 1753 [v(C=O)], 1631 [v(C=O)], 1203 [v(C-O)], 1018 [v(C-O)].

[0387] 1H NMR (400 MHz, Methanol-cU) 6 6.31 (s, 1 H, H1), 5.92 (s, 1 H, H3), 5.56 (s, 1H, H5), 4.08 (d, J = 5.4 Hz, 1 H, H6), 3.97 (ddd, J = 10.8, 10.8, 4.0 Hz, 1H, H8), 2.73 (qd, J = 7.6, 6.0 Hz 1 H, H11), 2.68 (dd, J = 12.0, 4.0 Hz, 1 H, H9a), 2.42 (dd, J = 12.0, 10.8 Hz, 1 H, H9b), 2.21 (ddd, J = 10.8, 6.0, 5.4 Hz, 1H, H7), 2.01 (d, J = 1.2 Hz, 3H, H14), 1.69 (s, 3H, H15), 1.36 (d, J = 7.6 Hz, 3H, H13).

[0388] 13C NMR (100 MHz, Methanol-d4) δ 198.4 (C2), 182.3 (C12), 165.1 (C4), 139.0 (C10), 133.7 (C1), 129.3 (C3), 84.6 (C6), 74.0 (overlapped forC5 and C8), 57.7 (C7), 49.8 (C9), 40.6 (C11), 21.0 (C14), 18.6 (C15), 18.4 (C13).

[0389] HRMS calculated for C15H20O5Na+[M+H]+303.1208; found 303.1205.

[0390] (Fig. 13)

[0391] Example 18. Synthesis of 25 - photoinduced cycloisomerization of molephantin (1)

[0392] Molephantin (1) (50 mg, 0.144 mmol) was dissolved in degassed CH2CI2(5 mL, degassed by blowing in Ar gas for 30 minutes) and the solution was irradiated with 370 nm light (40Wx 2) at 29 °C as an ambient temperature (with fan cooling) for 100 minutes (see Fig. 14). The solvent was removed in vacuo to afford 25 (50 mg, >99% yield), which was pure enough to be characterized and used for the next step.

[0393] Note 1: Compound 25 is unstable on silica gel.

[0394] Note 2: Monitoring of the photochemical reaction by1H NMR spectroscopy in CDCI3showed a quick formation of multiple intermediates having different alkene peaks, which gradually converged to 25 (Fig. 16).

[0395] Aspect: Pale yellow oil.

[0396] TLC: Rf= 0.4 (50% EtOAc / Hexane).

[0397] [a]o° +42.2° (C = 1 , CHCI3). FTIR (neat, cm’1) 3441 [v(O-H)], 2924 [v(C=C)], 1767 [v(C=O)], 1713 [v(C=O)], 1658 [v(C=C)], 1273 [v(C-O)], 1153 [v(C-O)], 1033 [v(C-O)].

[0398] 1H NMR (400 MHz, CDCI3) δ6.32 (d, J = 3.2 Hz, 1 H, H13a), 6.16 (q, J = 0.8 Hz, 1 H, H18a), 5.79 (d, J = 2.8 Hz, 1 H, H13b), 5.78-5.75 (m, 1 H, H3), 5.71 (q, J = 0.8 Hz, 1 H, H18b), 5.58 (s, 1H, H1), 5.26 (d, J= 4.0 Hz, 1 H, H5), 5.24 (ddd, J= 10.8, 4.4, 2.0 Hz, 1 H, H8), 4.65 (dd, J = 6.0, 4.0 Hz, 1H, H6), 3.77 (dd, J = 14.4, 2.0 1 H, H9b), 3.13 (dddd, J = 10.8, 6.0, 3.2, 2.8 Hz, 1 H, H7), 2.83 (s, 1 H, OH), 2.23 (dd, J = 14.4, 4.4 Hz, 1 H, H9a), 1.99 (dd, J = 0.8, 0.8 Hz, 3H, H19), 1.78 (s, 3H, H15), 1.72 (qd, J = 0.8, 0.8 Hz, 3H, H14).

[0399] 13C NMR (100 MHz, CDCI3) δ 169.0 (C12), 165.8 (C16), 138.4 (C4), 136.2 (C17), 135.0 (C11), 133.6 (C10), 130.8 (C3), 127.4 (C1), 127.3 (C13), 126.7 (C18), 110.6 (C2), 85.4 (C5), 79.4 (C6), 76.7 (C8), 39.0 (C7), 32.7 (C9), 28.8 (C15), 18.6 (C19), 13.3 (C4).

[0400] HRMS calculated for C19H23O6+[M+H]+347.1495; found 347.1490.

[0401] (Fig. 17)

[0402] Example 19. Synthesis of EM-2 (3) p-toluenesulfonic acid (TsOH«H2O, 160 μL, 8.4 pmol, 10 mg / mL solution in MeOH) was added to a solution of 25 (30 mg, 0.087 mmol) in MeOH (1 mL), and the reaction mixture was stirred at 25 °C for 10 minutes. The solvent was removed in vacuo and the resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 95:5 to 70:30) to give EM- 2 (3) (29 mg, 0.081 mmol) in 93% yield. Recrystallization of 3 from diisopropyl ether ( / -Pr20) afforded a single crystal, which was characterized by X-ray crystallographic analysis to confirm its structure and stereochemistry (CCDC-2324191, Fig. 18).

[0403] Table 7. X-ray crystallographic data for EM-2 (3) (CCDC-2324191). Aspect: White solid / colorless crystal when recrystallized.

[0404] Melting point: 102 °C.

[0405] TLC: Rf= 0.4 (20% EtOAc / Hexane).

[0406] [a]n° +48.6° (C = 1 , CHCI3).

[0407] FTIR (neat, cm-1) 2928 [v(C=C)]_ 1767 [v(C=O)], 1713 [v(C=O)], 1659 [v(C=C)], 1635 [v(C=C)], 1273 [v(C-O)], 1153 [v(C-O)], 1092 [v(C-O)], 1045 [v(C-O)].

[0408] 1H NMR (400 MHz, CDCI3) δ6.32 (d, J = 3.2 Hz, 1 H, H13a), 6.16 (qd, J= 1.2, 1.2 Hz 1 H, H18a), 5.79 (d, J = 2.8 Hz, 1 H, H13b), 5.71 (qd, J = 1.2, 1.2 Hz, 1 H, H18b), 5.63 (qd, J = 1.6, 1.6 Hz, 1H, H3), 5.49 (s, 1 H, H1), 5.26 - 5.21 (m, 2H, H8+H5), 4.66 (dd, J = 6.4, 4.0 Hz, 1 H, H6), 3.73 (qd, J = 1.2, 14.4 Hz, 1 H, H9b), 3.22 (s, 3H, OCH3), 3.15 (dddd, J = 11.2, 6.4, 3.2, 2.8 Hz, 1 H, H7), 2.23 (dd, J = 14.4, 4.4 Hz, 1 H, H9a), 1 .99 (dd, J = 1 .2, 1 .2 Hz, 3H, H19), 1 .78 (d, J = 1 .2

[0409] Hz, 3H, H15), 1.74 (dd, 3H, J = 1.6, 0.8 Hz, H14).

[0410] 13C NMR (100 MHz, CDCI3) δ 169.0 (C12), 165.8 (C16), 139.2 (C4), 136.3 (C17), 135.1 (C11), 133.9 (C10), 129.2 (C3), 127.3 (C1), 127.2 (C13), 126.6 (C18), 114.2 (C2), 85.9 (C5), 79.4 (C6), 76.7 (C8), 49.7 (OMe), 39.1 (C7), 32.8 (C9), 28.7 (C15), 18.6 (C19), 13.3 (C14). HRMS calculated for C20H25CV [M+H]+361.1651 ; found 361.1651.

[0411] (Fig. 19)

[0412] Example 20. Synthesis of phantomolin (4) molephantin (1) phantomolin (4) 85% via 2 steps

[0413] Molephantin (1) (50 mg, 0.144 mmol) was dissolved in degassed CH2CI2(0.5 mL) and irradiated with 370 nm light (40Wx2, 4 cm) at 29 °C for 100 minutes. The solvent was removed in vacuo and the resulting residue was dissolved in EtOH (2 mL) followed by the addition of p- toluenesulfonic acid (TsOH-H2O, 160 μL, 8.4 pmol, 10 mg / mL solution in EtOH). After stirring at 25 °C for 10 minutes, the solvent was removed in vacuo to give the crude material, which was purified by flash chromatography (silica gel, Hexane / EtOAc = 95:5 to 70:30) to give phantomolin (4) (46 mg, 0.123 mmol) in 85% yield.

[0414] Aspect: Colorless oil.

[0415] TLC: Rf= 0.4 (20% EtOAc / Hexane).

[0416] [a]o° +55.2° (C = 1 , CHCI3).

[0417] FTIR (neat, cm’1) 2924 [v(C=C)], 1771 [v(C=O)], 1717 [v(C=O)J, 1659 [v(C=C)], 1635 [v(C=C)], 1273 [v(C-O)], 1153 [v(C-O)], 1092 [v(C-O)], 1045 [v(C-O)].

[0418] 1H NMR (400 MHz, CDCI3) δ 6.32 (d, J = 3.2 Hz, 1 H, H13a), 6.16 (s, 1 H, H18a), 5.79 (d, J = 2.8 Hz, 1 H, H13b), 5.70 (qd, J = 1.6, 1.6 Hz, 1 H, H1sb), 5.66 (qd, J = 1.6, 1.6 Hz, 1 H, H3), 5.50 (s, 1H, H1), 5.26 - 5.21 (m, 2H, H8+H5), 4.64 (dd, J = 6.0, 4.0 Hz, 1 H, H6), 3.74 (qd, J = 1.6, 14.4 Hz, 1 H, H9b), 3.54 - 3.41 (m, 2H, OCH2CH3), 3.15 (dddd, J = 11.6, 6.0, 3.2, 2.8 Hz, 1 H, H7), 2.22 (dd, J = 14.4, 4.4 Hz, 1 H, H9a), 1.99 (s, 3H, H19), 1.78 (d, J = 1.6 Hz, 3H, H15), 1 73 (s, 3H, H14), 1.20 (t, J = 7.2 Hz, 3H, OCH2CH3).

[0419] 13C NMR (100 MHz, CDCI3) δ 169.1 (C12), 165.8 (C16), 138.7 (C4), 136.3 (C17), 135.2 (C11), 133.5 (C10), 129.7 (C3), 127.7 (C1), 127.2 (C13), 126.6 (C18), 114.0 (C2), 85.8 (C5), 79.5 (C6), 76.8 (C8), 57.9 (OCH2CH3), 39.1 (C7), 32.8 (C9), 28.8 (C15), 18.6 (C19), 15.6 (OCH2CH3), 13.3 (C14).

[0420] (Fig. 20) Example 21. Synthesis of 2-0-demethyltomenphantopin C (5)

[0421] 79%

[0422] Sodium methoxide (MeONa, 50 μL, 9.3 pmol, 10 mg / mL solution in MeOH:NaOMe powder was prepared freshly from NaOMe and MeOH) was added to a solution of 25 (30 mg, 0.087 mmol) in MeOH (1 mL), and the reaction mixture was stirred at 25 °C for 3 hours. The mixture was then diluted with EtOAc (20 mL) and H2O (20 mL). The separated organic phase was washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo. The resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 90:10 to 70:30) to give 2-O-demethyltomenphantopin C (5) (26 mg, 0.069 mmol) in 79% yield.

[0423] Aspect: White solid.

[0424] Melting point: 272 °C (decomposition).

[0425] TLC: Rf= 0.4 (50% EtOAc / Hexane).

[0426] [a]o° -15.1 ° (C = 1 , CHCI3).

[0427] FTIR (neat, cm1) 3444 [v(O-H)], 2924 [v(C=C)], 1782 [v(C=O)], 1713 [v(C=O)], 1666 [v(C=C)], 1635 [v(C=C)], 1296 [v(C-O)], 1165 [v(C-O)], 1034 [v(C-O)].

[0428] 1H NMR (400 MHz, CDCI3) 06.11 (qd, J = 1.6, 1.6 Hz, 1 H, H18a), 5.72 (qd, J = 1.6, 1.6 Hz, 1 H, H18b), 5.66 (qd, J = 1.6, 1.6 Hz, 1 H, H3), 5.57 (s, 1H, H1), 5.27 (ddd, J = 11.2, 4.0, 1.6 Hz, H8), 5.24 (dd, 1 H, J= 4.4, 1.6 Hz, H5), 4.58 (dd, J = 7.6, 4.4 Hz, 1 H, H6), 3.82 (qd, J = 1.2, 14.4 Hz, 1H, H9β), 3.76 (dd, J = 9.2, 2.4 Hz, 1H, H13a), 3.42 (dd, J = 9.2, 2.8 Hz, 1 H, H13b), 3.30 (s, 3H, OCH3), 2.81 (ddd, J = 11.2, 9.2, 7.6 Hz, 1 H, H7), 2.78 (br s, 1 H, OH), 2.56 (ddd, J = 9.2, 2.8,

[0429] 2.4 Hz, 1 H, H11), 2.15 (dd, J = 14.4, 4.0 Hz, 1 H, H9α), 1.97 (dd, J = 1.6, 1.6 Hz, 3H, H19), 1.79 (dd, J = 1 .6, 0.8 Hz, 3H, H14), 1 .76 (d, J = 1 .2 Hz, 3H, H15).

[0430] 13C NMR (100 MHz, CDCI3) δ 175.5, 166.3, 139.4, 136.2, 133.0, 130.2, 127.0, 126.7, 110.8, 85.4, 79.6, 79.5, 70.5, 59.4, 47.0, 37.3, 32.9, 28.7, 18.6, 13.3.

[0431] 1H NMR (400 MHz, CD3OD) δ 6.10 (qd, J = 1.2, 1.6 Hz, 1 H, Hua), 5.72 (qd, J = 1.6, 1.6 Hz, 1H, H18b), 5.70 (qd, J = 1.6, 1.2 Hz, 1 H, H3), 5.52 (s, 1 H, H1), 5.32 (ddd, J = 10.8, 4.4, 2.4 Hz, 1H, H8), 5.18 (d, J = 4.4 Hz, 1H, H5), 4.69 (dd, J = 7.6, 4.4 Hz, 1 H, H6), 3.85 (qdd, J = 1.2, 2.4,

[0432] 14.4 Hz, 1H, H9b), 3.73 (dd, J= 9.2, 2.4 Hz, 1H, H13a), 3.45 (dd, J= 9.2, 2.8 Hz, 1 H, H13b), 3.28 (s, 3H, OCH3). 2.83 (ddd, J = 10.8, 9.2, 7.6 Hz, 1H, H7), 2.72 (ddd, J = 9.2, 2.8, 2.4 Hz, 1 H, H11), 2.16 (dd, J = 14.4, 4.4 Hz, 1H, H9a), 1.96 (dd, J = 1.6, 1.2 Hz, 3H, H19), 1.76 (dd, J = 1.6, 0.8 Hz, 3H, H14), 1.74 (d, J = 1.2 Hz, 1 H, H15).

[0433] 13C NMR (100 MHz, CD3OD) 6 178.0 (C12), 167.5 (C16), 139.4 (C4), 137.8 (C17), 132.9 (C10), 131.6 (C3), 128.9 (C1), 126.8 (C18), 111.6 (C2), 86.5 (C5), 81.17 (C6), 81.08 (C8), 71.7 (C13), 59.4 (OMe), 48.2 (C11), 38.5 (C7), 33.5 (C9), 28.7 (C15), 18.6 (C19), 13.5 (C14).

[0434] HRMS calculated for C2oH2707+[M+H]+379.1757; found 379.1773.

[0435] (Fig. 21)

[0436] Example 22. Synthesis of tomenphantopin C (6)

[0437] ORTEP of B

[0438] Sodium methoxide (MeONa, 50 μL, 9.3 mmol, 10 mg / mL solution in MeOH) was added to a solution of 25 (30 mg, 0.087 mmol) in MeOH (1 mL), and the mixture was stirred at 25 °C for 3 hours. p-Toluenesulfonic acid (TsOH«H2O, 32 μL, 16.8 mmol, 10 mg / mL solution in MeOH) was added and the mixture was stirred at 25 °C for 10 minutes. The solvent was then removed in vacuo and the resulting crude residue was purified by flash chromatography (silica gel, Hexane / EtOAc = 95:5 to 80:20) to give tomenphantopin C (6) (26 mg, 0.066 mmol) in 76%. Recrystallization of 6 from diisopopyl ether ( / -Pr2O) afforded a single crystal, which was analyzed by the X-ray crystallographic analysis (CCDC-2312153, Fig. 22).

[0439] Table 8. X-ray crystallographic data for Tomenphantopin C (6) (CCDC-2312153).

[0440] Aspect: White solid / colorless crystal when recrystallized.

[0441] Melting point: 272 °C (decomposition).

[0442] TLC: Rf= 0.4 (30% EtOAc / Hexane).

[0443] [a]2D° -27.0° (C = 1 , CHCI3).

[0444] FTIR (neat, cm’1) 2924 [v(C=C)], 1778 [v(C=O)]> 1712 [v(C=O)], 1664 [v(C=C)], 1634 [v(C=C)], 1265 [v(C-O)], 1161 [v(C-O)], 1037 [v(C-O)].

[0445] 1H NMR (400 MHz, CDCI3) δ 6.11 (qd, J = 1.2, 1.2 Hz, H18a), 5.67 (qd, J = 1.2, 1.2 Hz, 1 H, H18b), 5.58 (s, 1 H, H3), 5.47 (s, 1 H, H1), 5.28 (ddd, J = 11.2, 4.4, 2.4 Hz, 1H, H8), 5.22 (d, J = 4.0 Hz, 1 H, H5), 4.60 (dd, J = 8.0, 4.0 Hz, 1H, H6), 3.82 - 3.73 (m, 2H, H9b+H13a), 3.43 (dd, J = 9.6, 2.8 Hz, 1H, H13b), 3.30 (s, 3H, C13OCH3). 3.21 (s, 3H, C2OCH3). 2.87 - 2.78 (m, 1H, H7), 2.57 (ddd, J = 8.8, 2.8, 2.8 Hz, 1 H, H11), 2.15 (dd, J = 14.4, 4.4 Hz, 1 H, H9a), 1.97 (s, 3H, H19), 1.82 (s, 3H, H14), 1.77 (s, 3H, H15).

[0446] 13C NMR (100 MHz, CDCI3) δ 175.5 (C12), 166.2 (C16), 140.2 (C4), 136.2 (C17), 133.4 (C10), 128.4 (C3), 126.8 (C1), 126.6 (C18), 114.3 (C2), 85.9 (C5), 79.64 (C6 or C8), 79.56 (C6 or C8), 70.5 (C13), 59.4 (C13-OMe). 49.6 (C2-OMe). 47.1 (C11), 37.4 (C7), 33.1 (C9), 28.6 (C15), 18.5 (C19), 13.3 (C14).

[0447] HRMS calculated for C21H29O7+[M+H]+393.1913; found 393.1906.

[0448] (Fig. 23)

[0449] Comparative Example 1 Table 9. Comparison of natural and synthetic molephantin (1) (CDCI3). Comparative Example 2

[0450] Table 10. Comparison of natural and synthetic tomenphantopin F (2) (CD3OD).

[0451] Comparative Example 3

[0452] Table 11. Comparison of natural and synthetic EM-2 (3) (CDCI3).

[0453] Comparative Example 4

[0454] Table 12. Comparison of natural and synthetic Phantomolin (4) (CDCI3).

[0455] aThe report did not assign1H NMR signals of 9α and 9β. To the best of our knowledge, no

[0456] 13C NMR data have been reported.

[0457] Comparative Example 5 Table 13. Comparison of natural and synthetic 2-O-demethyltomenphantopin C (5) (CD3OD). a 1H and13C NMR data of natural 2-O-demethyltomenphantopin C are found in CD3OD. To the best of our knowledge, no NMR data in CDCI3have previously been reported.

[0458] Comparative Example 6 Table 14. Comparison of natural and synthetic tomenphantopin C (6) (CDCI3).

[0459] Comparative Example 7 Table 15. Comparison of natural and synthetic 25 (CDCI3).

[0460] Example 23. Retrosynthetic approach toward molephantin (1)

[0461] Our retrosynthetic approach toward molephantin (1) began with the construction of the highly strained C(sp2)-rich ten-membered ring framework. This involves the construction of the C2- C3 bond through the Nozaki-Hiyama-Kishi (NHK) (A. Gil etal., Chem. Rev. 2017, 117, 8420- 8446) macrocyclization of E-enal I tethered with a Z-iodoalkene, followed by oxidation of the resulting secondary alcohol (Fig. 24). The stereoselective construction of the a-methylene-y- butyrolactone moiety of I would be achieved by forging the C7-C8 bond through the Barbier allylation of β,γ-unsaturated aldehyde II with optically active 3-bromomethyl-5H-furan-2-one III (D. M. Hodgson et al., Org. Lett. 2011 , 13, 2594-2597). We envisioned that the preparation of aldehyde II could be started from commercially available trimethylphosphonoacetate (7) and 4,4-dimethoxy-2-butanone (8), whereas 3-bromomethyl-5 / - / -furan-2-one III was anticipated to be synthesized from dimethyl 2,3-O-isopropylidene-L-tartrate (9) derived from L-tartaric acid as a cheap chiral source of C5 and C6, ensuring the potential scalability of the developed synthetic route.

[0462] We embarked on our studies with the synthesis of aldehyde II, containing the C8-10-1-2 fragment (Fig. 25A). This could be achieved via the following three steps: (i) the Horner-Wadsworth-Emmons reaction of ketone 8 with phosphonoacetate 7, providing the trisubstituted alkene 10 as an E / Z-mixture (71 : 29); (ii) DIBAL reduction of the ester moiety of 10 to give allylic alcohol 11 , where the desired E-11 could be separated from Z-11 through silica gel column chromatography; (iii) the treatment of E-11 with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the presence of 2,6-lutidine (H. Fujioka et al., J. Am. Chem. Soc. 2004, 126, 11800-11801) to afford β,y-unsaturated aldehyde 12 bearing a trimethylsilyl ether moiety. Due to the instability of 12, it was utilized without purification for the next step (Fig. 25C). In parallel, optically active 3-bromomethyl-5 / 7-furan-2-one III was synthesized in five steps from dimethyl 2,3-O-isopropylidene- L-tartrate (9) (Fig. 25B). Nucleophilic acyl substitution at one of the methoxy carbonyl groups of 9 with MeLi allowed for the construction of methyl ketone 13 and subsequent Wittig iodoalkenylation proceeded stereoselectively to afford the desired (Z)-iodoalkene 14 (>98% purity) (G. Stork & K. Zhao, Tetrahedron Lett. 1989, 30, 2173-2174). This two-step sequence was scalable to a multi decagram scale. Upon mono-hydride reduction of the ester moiety of 14 with diisobutylaluminum hydride (DI BAL), the resulting crude aldehyde was treated with methyl acrylate in the presence of 1 ,4-diazabicylo[2,2,2]octane (DABCO), yielding a-methylene-p- hydroxyester 15 as an inconsequential mixture of diastereoisomers (D. Basavaiah etal., Chem. Rev. 2010, 110, 5447-5674). Following the protocol developed by Winssinger (R. Lagoutte et al., Tetrahedron 2018, 74, 6012-6021), the treatment of 15 with aqueous HBr enabled the construction of optically active 3-bromomethyl-5H-furan-2-one 16 as the major product, along with 3-bromomethyl-5,6-dihydro-2H-pyran-2-one 16’ as the minor component. After the isolation of pure 16 through reprecipitation from diisopropylether, its free hydroxy group was protected as a methoxymethyl ether, resulting in 17. With the two key fragment parts, p,y-unsaturated aldehyde 12 and 3-bromomethyl-5 / - / -furan- 2-one 17 in hand, their coupling via the intermolecular Barbier allylation was performed by treating a mixture of 12 (ca. 2 equiv) and 17 with chromium(ll) chloride (CrCI2) in dimethylformamide (DMF), affording a-methylene-y-butyrolactone 18 having the desired stereochemical configuration at C7 and C8 with an excellent selectivity (d.r.= >99 : 1 , no other diastereomers detected in 400 MHz 1H NMR spectroscopy scale) (Fig. 25C). The workup with aqueous acid resulted in concomitant deprotection of the trimethylsilyl ether at the C2 position. This stereocontrol could be rationalized by the Zimmerman-Traxler pseudo-chair transition state B between aldehyde 12 and allylchromium species derived from 17, in which aldehyde 12 predominantly approached from the top face of the sp2-hybridized C7, opposite to the C5-C6 bond (H. E. Zimmerman & M. D. Traxler, J. Am. Chem. Soc. 1957, 79, 1920-1923). The C2-al lyl ic alcohol moiety of 18 was then chemoselectively oxidized by manganese dioxide (MnC>2), resulting in a,p-unsaturated aldehyde 19. Extensive screening of the reaction conditions for the NHK macrocyclization of 19 (see the above examples) revealed that the treatment of 19 with CrCI2(4 equiv) and Ni(acac)2(2 mol%) in DMSO (5 mM) at 25 °C afforded the desired 10-membered macrocycle 20 in 51% yield as a single diastereomer (d.r.= >99 : 1). The structure of 20 could unambiguously be confirmed by the single X-ray crystallographic analysis (see Example 11). MnC>2 oxidation of the bis-allylic alcohol moiety of 20 furnished dienone 21 and subsequent acylation of the remaining C8 hydroxyl group with methacrylic anhydride gave 22. Finally, the methoxymethyl ether at C5 was deprotected using trifluoroacetic acid (TFA) to give molephantin (1), with its spectral data matching the reported values (B. Wang et a / ., Chin. J. Chem. 2012, 30, 1320-1322).

[0463] Furthermore, we took advantage of 10-membered macrocyclic intermediate 20 for the synthesis of tomenphantopin F (2) (Fig. 25D). The treatment of 20 with sodium borohydride (NaBH4) in MeOH enabled diastereoselective reduction of the exo-methylene moiety, providing a-(S)-methyl-y-butyrolactone 23 as a single stereoisomer. The stereochemical configuration of 23 was verified by the X-ray diffraction analysis (see Example 15). Subsequent MnC>2 oxidation of 23 facilitated the construction of dienone 24, and the ensuing MOM deprotection with TFA delivered tomenphantopin F (2).

[0464] Example 24. Method for converting molephantin (1) into the furanogermacranolides

[0465] Our next objective was to explore a method to convert molephantin (1) into the furanogermacranolides. The hypothetical skeletal transformation via isomerization of the (E,Z)-dienone moiety of 1 to the (Z,Z)-dienone [(Z,Z)-1] and its subsequent hemiketalization with the C5-hydroxyl group could afford 2-deethoxy-2p-hydroxyphantomolin (25), which was also isolated from Elephantopus mollis (P. P.-H. But et al., Planta Med. 1996, 62, 474-476).

[0466] We investigated the analogous photochemical dienoneisomerization of molephantin (1). Indeed, we observed a weak absorption band at Amax = 348 nm in the ultraviolet-visible (UVA / is) spectrum of molephantin (1) in CH2CI2(0.5 mM), which was characterized as the n- rr* transition of the carbonyl group of the dienone moiety (see the above examples) (V. N. Gutrov et al., J. Photochem. Photobiol. A 2022, 425, 113678). We found that irradiation of a solution of 1 in degassed CH2CI2with ultraviolet A light (λmax = 370 nm) could generate multiple alkene isomers within a few minutes, as confirmed by the1H NMR analyses, suggesting that the dienone isomers (E,E)-1 , (Z,E)-1 and (Z,Z)-1 could be formed under photoequilibrium. We observed that these dienone congeners could eventually converge to 25 in a quantitative yield via hemiketalization of (Z,Z)-1.

[0467] Hemiketal 25 served as a primary scaffold to synthesize a set of other furanogermacranolides such as EM-2 (3) and phantomolin (4), through ketalization by the simple treatment of 25 with the corresponding alcohol in the presence of a catalytic amount of p-toluenesulfonic acid (TsOH) (Fig. 26). On the other hand, the treatment of 25 with sodium methoxide (NaOMe) in methanol enabled the chemo- and diastereoselective addition of methanol to the exo- methylene-y-butyrolactone moiety, yielding 2-Odemethyltomenphantopin C (5). In turn, after the addition of methanol to 25 under basic reaction conditions, acidification of the solution induced successive C2 ketalization to afford tomenphantopin C (6).

[0468] Example 25. Stereoselective synthetic route

[0469] Fig. 27 describes the synthetic route using MOM as alcohol protective group.

[0470] Example 26. Bromolactone synthon (Fig. 28) (L)-Tartaric acid dimethyl-(L)-tartrate

[0471] H3BO3 (8.22 g, 133 mmol) was added to a solution of L-tartaric acid 1(200 g, 1.33 mol) in MeOH (2.5 L). The mixture was stirred 36 hours and the solvent was removed to afford 234 g (Yield = 99%) of (+)-dimethyl-L-tartrate. The crude was used without any further purification.

[0472] TLC: Rf= 0.2 (40% EtOAc / Hex). [O]D +1.0° (C = 1 , CHCI3).

[0473] FTIR (neat, cm1) 3458, 1748, 1439, 1277, 1240, 1128, 1090, 908, 735, 650.

[0474] 1H NMR (396 MHz, CDCI3) δ 4.59 (s, 2H), 3.86 (s, 6H).

[0475] 13C NMR (100 MHz, CDCI3) δ 172.06, 72.21, 53.24.

[0476] HRMS calculated for C6H11O6 [M+H]+179.0556; found 179.0557. , dimethyl-(L)-tartrate p-Toluenesulfonic acid (PTSA) (1.6 g, 9 mmol) was added to a solution of (+)-dimethyl-L- tartrate (20 g, 112 mmol), 2,2-dimethoxypropane (80 mL, 672 mmol) in CH2CI2(280 mL). The mixture was refluxed for 4 h and allowed to cool to room temperature. The organic phase was washed with saturated NaHCO3 (NaHCO3sat), dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 95 / 5 to 60 / 40) to give 19.3 g (Yield = 79%) of (-)-dimethyl-2,3-O-isopropylidene-L-tartrate 9.

[0477] TLC: Rf= 0.3 (20% EtOAc / Hex).

[0478] [a]” -46° (C = 1 , CHCI3).

[0479] FTIR (neat, cm’1) 2994, 2957, 1759, 1375, 1254, 1211 , 1161 , 1113, 1014, 858, 748.

[0480] 1H NMR (396 MHz, CDCI3) δ 4.81 (s, 2H), 3.83 (s, 6H), 1.50 (s, 6H).

[0481] 13C NMR (100 MHz, CDCI3) δ. 170.21, 114.00, 77.11 , 52.94, 26.41.

[0482] HRMS calculated for C9H15O6+[M+H]+219.0869; found 219.0863.

[0483] Methyllithium (60 mL, 180 mmol, 3M in DME) was added dropwise to dimethyl tartrate isopropylidene 9 (24 g, 720 mmol) in CH2CI2(250 mL) at -78 °C. The mixture was stirred for 2 hours and quenched with saturated NH4CI (NH4Clsat). The mixture was allowed to warm to room temperature and was stirred for 5 minutes. The aqueous phase was extracted with CH2CI2, the organic phases were combined and washed with brine, dried over magnesium sulfate and solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 95 / 5 to 60 / 40) to give 16.1 g (Yield = 72%) of the methyl ketone 13. The presence of non-separable diketone was noted.

[0484] TLC: Rf= 0.3 (20% EtOAc / Hex).

[0485] [a]™ -3.5° (C = 1 , CHCI3).

[0486] FTIR (neat, cm-1) 2993, 2954, 1759, 1724, 1439, 1377, 1358, 1254, 1211 , 1157, 1107, 1022, 860, 806, 737, 579, 513.

[0487] 1H NMR (396 MHz, CDCI3) δ 4.74 (d, J = 5.6 Hz, 1 H), 4.64 (d, J = 5.5 Hz, 1 H), 3.82 (s, 3H), 2.32 (s, 3H), 1 .49 (d, J = 0.7 Hz, 3H), 1 .46 (d, J = 0.8 Hz, 3H).

[0488] NaHMDS (111 mL, 111 mmol, 1M in THF) was added dropwise to

[0489] (iodomethyl)triphenylphosphonium iodide (58.8 g, 111 mmol) in THF (500 mL) at 0 °C and stirred for 30 minutes. The mixture was allowed to cool at -78 °C and 13 (18.7 g, 92.5 mmol) was added dropwise. The mixture was stirred for 30 minutes at -78 °C and allowed to warm to 0 °C. The mixture was quenched with NH+CIsat. and diluted in Et20. The aqueous phase was extracted with Et20, the organic phases were combined and dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 60 / 40) to give 15.8 g (Yield = 52%) of the trisubstituted alkene 14. Taking account the diketone present in the starting material, the yield would be 70%.

[0490] TLC: Rf= 0.6 (5% Et2O / Hex).

[0491] [a]2DQ+69.9° (C = 1 , CHCI3).

[0492] FTIR (neat, cm’1) 3059, 2990, 2920, 2851 , 1759, 1620, 1439, 1377, 1292, 1258, 1207, 1165, 1103, 1057, 1026, 984, 887, 856, 806, 756, 694, 509.

[0493] 1H NMR (396 MHz, CDCI3) δ 6.26 (dd, J = 1.5, 0.6 Hz, 1 H), 5.08 (dd, J= 8.0, 0.6 Hz, 1H), 4.21 (d, J = 7.9 Hz, 1 H), 3.80 (s, 3H), 1.93 (d, J = 1.5 Hz, 3H), 1.53 (dd, J = 6.1, 0.7 Hz, 6H).

[0494] HRMS calculated for C10H16IO4+[M+H]+327.0094; found 327.0090.

[0495] DIBAI-H (63 mL, 63 mmol, 1M in cyclohexane) was added to a solution of 14 (15.8 g, 48.5 mmol) in CH2CI2(200 mL) at -78 °C. The mixture was stirred for 1 hour at -78 °C and quenched with EtOAc, followed by tartrate solution. The mixture was allowed to warm to room temperature and stirred for 2 hours, followed by filtration through celite. The aqueous phase was extracted with EtOAc and the organic phases were combined, washed with brine, dried over magnesium sulfate, and the solvents were removed under vacuum to give 15.7 g of aldehyde. The crude product was used without further purification.

[0496] The sample partially decomposed on silica.

[0497] TLC: Rf= 0.3 (20% EtOAc / Hex).

[0498] [a]2D° +61.2° (C = 1, CHCI3).

[0499] FTIR (neat, cm1) 441, 3055, 2985, 2920, 1735,1618, 1438, 1377, 1285, 1242, 1219, 1150, 1072, 1026, 887, 810, 783, 737, 702, 509.

[0500] 1H NMR (396 MHz, CDCI3) δ 9.80 (d, J = 2.3 Hz, 1 H), 6.23 (dd, J = 1.5, 0.7 Hz, 1 H), 5.08 (dd, J = 7.9, 0.7 Hz, 1 H), 4.08 (dd, J = 7.9, 2.3 Hz, 1 H), 1 .95 - 1 .92 (m, 3H), 1 .54 (d, J = 0.7 Hz, 3H), 1.49 (d, J = 0.7 Hz, 3H).

[0501] 13C NMR (100 MHz, CDCI3) δ 141.43, 133.40, 132.61, 132.60, 79.93, 63.54, 21.26.

[0502] HRMS calculated for CgH14lO4[M+H]+296.9988; found 296.9986.

[0503] Diazabicyclo[2.2.2]octane (DABCO, 8 g, 71.3 mmol) was added to a solution of aldehyde (14.3 g, 48.5 mmol) in methyl acrylate (208 mL, 2.42 mol) and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with CH2CI2and NH4Clsat . The aqueous phase was extracted with CH2CI2and the organic phases were combined, dried over magnesium sulfate, and the solvents were removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 90 / 10 to 70 / 30) to give 10.7 g (Yield = 58% on 2 steps) of 15, characterized by a mixture of diastereoisomers. Diastereoisomer 1

[0504] TLC: Rf= 0.3 (30% EtOAc / Hex)

[0505] HRMS calculated for C13H20IO5+[M+H]+383.0355; found 383.0355.

[0506] Diastereoisomer 2

[0507] TLC: Rf= 0.3 (30% EtOAc / Hex).

[0508] HRMS calculated for C13H20IO5+[M+H]+383.355; found 383.0356.

[0509] 15 (10.7 g, 28 mmol) was dissolved in HBr / EtOAc 1 / 1 (50 mL) and the mixture was stirred for

[0510] 16 hours at room temperature. The mixture was diluted with EtOAc and water. The organic phase was washed with H2O, brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / EtOAc 90 / 10 to 70 / 30). The yellow powder obtained was tritured in diisopropyl ether to give 5.2 g (Yield = 50%) of 16.

[0511] TLC: Rf= 0.2 (25% EtOAc / Hex)

[0512] [a]2D° +70.0° (C = 1 , CHCI3).

[0513] FTIR (neat, cm1) 3437, 3082, 2916, 2357, 1748, 1643, 1431 , 1350, 1277, 1242, 1222, 1130, 1061 , 1015, 957, 779, 676.

[0514] 1H NMR (396 MHz CDCI3) δ 7.35 (d, J = 1.5 Hz, 1H), 6.26 (dd, J = 1.6, 0.7 Hz, 1 H), 5.05 (dd, J = 6.3, 1.6 Hz, 1 H), 4.66 (d, J = 6.3 Hz, 1 H), 4.13 (d, J = 1.4 Hz, 2H), 2.53 (s, 1 H), 2.01 (d, J = 1.6 Hz, 3H).

[0515] 13C NMR (100 MHz, CDCI3) δ 170.56, 149.35, 144.08, 132.52, 83.22, 78.39, 77.21 , 20.71 ,

[0516] 20.21. TfOH (330 μL, 3.75 mmol) was added dropwise to a solution of 16 (4 g, 10.7 mmol) in dimethoxymethane (150 mL) at room temperature and stirred for 2 hours. The mixture was diluted Et20 and brine. The aqueous phase was extracted with Et2O, organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 80 / 20) to give 3.46 g (Yield = 77%) of 17.

[0517] TLC: Rf= 0.4 (25% EtOAc / Hex).

[0518] [a]2D° +92.2° (C = 1 , CHCI3).

[0519] FTIR (neat, cm’1) 3441, 3082, 2924, 2820, 1755, 1638, 1616, 1427, 1354, 1281, 1211 , 1150, 1096, 1065, 1015, 984, 922, 864, 779, 737, 679, 621.

[0520] 1H NMR (396 MHz, CDCI3) δ 7.34 - 7.30 (m, 1 H), 6.37 - 6.31 (m, 1 H), 5.11 (ddd, J = Q.O, 1.7, 0.5 Hz, 1 H), 4.67 (d, J = 6.0 Hz, 1H), 4.61 - 4.53 (m, 2H), 4.12 (s, 2H), 3.39 (d, J = 0.5 Hz, 3H), 1 .95 (dd, J = 1 .5, 0.5 Hz, 3H).

[0521] 13C NMR (100 MHz, CDCI3) δ 170.56, 149.05, 143.03, 132.68, 94.92, 82.13, 79.98, 79.79, 56.20, 20.82, 20.67.

[0522] HRMS calculated for C11H15BrlO4+[M+H]+416.9198; found 416.9196.

[0523] Example 27. Aldehyde synthon (Fig. 29)

[0524] (E) / (Z) 2.4 / 1 n-BuLi (183 mL, 275 mmol, 1.5 M in hexane) was added dropwise to trimethylphonoacetate 7 (50 g, 275 mmol) in THF (600 mL) at -20 °C. After 30 minutes, 1 ,1-dimethoxypropan-2-one 8 (40 g, 302 mmol) was added. The mixture was allowed to warm to 4 °C and stirred for 4 hours. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to 4 °C and quenched with NH4Clsat. The aqueous phase was extracted two times with diethyl ether and the organic phases were combined, dried over magnesium sulfate, and the solvents were removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 80 / 20) to give 41.5 g (Yield = 80%) of 10 as a mixture of diastereoisomers (Ratio (E) / (Z) 2.4 / 1) which (E) isomer will be separated more easily in the next step.

[0525] Analysis of a purified sample of (E) isomer TLC: Rf= 0.4 (10% EtOAc / Hex).

[0526] FTIR (neat, cm1) 2951 , 2831 , 1717, 1647, 1435, 1354, 1223, 1153, 1119, 1080, 1065, 968, 918, 868, 814, 598.

[0527] 1H NMR (396 MHz, CDCI3) δ 5.74 (q, J = 1.2 Hz, 1 H), 4.54 (t, J = 5.7 Hz, 1 H), 3.68 (s, 3H), 3.33 (s, 6H), 2.44 (dd, J = 5.7, 1.1 Hz, 2H), 2.20 (d, J = 1.3 Hz, 3H).

[0528] 13C NMR (100 MHz, CDCI3) δ 167.08, 155.11 , 117.95, 102.95, 53.19, 50.98, 44.08, 19.38.

[0529] HRMS calculated for C9H14O5+ [M+H]+189.1127; found 189.1126.

[0530] (E)I(Z) 2.4 / 1 Pure (E)

[0531] DIBAI-H (530 mL, 530 mmol, 1M in cyclohexane) was added dropwise to a solution of 10 (41.5 g, 220 mmol) in CH2CI2(800 mL) at 4 °C and stirred for 0.5 hour. The mixture was carefully quenched with EtOAc + NH^Isat., followed by tartrate solution. The mixture was allowed to warm to room temperature and stirred for 2 hours. The aqueous phase was extracted with EtOAc and the organic phases were combined, dried over magnesium sulfate, and the solvents were removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 80 / 20 to 50 / 50) to give 17.4 g (Yield = 49%) of E-11 with pure (E) configuration.

[0532] TLC: Rf= 0.3 (50% EtOAc / Hex).

[0533] FTIR (neat, cm’1) 3410, 2920, 2835, 1666, 1447, 1366, 1296, 1234, 1188, 1123, 1065, 1003, 964, 808, 567.

[0534] 1H NMR (396 MHz, CDCI3) δ 5.51 - 5.43 (m, 1 H), 4.49 (t, J = 5.8 Hz, 1 H), 4.14 (d, J = 6.8 Hz, 2H), 3.31 (s, 6H), 2.32 (d, J = 5.8 Hz, 2H), 1.72 - 1 .69 (m, 3H), 1 .66 (s, 1 H).

[0535] 13C NMR (100 MHz, CDCI3) δ 126.71, 103.42, 59.29, 52.86, 42.63, 16.86.

[0536] HRMS calculated for C8H17O3+[M+H]+161.1178; found 161.1180.

[0537] 2,6-lutidine (5 mL, 42.72 mmol) was added to E-11 (1.14 g, 7.12 mmol) at 4 °C, followed by TMSOTf (5.2 mL, 28.46 mmol) dropwise. The mixture was stirred for 30 minutes at 4 °C and 33 mL of water was added, followed by an additional stirring of 30 minutes at 4 °C. The mixture was diluted with CH2CI2and NH4Clsat.. The organic phase was washed with water, brine, dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 95 / 5 to 70 / 30) to give 695 mg (Yield = 52%) of 12.

[0538] TLC: Rf= 0.5 (5% EtOAc / Hex).

[0539] FTIR (neat, cm1) 2924, 2837, 1720, 1663, 1439, 1385, 1096, 1045, 1007, 880, 841 , 779, 605.1H NMR (396 MHz, CDCI3) <5 9.68 - 9.60 (m, 1H), 5.54 - 5.45 (m, 1 H), 4.20 (dt, J = 6.4, 0.8 Hz, 2H), 3.08 (dd, J = 2.1, 1.2 Hz, 2H), 1.71 (dt, J = 1.4, 0.7 Hz, 3H), 0.13 (d, J = 0.5 Hz, 9H).13C NMR (100 MHz, CDCI3) δ 198.51, 128.66, 127.34, 57.76, 52.67, -1.81.

[0540] HRMS calculated for C9H19O2Si+[M+H]+187.1154; found 187.1159.

[0541] Example 28. Late-stage sequence (Fig. 30)

[0542] 17 18

[0543] A solution of CrCl2 (2.65 g, 21.6 mmol) in DMF (30 mL) was added to a solution of 17 (3.00 g, 7.19 mmol) and 12 (2.6 g, 14.0 mmol) in DMF (50 mL) at 10 °C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with NH4Clsatand stirred for 30 minutes at room temperature. The aqueous phase was extracted 3 times with EtOAc and the organic phases were combined, washed with NH4CIsat, brine, dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (CH2CI2 / EtOAc 70 / 30 to 20 / 80) to give 2.76 g (Yield = 85%) of 18.

[0544] TLC: Rf= 0.3 (70% EtOAc / Hex)

[0545] [a]o° +51.3° (C = 1, CHCI3).

[0546] FTIR (neat, cm’1) 3402, 2928, 2893, 2361 , 1759, 1662, 1639, 1439, 1411 , 1277, 1238, 1153, 1099, 1061 , 1018, 922, 818, 787, 733, 679.

[0547] 1H NMR (396 MHz CDCI3) δ 6.37 (d, J = 2.0 Hz, 1 H), 6.31 - 6.26 (m, 1H), 5.76 (d, J = 1.7 Hz, 1H), 5.53 (t, J = 6.7 Hz, 1 H), 4.63 (dd, J = 4.7, 2.3 Hz, 1 H), 4.58 - 4.46 (m, 3H), 4.15 (s, 2H), 3.85 (d, J = 3.7 Hz, 1 H), 3.39 (s, 3H), 3.08 (dd, J = 5.3, 2.2 Hz, 1 H), 2.80 (s, OH), 2.31 - 2.20 (m, 1 H+OH), 2.16 (d, J = 9.8 Hz, 1 H), 1.94 (d, J = 1.4 Hz, 3H), 1.69 (s, 3H).

[0548] 13C NMR (100 MHz, CDCI3) δ 170.41 , 144.22, 135.32, 135.08, 127.99, 124.22, 94.85, 81.55, 80.52, 79.68, 70.34, 58.99, 56.41 , 46.99, 43.32, 20.97, 16.42.

[0549] HRMS calculated for C17H26lO6+[M+H]+453.0774; found 453.0775.

[0550] 18 19

[0551] MnO2(2.88 g, 33.2 mmol) was added to a solution of 18 (1 g, 2.21 mmol) in CH2CI2(30 mL) and stirred at room temperature for 4 hours. The mixture was filtered through celite, and the solvent was removed. The crude was purified by flash chromatography (Hex / EtOAc 80 / 20 to 50 / 50) to give 650 mg (Yield = 71%) of 19.

[0552] TLC: Rf= 0.3 (50% EtOAc / Hex).

[0553] [a]2D° +130° (C = 1, CHCI3).

[0554] FTIR (neat, cm1) 3441 , 2947, 2924, 1767, 1666, 1439, 1408, 1273, 123, 1068, 1018, 922, 818, 733, 698.

[0555] 1H NMR (396 MHz CDCI3) δ 9.98 (d, J = 7.8 Hz, 1 H), 6.41 (d, J = 2.0 Hz, 1 H), 6.32 - 6.24 (m, 1H), 5.97 (d, J = 7.8 Hz, 1H), 5.78 (d, J = 1.7 Hz, 1 H), 4.61 (dd, J = 4.3, 2.2 Hz, 1 H), 4.56 - 4.48 (m, 3H), 3.96 (d, J = 3.6 Hz, 1H), 3.38 (s, 3H), 3.09 (dd, J = 5.8, 2.0 Hz, 1 H), 2.57 (d, J = 4.3 Hz, 1 H), 2.48 - 2.35 (m, 2H), 2.23 (s, 3H), 1.94 (d, J = 1.3 Hz, 3H).

[0556] 13C NMR (100 MHz, CDCI3) δ 190.98, 169.88, 159.28, 144.26, 135.08, 129.75, 124.60, 94.98, 81.52, 80.45, 79.66, 70.89, 56.48, 47.82, 44.04, 21.06, 18.21.

[0557] HRMS calculated for C17H24IO6[M+H]+451.0618; found 451.0617.

[0558] A solution of 19 (700 mg, 1.55 mmol) in DMSO (5 mL) was added to a solution of CrCI2(1.15 g, 9.33 mmol) in DMSO (240 mL), followed by a first addition of Ni(acac)2(12 mg, 0.016 mmol). The mixture was stirred for 1 hour at room temperature and Ni(acac)2(12 mg, 0.016 mmol) was added. The mixture was stirred for 5 hours and was diluted with EtOAc / NH+CIsat. solutions and stirred for 1 hour at room temperature. The aqueous phase was extracted three times with EtOAc, the organic phases were combined, washed with NH4Clsat, brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was purified by flash chromatography (CH2CI2 / EtOAc 50 / 50 to 10 / 90) to give 245 mg (Yield = 49%) of 20. TLC: Rf= 0.25 (70% EtOAc / CH2CI2).

[0559] [a]o° +132° (C= 1, CHCI3).

[0560] FTIR (neat, cm’1) 3381, 2939, 2914, 2848, 2351, 1728, 1714, 1651, 1556, 1267, 1153, 1099, 1064, 1020, 995, 918, 871, 815, 797, 732, 702, 615.

[0561] 1H NMR (396 MHz CDCI3) δ 6.39 (dd, J= 2.5, 1.3 Hz, 1H), 5.92 (s, 1H), 5.81 (d, J= 7.1 Hz, 1H), 5.77-5.67 (m, 1H), 5.17 (s, 1H), 4.87 (s, 1H), 4.52 (d, J= 1.5 Hz, 2H), 3.93 (dd, J= 3.1, 1.4 Hz, 1H), 3.77 (d, J = 3.9 Hz, 1H), 3.30 (d, J= 1.6 Hz, 3H), 2.96-2.86 (m, 1H), 2.67 (dd, J= 12.5, 3.9 Hz, 1H), 2.50-2.35 (m, 1H+OH), 1.79 (d, J= 1.8 Hz, 3H), 1.63 (s, 3H).

[0562] 13C NMR (100 MHz, CDCI3) δ 170.50, 142.07, 136.12, 135.14, 129.42, 127.47, 126.27, 94.74, 82.18, 76.09, 71.07, 67.12, 56.24, 52.40, 49.31, 19.05, 18.22.

[0563] HRMS calculated for C17H25O6+[M+H]+325.1651; found 325.1644.

[0564] MnO2(964 mg, 11.1 mmol) was added to a solution of 20 (240 mg, 0.74 mmol) in CH2CI2(25 mL) and stirred at room temperature for 3 hours. The mixture was filtered through celite, and the solvent was removed. The crude was purified by flash chromatography (CH2Cl2 / EtOAc 80 / 20 to 50 / 50) to give 190 mg (Yield = 80%) of 21.

[0565] TLC: Rf= 0.3 (50% EtOAc / CH2CI2).

[0566] [a]2D° +136° (C= 1, CHCI3).

[0567] FTIR (neat, cm1) 3518, 2945, 2922, 1755, 1633, 1608, 1435, 1381, 1269, 1246, 1151, 1130, 1103, 1070, 1018, 933, 918, 815, 732, 704.

[0568] 1H NMR (396 MHz, CDCI3) δ 7.36 (dd, J= 1.7, 1.1 Hz, 1H), 7.29 (dd, J= 1.7, 1.1 Hz, 1H), 6.34 (dt, J= 1.7, 0.8 Hz, 1H), 6.23 -6.18 (m, 1H), 5.17-5.11 (m, 1H), 5.08 (ddd, J = 6.5, 1.6, 1.0 Hz, 1H), 4.81 -4.78 (m, 2H), 4.63 (dd, J = 6.2, 0.8 Hz, 1H), 4.48 (s, 1H), 4.13-4.09 (m, 5H), 3.93 - 3.84 (m, 1 H), 3.68 - 3.60 (m, 1 H), 3.59 - 3.48 (m, 2H), 2.04 - 2.02 (m, 3H), 1.90 (t, J = 1.2 Hz, 3H), 1.84- 1.72 (m, 3H), 1.72-1.63 (m, 3H), 1.62-1.60 (m, 1H), 1.58-1.44 (m, 7H).

[0569] 13C NMR (100 MHz, CDCI3) δ 170.84, 170.77, 149.58, 149.04, 143.18, 132.36, 99.54, 95.37, 83.02, 82.10, 80.84, 80.33, 78.23, 77.78, 62.64, 61.99, 30.30, 30.16, 25.32, 20.89, 20.79, 20.69, 19.23, 18.67. HRMS calculated for C17H22O6Na+[M+Na]+345.1314; found 345.1310.

[0570] Methacrylic anhydride (103 μL, 0.689 mmol) was added to a solution of 21 (185 mg, 0.574 mmol), Et3N (242 μL, 1.72 mmol), DMAP (14 mg, 0.115 mmol) in THF (5 mL). The mixture was stirred for 3 hours at room temperature and the solvent was removed. The crude was diluted with EtOAc and NH4Clsat. The organic phase was dried over magnesium sulfate and solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 70 / 30 to 50 / 50) to give 170 mg (Yield = 76%) of 22.

[0571] TLC: Rf= 0.3 (50% EtOAc / Hex).

[0572] [a]2D° +163° (C = 1, CHCb).

[0573] FTIR (neat, cm’1) 2954, 2852, 1769, 1717, 1643, 1611, 1439, 1317, 1269, 1155, 1111 , 1076, 1020, 918, 814, 734, 702.

[0574] 1H NMR (396 MHz, CDCI3) δ 6.35 (d, J = 2.4 Hz, 1 H), 6.25 (s, 1 H), 6.16 (q, J = 1.1 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1 H), 5.81 - 5.76 (m, 1 H), 5.70 - 5.64 (m, 1H), 5.41 (s, 1 H), 5.23 (td, J = 10.8, 3.9 Hz, 1 H), 4.59 - 4.48 (m, 2H), 4.25 (d, J = 3.2 Hz, 1 H), 3.32 (d, J = 0.8 Hz, 4H), 2.76 (d, J = 3.9 Hz, 1 H), 2.54 (t, J = 11.5 Hz, 1 H), 2.03 - 2.00 (m, 3H), 1.99 - 1.95 (m, 3H), 1.79 (s, 3H).

[0575] 13C NMR (100 MHz, CDCI3) 3 195.38, 169.34, 165.64, 158.03, 136.85, 133.78, 133.47, 130.91 , 126.90, 126.53, 95.26, 81.09, 76.91 , 72.28, 50.10, 45.42, 20.67, 19.10, 18.38.

[0576] HRMS calculated for C21H27CV [M+H]+391.1757; found 391.1759.

[0577] 22 (157 mg, 0.402 mmol) was dissolved in a solution of CH2CI2 / TFA (1 / 1, 5 mL) and the mixture was stirred for 3 hours at room temperature. The mixture was quenched with NaHCO3satand the aqueous phase was extracted 2 times with CH2CI2The organic phases were collected, dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 80 / 20 to 40 / 60) to obtain 101 mg of (+)-molephantin 1 (Yield = 73%).

[0578] TLC: Rf= 0.2 (50% EtOAc / Hex).

[0579] [a]2D° +158.0° (C = 1, CHCI3).

[0580] FTIR (neat, cm’1) 2955, 2924, 2851, 1759, 1730, 1697, 1639, 1462, 1377, 1263, 1161, 1082, 1047, 743, 706.

[0581] 1H NMR (396 MHz, CDCI3) δ 6.36 (d, J= 2.5 Hz, 1H, H13a), 6.23 (s, 1H, H1), 6.15 (t, J= 1.2 Hz, 1H, H19a), 6.01 (t, J= 1.4 Hz, 1H, H3), 5.82 (dd, J= 2.3, 0.7 Hz, 1H, H13b), 5.68 (t, J = 1.5 Hz, 1H, H19b), 5.47 (d, J= 6.2 Hz, 1H, H5), 5.30-5.18 (m, 1H, H8), 4.25 (d, J= 3.7 Hz, 1H, H6), 3.40 (dd, J= 10.8, 3.7 Hz, 1H, H7), 2.77 (dd, J= 12.1, 4.1 Hz, 2H, H9a+OH), 2.52 (dd, J = 12.2, 10.9 Hz, 1H, H9b), 2.02 (d, J= 1.4 Hz, 3H, H14), 1.96 (d, J= 0.6 Hz, 3H, H18), 1.80 (d, J= 1.0 Hz, 3H, H15).

[0582] 13C NMR (100 MHz, CDCI3) δ 195.26 (C-2), 169.49 (C-12), 165.74 (C-16), 159.15 (C-4), 137.03 (C-10), 135.82 (C-17), 133.50 (C-1), 133.20 (C-11), 129.34 (C-3), 128.25 (C-13), 126.72 (C19), 81.39 (C-6), 73.81 (C-5), 72.50 (C-8), 49.62 (C-7), 45.48 (C-9), 20.22 (C-15), 19.00 (C-14), 18.42 (C-18).

[0583] Table 16.2D NMR correlations for 1.

[0584] 1H-1H COSY correlations: (H9a,b / H8), (H19 / H20), (H8 / H7), (H18 / H19a,b), (H7 / H6), (H3 / H14), (H1 / H15). HMBC correlations: (C12 / H13a,b), (C16 / H18 / H19a,b), (C4 / H14), (C10 / H1 / H15), (C3 / H14), (C2 / H1), (C5 / H3 / H14), (C6 / H8), (C15 / H1 / H9), (C9 / H1 / H15), (C7 / H13a,b), (C17 / H18 / H19a) NOESY correlations : (H5 / H1), (H6 / H15), (H5 / H7), (H6-H8).

[0585] HRMS calculated for C19H23O6+[M+H]+347.1495; found 347.1490.

[0586] Analysis of molephantinin 100

[0587] TLC: Rf= 0.2 (50% EtOAc / Hex).

[0588] [a]” +184.5° (C = 1 , CHCI3).

[0589] FTIR (neat, cnr1) 3427, 3053, 2986, 2940, 1759, 1692, 1639, 1601 , 1441 , 1265, 1238, 1138, 1084, 1047, 1022, 947, 914, 806, 737, 704.

[0590] 1H NMR (396 MHz, CDCI3) δ 6.98 - 6.86 (m, 1 H, H-19), 6.34 (s, 1 H, H-13a), 6.22 (s, 1 H, H- 1), 6.01 (s, 1 H, H-3), 5.81 (s, 1 H, H-13b), 5.48 (s, 1H, H-5), 5.25 (dt, J = 10.8, 5.4 Hz, 1 H, H- 8), 4.25 (d, J = 3.6 Hz, 1 H, H-6), 3.44 - 3.32 (m, 1 H, H-7), 2.75 (dd, J = 12.1 , 3.7 Hz, 2H, H- 9a+OH), 2.49 (t, J = 11.5 Hz, 1 H, H-9b), 2.02 (s, 3H, H-14), 1.90 - 1.82 (m, 6H, H-20+H-18), 1.79 (s, 3H, H-15).

[0591] 13C NMR (100 MHz, CDCI3) δ 195.28 (C-2), 169.51 (C-12), 166.28 (C16), 159.16 (C-4), 138.90 (C-19), 137.14 (C-10), 133.35 (C-1), 133.20 (C-11), 129.28 (C-3), 128.16 (C-13), 128.08 (C- 17), 81.39 (C-6), 73.77 (C-5), 72.19 (C-8), 49.58 (C-7), 45.55 (C-9), 20.20 (C-14), 18.95 (C- 15), 14.65 (C-18), 12.15 (C-20).

[0592] Table 17. 2D NMR correlations for 100. 1H-1H COSY correlations: (H13a,b / 7), (H19 / H20), (H8 / H7), (H8 / H9a,b), (H7 / H6), (H3 / H14), (H1 / H15).

[0593] HMBC correlations: (C12 / H13a,b / H6), (C16 / H8), (C4 / H6), (C10 / H1 / H9a,b), (C3 / H14), (C20 / H19), (C2 / H1 / H15), (C5 / H3 / H14), (C6 / H8), (C8 / H6 / H13a,b), (C15 / H1 / H9), (C14H3), (C9 / H1 / H15), (C7 / H6 / H9a,b / H13a,b).

[0594] NOESY correlations : (H5 / H1), (H6 / H15), (H9 / H15).

[0595] HRMS calculated for C20H2506+[M+H]+361.1652; found 361.1649.

[0596] Example 29. Phantomolin-type family

[0597] Molephantin 1 (10 mg, 0.029 mmol) was dissolved in CH2CI2(0.5 mL) and irradiated with 370 nM light (40 Watt, 4 cm) for 1 hour 45 minutes. The solvent was removed under vacuum and the crude obtained of 25 (10 mg, Yield = 100 %) was used for the next step without further purification.

[0598] Analysis of a purified sample

[0599] TLC: Rf= 0.4 (50% EtOAc / Hex).

[0600] [a]2D° +42.2° (C = 1, CHCI3).

[0601] 1H NMR (400 MHz, C6D6) 6 6.27 (d, J = 2.9 Hz, 1 H, H13a), 5.89 (s, 1 H, H19a), 5.54 (d, J = 2.2 Hz, 1 H, H13b), 5.43 (s, 1 H, H1), 5.21 - 5.14 (m, 2H, H3+H19b), 5.09 (dd, J = 11.1, 2.3 Hz, 1 H, H8), 4.91 (d, J = 3.6 Hz, 1 H, H5), 4.00 (dd, J = 6.1, 3.9 Hz, 1H, H6), 3.60 (d, J = 14.0 Hz, 1 H, H9a), 2.98 (d, J = 5.0 Hz, 1 H, H7), 2.53 (s, 1 H, OH), 2.12 (dd, J = 14.3, 4.4 Hz, 1 H H9b), 1.77 (s, 3H, H18), 1.62 (d, J = 1.1 Hz, 3H, H15), 1.36 (s, 3H, H14).

[0602] 13C NMR (101 MHz, C6D6) δ 168.16 (C-12), 165.25 (C-16), 137.34 (C-4), 136.38 (C-17), 136.01 (C-11), 132.06 (C-10), 131.02 (C-3), 128.28 (C-1), 125.68 (C-13), 125.64 (C-19), 110.33 (C-2), 85.10 (C-5), 78.71 (C-6), 76.94 (C-8), 38.88 (C-7), 32.32 (C-9), 28.38 (C-15), 18.18 (C-18), 12.74 (C-14).

[0603] Table 18. 2D NMR correlations for 25.

[0604] 1H-1H COSY correlations: (H13a,b / 7), (H19a / H18), (H8, H7), (H8, H9b), (H5 / H6).

[0605] HMBC correlations: (C12 / H13a,b), (C16 / H19a,b / H18), (C4 / H5 / H6 / H14), (C10 / H8 / H9a,b / H15), (C3 / H5 / H14), (C1 / H15), (C2 / H1), (C5 / H7 / H14), (C6 / H14), (C8 / H13).

[0606] NOESY correlations : (H5 / H6), (H5 / H14), (H6 / H8), (H6 / H9a), (H1 / H15).

[0607] HRMS calculated for C19H23O6+[M+H]+347.1495; found 347.1490.

[0608] Molephantinin 100 (10 mg, 0.029 mmol) was dissolved in CH2CI2(0.5 mL) and irradiated with 370 nM light (40 Watt, 4 cm) for 1 hour 45 minutes. The solvent was removed under vacuum and the crude obtained of 101 (10 mg, Yield = 100 %) was used for the next step without further purification.

[0609] 1H NMR (396 MHz, C6D6) δ 6.73 (dq, J = 7.1 , 1.5 Hz, 1 H, H19), 6.29 (dd, J = 3.2, 1.1 Hz, 1 H, H13a), 5.57 (dd, J = 2.8, 1.1 Hz, 1H, H13b), 5.43 (t, J = 1.3 Hz, 1 H, H1), 5.18 - 5.10 (m, 2H, H3+H8), 4.92 - 4.88 (m, 1 H, H5), 3.97 (dd, J = 6.2, 3.9 Hz, 1 H, H6), 3.60 (ddd, J = 14.2, 2.2, 1.2 Hz, 1 H, H9a), 3.04 - 2.97 (m, 1 H, H7), 2.27 (s, 1 H, OH), 2.16 (dd, J = 14.2, 4.5 Hz, 1 H, H9b), 1.73 (t, J= 1.3 Hz, 3H, H18), 1.65 (d, J= 1.4 Hz, 3H, H15), 1.36 (dd, J= 1.6, 0.9 Hz, 3H, H14), 1.33 (dd, J = 7.1 , 1.2 Hz, 3H, H20).

[0610] 13C NMR (100 MHz, C6D6) δ 168.41 (C-12), 165.94 (C-16), 137.94 (C-19), 1133..66 (C-4), 136.47 (C-11), 132.63 (C-10), 131.26 (C-3), 128.95 (C-17), 128.37 (C-1), 125.77 (C-13), 110.57 (C-2), 85.40 (C-5), 78.95 (C-6), 76.89 (C-8), 39.25 (C-7), 32.64 (C-9), 28.72 (C-15), 14.19 (C-15), 12.99 (C-14), 12.17 (C-18).

[0611] Table 19. 2D NMR correlations for 101.

[0612] 1H-1H COSY correlations: (H13a,b / H7), (H19 / H18), (H19 / H20), (H8, H7), (H8, H9b), (H5 / H6), (H6 / H7), (H3 / H14), (H1 / H15).

[0613] HMBC correlations: (C12 / H6), (C16 / H19 / H18 / H8), (C4 / H5 / H6 / H3), (C10 / H8 / H9a,b / H15), (C3 / H5 / H14), (C1 / H15 / H9a,b). (C2 / H1 / H3), (C5 / H6 / H14), (C8 / H6 / H9b), (C7 / H13a,b / H5), (C9 / H1 / H15), (C15 / H9a,b), (C17 / H18 / H20).

[0614] NOESY correlations: (H5 / H6), (H1 / H8), (H6 / H9a).

[0615] HRMS calculated for C20H25O6+[M+H]+361.1651 ; found 361.1651.

[0616] PTSA (50 mg, 0.29 mmol) was added to 25 (200 mg, 0.5 mmol) in EtOH (5 mL) and the mixture was stirred for one hour at room temperature. The solvent was removed under vacuum and the crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 80 / 0) to give 143 mg (Yield = 66%) of phantomolin 4. TLC: Rf= 0.4 (30% EtOAc / Hex).

[0617] [a]o° +55.2° (C = 1, CHCI3).

[0618] FTIR (neat, cm’1) 3055, 2974, 2924, 2882, 1771, 1717, 1659, 1636, 1443, 1404,1385, 1292, 1273, 1219, 1153, 1092, 1045, 1007, 953, 903, 845, 818, 737, 683, 663.

[0619] 1H NMR (396 MHz, CDCI3) δ 6.31 (dd, J= 3.2, 0.9 Hz, 1H), 6.16 (t, J= 1.2 Hz, 1H), 5.79 (dd, J = 2.9, 0.9 Hz, 1H), 5.73 - 5.68 (m, 1H), 5.65 (d, J = 1.5 Hz, 1H), 5.50 (t, J = 1.3 Hz, 1H), 5.28-5.18 (m, 2H), 4.64 (dd, J = 6.2, 3.8 Hz, 1H), 3.78-3.69 (m, 1H), 3.55-3.38 (m, 2H), 3.21-3.09 (m, 1H), 2.21 (dd, J = 14.3, 4.3 Hz, 1H), 1.98 (q, J = 1.2 Hz, 3H), 1.78 (d, J = 1.2 Hz, 3H), 1.72 (q, J = 1.2 Hz, 3H), 1.19 (td, J= 7.1, 0.9 Hz, 3H).

[0620] 13C NMR (100 MHz, CDCI3) δ 169.09, 165.83, 138.74, 136.29, 135.19, 129.68, 127.73, 127.23, 126.59, 113.98, 85.77, 79.50, 76.78, 57.93, 39.13, 32.84, 28.77, 18.59, 15.58, 13.34.

[0621] HRMS calculated for C21H27O6+[M+H]+375.1808; found 375.1794.

[0622] PTSA (25 mg, 0.15 mmol) was added to 25 (100 mg, 0.25 mmol) in MeOH (3 mL) and the mixture was stirred for one hour at room temperature. The solvent was removed under vacuum and the crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 80 / 0) to give 68 mg (Yield = 64%) of 2-deethoxy-2|3-methoxyphantomolin 3.

[0623] TLC: Rf= 0.4 (30% EtOAc / Hex).

[0624] [a]” +48.6° (C = 1, CHCI3).

[0625] FTIR (neat, cm’1) 2974, 2928, 2886, 1767, 1713, 1659, 1636, 1443, 1404, 1381, 1273, 1153, 1092, 1045, 1011, 964,841, 818, 737, 683, 664, 610.

[0626] 1H NMR (396 MHz, CDCI3) δ 6.35-6.30 (m, 1H), 6.20-6.12 (m, 1H), 5.84-5.77 (m, 1H), 5.71 (s, 1H), 5.63 (s, 1H), 5.49 (s, 1H), 5.28 - 5.21 (m, 2H), 4.66 (dd, J = 6.1, 3.9 Hz, 1H), 3.78-3.69 (m, 1H), 3.22 (s, 3H), 3.15 (dq, J = 8.4, 3.0 Hz, 1H), 2.23 (dd, J= 14.4, 4.3 Hz, 1H), 1.99 (s, 3H), 1.78 (d, J= 1.3 Hz, 3H), 1.77-1.73 (m, 3H).

[0627] 13C NMR (100 MHz, CDCI3) δ 169.04, 165.80, 136.26, 135.13, 133.89, 129.14, 127.27, 127.24, 126.59, 114.17, 85.87, 79.43, 77.48, 77.16, 76.84, 76.73, 49.71, 39.08, 32.80, 28.74, 18.58, 13.33.

[0628] HRMS calculated for C20H25O6+[M+H]+361.1651; found 361.1651.

[0629] MeONa (19 mg, 0.35 mmol) was added to 25 (100 mg, 0.29 mmol) in MeOH (3 mL) and the mixture was stirred for one hour at room temperature. The solvent was diluted in CH2Cl2and NH4Clsat- The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 80 / 0) then by GPC to give 54 mg (Yield = 51 %) of 5.

[0630] TLC: Rf= 0.4 (50% EtOAc / Hex).

[0631] 1H NMR (396 MHz, CDCI3) δ 6.95 - 6.81 (m, 1H), 5.74 - 5.67 (m, 1 H), 5.55 (s, 1 H), 5.32 - 5.19 (m, 2H), 4.58 (dd, J = 7.6, 4.3 Hz, 1H), 3.86 - 3.67 (m, 2H), 3.45 - 3.37 (m, 1 H), 3.30 (s, 3H), 3.01 (s, 1 H), 2.84 - 2.72 (m, 1 H), 2.56 (d, J = 8.9 Hz, 1 H), 2.13 (dd, J = 14.3, 4.3 Hz, 1H), 1.87 - 1.81 (m, 6H), 1.79 - 1.77 (m, 3H), 1.75 (d, J = 1.3 Hz, 3H).

[0632] 13C NMR (100 MHz, CDCI3) δ 175.59, 166.80, 139.18, 138.74, 133.10, 130.16, 128.35, 126.88, 110.73, 85.36, 79.53, 79.16, 70.52, 59.34, 47.02, 37.30, 32.92, 28.66, 14.69, 13.29, 12.21.

[0633] MeONa (0.8 mg, 0.015 mmol) was added to 24 (55 mg, 0.15 mmol) in MeOH (3 mL) and the mixture was stirred for 16 hours at room temperature. The solvent was diluted in CH2CI2and NH4Clsat. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 80 / 0) to give 43 mg (Yield = 72%) of 26.

[0634] Example 30. Racemic synthetic route (Fig. 31) MeM Br Cui

[0635] Propargyl

[0636] 50 alcohol

[0637] Methylmagnesium bromide (240 mL, 720 mmol) was added dropwise at -10 °C to propargyl alcohol (20.12 g, 360 mmol), copper iodide (68 g, 360 mmol) and diethyl ether (1.2 L). The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was cooled to -5 °C, and iodine (91 g, 360 mmol) in THF (400 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was quenched with NH4Clsatat 4 °C, and filtration through celite was performed. The aqueous phase was extracted with diethyl ether, organic phases were combined and washed with water, brine, dried over magnesium sulfate and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 95 / 5 to 60 / 40) to give 44.8 g (Yield = 63%) of the trisubstituted alkene 50.

[0638] 1H NMR (396 MHz, CDCI3) δ 5.98 (d, J = 1.4 Hz, 1 H), 4.24 (s, 2H), 1.98 (d, J = 1.5 Hz, 3H), 1.97 - 1.92 (m, 1 H).

[0639] 13C NMR (100 MHz, CDCI3) δ 146.20, 74.99, 68.24, 21.77.

[0640] MnO2 (225 g, 2.59 mol) was added by portion to 50 (51 .2 g, 259 mmol) in CH2CI2(1 .2 L) and stirred at room temperature until complete disappearance of the starting material (TLC monitoring, around 36 hours). The mixture was filtered through celite and allowed to cool at 4 °C. Phospho (86.5 g, 259 mmol) in CH2CI2(500 mL) was added dropwise and the mixture was stirred for 30 minutes at 4 °C. The mixture was filtered on a pad of silica and the solvent was removed under vacuum to give 60.09 g (yield crude = 92%) of 51. The crude was used without further purification.

[0641] 1H NMR (396 MHz, CDCI3) δ 7.64 (dt, J = 15.7, 0.7 Hz, 1 H), 6.64 (d, J= 0.7 Hz, 1H), 6.05 (dq,

[0642] J = 15.7, 0.6 Hz, 1 H), 3.80 (s, 3H), 2.00 (d, J = 1.3 Hz, 3H).

[0643] 13C NMR (100 MHz, CDCI3) δ 167.35, 145.14, 140.99, 122.36, 88.41 , 51.98, 21.10.

[0644] DIBAI-H (454 mL, 454 mmol, 1M in THF) was added to a solution of 51 (52 g, 206 mmol) in CH2CI2(500 mL) at -78 °C. The mixture was allowed to warm to 4 °C and stirred for 15 min. The mixture was cooled to -10 °C and quenched with tartrate solution. The mixture was allowed to warm to room temperature, followed by dilution with EtOAc and tartrate solution. The aqueous phase was extracted with EtOAc and the organic phases were combined, washed with brine, dried over magnesium sulfate and the solvents were removed under vacuum to give 47 g (yield crude 88%) of 52. The crude product was used without further purification.

[0645] 1H NMR (396 MHz, CDCI3) δ 6.64 (dd, J= 15.7, 1.7 Hz, 1 H), 6.16 (s, 1H), 6.08 - 5.99 (m, 1H), 4.32 - 4.25 (m, 2H), 1.98 (d, J = 1.4 Hz, 3H), 1.54 (s, 1 H).

[0646] 13C NMR (100 MHz, CDCI3) δ 141.43, 133.40, 132.61, 132.60, 79.93, 63.54, 21.26.

[0647] 52 53

[0648] A solution of TBSCI (31 .5 g, 209 mmol) in CH2CI2(300 mL) was added dropwise to a solution of 52 (47 g, 209 mmol), imidazole (21.4 g, 315 mmol) in CH2CI2(500 mL) at 4 °C, allowed to warm at room temperature and stirred for 1 hour. The mixture was diluted with HCI 0.1 M and the organic phase was washed with HCI 0.1 M, brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was dissolved in a minimum of CH2CI2and filtered on a pad of silica. The solvent was removed to give 51.3 g (yield crude 72%) of 53. The crude was used without further purification.

[0649] 1H NMR (396 MHz, CDCI3) δ 6.74 - 6.61 (m, 1 H), 6.09 (tq, J = 1.4, 0.7 Hz, 1H), 6.00 - 5.92 (m, 1 H), 4.32 - 4.29 (m, 2H), 1.96 (d, J = 1.2 Hz, 3H), 0.95 (s, 10H), 0.11 (s, 6H).

[0650] 13C NMR (100 MHz, CDCI3) δ 141.61, 134.07, 131.02, 78.87, 63.52, 26.13, 25.80, 21.22, -

[0651] 5.04.

[0652] 53 54

[0653] 53 (24 g, 70.94 mmol) was added dropwise to a solution of K2OsO2(OH)4(1 g, 2.71 mmol), NMO.H2O (9.14 g, 78.03 mmol, 50%wtin water) in tBuOH / H2O 1 / 1 (500 mL). The mixture was stirred for 24 hours at room temperature. The mixture was quenched with sodium sulfite, stirred for 20 minutes, filtered through celite and extracted three times with CH2CI2. The organic phases were combined, dried over magnesium sulfate and the solvents were removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 95 / 5 to 70 / 30) to give 18.1 g (Yield = 68%) of 54.

[0654] 1H NMR (396 MHz, CDCI3) δ 6.03 (dt, J = 2.1 , 1.0 Hz, 1 H), 4.55 (ddt, J= 3.1, 2.1, 1.2 Hz, 1H), 3.73 (dt, J = 3.2, 1 .0 Hz, 3H), 2.93 (dd, J = 4.0, 1 .3 Hz, 1 H), 2.79 - 2.73 (m, 1 H), 1 .94 (d, J = 1.5 Hz, 3H), 0.92 (s, 10H), 0.11 (dd, J = 2.2, 1.2 Hz, 6H).

[0655] 13C NMR (100 MHz, CDCI3) δ 147.12, 76.31, 75.58, 73.28, 65.28, 26.05, 20.56, 18.41 , -5.21.

[0656] 54 55

[0657] Acetone (100 mL) was added to 54 (2.15 g, 5.77 mmol, PTSA (1.99 g, 1.55 mmol), CuSO4(1.84 g, 11.55 mmol), and the mixture was stirred for 16 hours at room temperature. NaHCO3(2.13g, 12.69 mmol) was added and the mixture was stirred for 30 minutes. The solvent was removed under pressure and crude was dissolved in CH2CI2, filtered through celite and the solvent was removed under pressure. The crude was purified by flash chromatography (Hex / EtOAc 95 / 5 to 70 / 30) to give 1.08 g (Yield = 63%) of 55.

[0658] 1H NMR (396 MHz, CDCI3) δ 6.15 (dt, J = 1.5, 0.7 Hz, 1 H), 4.82 (dd, J = 8.5, 0.7 Hz, 1 H), 3.90 - 3.81 (m, 2H), 3.76 - 3.65 (m, 1 H), 2.11 (t, J = 6.3 Hz, 1 H), 1.90 (d, J = 1.5 Hz, 3H), 1.46 (s, 6H).

[0659] 13C NMR (100 MHz, CDCI3) δ 142.82, 110.08, 80.85, 79.72, 77.50, 61.88, 27.28, 27.23, 19.70.

[0660] Oxalyl chloride (1.97 mL, 22.98 mmol) was added dropwise to a solution of DMSO (2.5 mL, 35.36 mmol) in CH2CI2(80 mL) at -78 °C. After stirring for 15 minutes, 55 (5.27 g, 17.68 mmol) was added dropwise and the mixture was stirred for 15 minutes, followed by a dropwise addition of Et3N (12.4 mL, 88.4 mmol). The mixture was allowed to warm to room temperature and stirred for 30 minutes. A solution of Hexane / Et2O 1 / 1 was added and the mixture was filtered through a pad of silica. The solvent was removed and gave 5.25 g (yield crude >100%) of 56. The crude was used without further purification.

[0661] DABCO (2.18 g, 19.45 mmol) was added to a solution of 56 (5.23 g, 17.67 mmol) in methyl acrylate (60 mL) and mixture stirred for 16 hours at room temperature. The mixture was diluted with CH2CI2and NH4CIsat. The aqueous phase was extracted with CH2CI2and the organic phases were combined, dried over magnesium sulfate, and the solvents were removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 90 / 10 to 70 / 30) to give 3.86 g (Yield = 57% on 2 steps) of 57 characterized by a mixture of diastereoisomers.

[0662] 57 (4.1 g, 0.060 mmol) was dissolved in HBr / EtOAc 1 / 1 (30 mL) and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with EtOAc and water. The organic phase was washed with H2O, brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 90 / 10 to 70 / 30) to give 2.03 g (Yield = 51%) of 58.1H NMR (396 MHz CDCI3) δ 7.35 (d, J = 1.5 Hz, 1H), 6.26 (dd, J = 1.6, 0.7 Hz, 1 H), 5.05 (dd, J= 6.3, 1.6 Hz, 1 H), 4.66 (d, J = 6.3 Hz, 1 H), 4.13 (d, J = 1.4 Hz, 2H), 2.53 (s, 1 H), 2.01 (d, J = 1.6 Hz, 3H).

[0663] 13C NMR (100 MHz, CDCI3) δ 170.56, 149.35, 144.08, 132.52, 83.22, 78.39, 77.21 , 20.71 , 20.21.

[0664] Pyridinium p-toluenesulfonate (PPTS, 67 mg, 0.268 mmol) was added to a solution of 58 (1 g, 2.68 mmol), 3,4-Dehydro-2 / 7-pyran (367 μL, 4.02 mmol) in CH2CI2(10 mL) at 4 °C and stirred for 2 hours 30 minutes. The mixture was diluted with brine and the aqueous phase was extracted with CH2CI2. The organic phases were combined, dried over magnesium sulfate, the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 100 / 0 to 70 / 30) to give 1.11 g (Yield = 90%) of 59 as a mixture of diastereoisomers.

[0665] 1H NMR (396 MHz, CDCI3) δ 7.36 (dd, J = 1.7, 1.1 Hz, 1 H), 7.29 (dd, J = 1.7, 1.1 Hz, 1H), 6.34 (dt, J = 1.7, 0.8 Hz, 1 H), 6.23 - 6.18 (m, 1 H), 5.17 - 5.11 (m, 1 H), 5.08 (ddd, J = 6.5, 1.6, 1.0 Hz, 1H), 4.81 - 4.78 (m, 2H), 4.63 (dd, J = 6.2, 0.8 Hz, 1 H), 4.48 (s, 1 H), 4.13 - 4.09 (m, 5H), 3.93 - 3.84 (m, 1 H), 3.68 - 3.60 (m, 1 H), 3.59 - 3.48 (m, 2H), 2.04 - 2.02 (m, 3H), 1 .90 (t, J = 1.2 Hz, 3H), 1.84 - 1.72 (m, 3H), 1.72 - 1.63 (m, 3H), 1.62 - 1.60 (m, 1H), 1.58 - 1.44 (m, 7H).

[0666] 13C NMR (100 MHz, CDCI3) δ 170.84, 170.77, 149.58, 149.04, 143.18, 132.36, 99.54, 95.37, 83.02, 82.10, 80.84, 80.33, 78.23, 77.78, 62.64, 61.99, 30.30, 30.16, 25.32, 20.89, 20.79, 20.69, 19.23, 18.67.

[0667] A solution of 59 (449 mg, 0.982 mmol) and 12 (311 mg, 1.67 mmol) in DMF (5 mL) was added to a solution of CrCI2(338 mg, 2.75 mmol) in DMF (5 mL) at 4 °C, allowed to warm to room temperature and stirred for 1 hour. The mixture was diluted with EtOAc and serinate solution, and the mixture was stirred for 30 min at room temperature. The aqueous phase was extracted 2 times with EtOAc and the organic phases were combined, washed with water, brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was purified by flash chromatography (Hex / EtOAc 70 / 30 to 20 / 80) to give 299 mg (Yield = 62%) of 60 as a mixture of diastereoisomers.

[0668] 1H NMR (396 MHz, CDCI3) δ6.34 (d, J = 2.0 Hz, 2H), 6.26 (d, J= 1.6 Hz, 1H), 6.14 (d, J= 1.8 Hz, 1H), 5.73 (t, J = 1.6 Hz, 2H), 5.56-5.47 (m, 2H), 4.73 (d, J = 1.4 Hz, 1H), 4.67-4.59 (m, 3H), 4.47 (d, J= 5.7 Hz, 1H), 4.40 (s, 1H), 4.20-4.12 (m, 4H), 3.84 (d, J= 8.5 Hz, 3H), 3.67 (d, J = 3.3 Hz, 1H), 3.59 - 3.44 (m, 2H), 3.19 (d, J = 3.5 Hz, 1H), 3.02 (dd, J = 5.3, 2.3 Hz, 1H), 2.53 (d, J= 3.9 Hz, 2H), 2.31-2.17 (m, 3H), 2.17-2.09 (m, 2H), 2.01 (t, J= 1.1 Hz, 3H), 1.90 (d, J= 1.4 Hz, 3H), 1.79-1.62 (m, 11 H), 1.51 (s, 8H).

[0669] 13C NMR (100 MHz, CDCI3) δ 170.52, 145.41, 144.61, 135.68, 128.12, 128.04, 124.17, 123.58, 100.67, 96.00, 82.88, 81.14, 80.65, 80.33, 79.44, 70.40, 70.35, 63.06, 62.86, 59.08, 59.06, 47.21, 46.72, 43.39, 43.21, 30.53, 30.38, 25.42, 25.32, 21.10, 19.48, 19.21, 16.47, 16.41, 14.30.

[0670] MnO2(702 mg, 8.08 mmol) was added to a solution of 60 (398 mg, 0.808 mmol) in CH2CI2(15 mL) and stirred at room temperature for 16 hours. The mixture was filtered through celite, and the solvent was removed. The crude was purified by flash chromatography (Hex / EtOAc 90 / 10 to 50 / 50) to give 321 mg (Yield = 81%) of 61 as a mixture of diastereoisomers.

[0671] 1H NMR (396 MHz, CDCI3) δ 10.00 (dd, J = 7.8, 3.0 Hz, 2H), 6.40 (dd, J = 3.4, 2.2 Hz, 2H), 6.29-6.25 (m, 1H), 6.15 (d, J = 1.6 Hz, 1H), 5.97 (s, 2H), 5.75 (dd, J= 3.8, 1.9 Hz, 2H), 4.72 (s, 1H), 4.67 (d, J= 3.5 Hz, 1H), 4.60 (dt, J= 5.2, 2.7 Hz, 2H), 4.50 (d, J= 5.4 Hz, 1H), 4.39 (s, 1H), 4.00-3.83 (m, 3H), 3.70 (s, 1H), 3.57-3.46 (m, 2H), 3.27 (dd, J = 6.1, 2.5 Hz, 1H), 3.06 (dd, J= 5.9, 2.1 Hz, 1H), 2.45 (s, 5H), 2.22 (dd, J= 7.9, 1.4 Hz, 8H), 2.04 (s, 5H), 2.02 (d, J= 1.5 Hz, 3H), 1.91 (d, J= 1.5 Hz, 3H), 1.80-1.73 (m, 2H), 1.70 (d, J=2.9 Hz, 1H), 1.69 -1.62 (m, 2H), 1.51 (d, J= 10.5 Hz, 9H).

[0672] A solution of 61 (110 mg, 0.224 mmol) in DMSO (2 mL) was added to a solution of CrCI2(149 mg, 1.212 mmol), NiCI2(2.9 mg, 0.0224 mmol) in DMSO (38 mL) and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with EtOAc and serinate solution and stirred for 30 min at room temperature. The aqueous phase was extracted two times with EtOAc, the organic phases were combined, washed with NH4Clsat, water, brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude was purified by flash chromatography (CH2CI2 / EtOAc 80 / 20 to 30 / 70) to give 23 mg (Yield = 28%) of 62 as a mixture of diastereoisomers.

[0673] 1H NMR (396 MHz, CDCI3) δ 6.40 (dd, J= 2.4, 1.2 Hz, 1 H), 5.89 (dq, J= 2.7, 1.2 Hz, 1H), 5.81 (d, J = 6.9 Hz, 1 H), 5.76 - 5.59 (m, 1 H), 5.20 (s, 1 H), 4.84 (t, J = 6.9 Hz, 1H), 4.50 (s, 1 H), 3.88 (dd, J = 37.5, 2.9 Hz, 1 H), 3.80 - 3.61 (m, 2H), 3.53 (d, J = 11 .2 Hz, 1 H), 3.00 - 2.86 (m, 1H), 2.72 - 2.61 (m, 1 H), 2.46 - 2.30 (m, 2H), 1.88 (d, J = 1.5 Hz, 3H), 1.75 (d, J = 1.5 Hz, 3H), 1.62 (s, 11 H).

[0674] MnCh (79 mg, 0.906 mmol) was added to a solution of 62 (33 mg, 0.091 mmol) in CH2CI2(5 mL) and stirred at room temperature 16 hours. The mixture was filtered through celite, and the solvent was removed. The crude was purified by flash chromatography (Hex / EtOAc 90 / 10 to 50 / 50) to give 27 mg (Yield = 82%) of 63 as a mixture of diastereoisomers.

[0675] 1H NMR (396 MHz, CDCI3) δ 6.43 (d, J = 2.7 Hz, 1 H), 6.19 (s, 1 H), 6.05 (t, J = 1.5 Hz, 1 H), 5.99 - 5.91 (m, 1 H), 5.41 (d, J = 36.3 Hz, 1H), 4.58 - 4.39 (m, 1 H), 4.16 (d, J = 3.1 Hz, 1 H), 3.91 (s, 1 H), 3.74 - 3.63 (m, 1 H), 3.56 - 3.42 (m, 1 H), 3.07 (dd, J = 10.1 , 2.7 Hz, 1 H), 2.77 (dd, J = 12.3, 3.9 Hz, 1 H), 2.45 (t, J = 3.6 Hz, 2H), 2.04 - 1 .90 (m, 3H), 1 .84 - 1 .37 (m, 11 H).13C NMR (100 MHz, CDCI3) δ 196.05, 158.83, 137.63, 137.33, 134.76, 134.27, 133.15, 133.04, 131.13, 128.41 , 127.03, 126.64, 96.42, 81.67, 77.61, 75.80, 63.59, 62.67, 52.82, 30.34, 25.40, 25.18, 21.01 , 20.66, 19.50, 18.84.

[0676] Methacrylic anhydride (13 μL, 0.0894 mmol) was added to a solution of 63 (27 mg, 0.0745 mmol), Et3N (31 μL, 0.223 mmol), dimethylaminopyridine (DMAP, 1.8 mg, 0.0149 mmol) in THF (2 mL). The mixture was stirred for 16 hours at room temperature and the solvent was removed. The crude was diluted with EtOAc and NH4Clsat. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum to obtain 29 mg (Yield = 91% Crude) of 64. The crude was used without further purification.

[0677] PTSA (5.8 mg, 0.034 mmol) was added to 64 (29 mg, 0.067 mmol) in MeOH (1 mL). The mixture was stirred 4 hours at room temperature. The solvent was removed under vacuum and the crude was purified by flash chromatography (Hex / EtOAc 80 / 20 to 40 / 60) to obtain 15 mg of (+ / -)-molephantin 65 (Yield = 60% on 2 steps). A sample was purified by GPC for bioassays.

[0678] 1H NMR (396 MHz, CDCI3) δ 6.37 (s, 1 H), 6.21 (s, 1H), 6.18 - 6.10 (m, 1 H), 6.04 - 5.98 (m, 1H), 5.83 (s, 1H), 5.68 (d, J = 1.8 Hz, 1 H), 5.45 (d, J = 11.6 Hz, 1 H), 5.23 (dd, J = 3.9, 1.8 Hz, 1H), 4.24 (d, J = 3.7 Hz, 1 H), 3.45 - 3.33 (m, 1 H), 2.76 (d, J = 3.9 Hz, 1 H), 2.56 - 2.44 (m, 1H), 2.36 (dd, J = 11.7, 1.8 Hz, 1 H), 2.01 (s, 3H), 1.96 (s, 3H), 1.79 (s, 3H).

[0679] Conclusion In this work, we have accomplished the first collective synthesis of (furano)germacranolides derived from Elephantopus mollis and Elephantopus tomentosus. The key to the stereoselective assembly of highly oxygenated and strained ten-membered macrocyclic core of molephantin (1) and tomenphantopin F (2) was the employment of the diastereoselective intermolecular Barbier allylation, coupled with the Nozaki-Hiyama-Kishi (NHK) macrocyclization. In addition, the photoinduced isomerization of the (E,Z)-dienone moiety of molephantin (1) to (Z,Z)-dienone followed by hemiketalization enabled the concise access to four furanogermacranolides, EM-2 (3), phantomolin (4), 2-O-demethyltomenphantopin C (5), and tomen-phantopin C (6), implicating that molephantin (1) might likely be a biosynthetic precursor of furanogermacranolides found from Elephantopus mollis and Elephantopus tomentosus.

Claims

Claims1. A process to generate an intermediate in the total synthesis of (+)-molephantin or a derivative thereof, the process comprising:(a) providing a compound of formula I:where:Prot1represents an acid-labile protecting group;X represents Cl or, more particularly, Br; and(b) reacting the compound of formula I for a period of time with a compound of formula II:where Prot2is selected from a triethylsilyl group, a triisopropylsilyl group, a tert- butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or, more particularly, a tri methylsilyl group, under reaction conditions involving a stoichiometric excess of one or both of a metal salt and a metal relative to the compound of formula I, a solvent and at a temperature of from 0 to 25 °C to provide a compound of formula III:where Prot1is as defined above.

2. The process according to Claim 1 , wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p- methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1- (2-chloroethoxy)ethyl ether, 1-methyl-1 -methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1 -methyl- 1 -phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

3. The process according to Claim 1 or Claim 2, wherein one or more of the following apply:(ai) the metal and / or metal salt is selected from one or more of zinc metal, indium metal, a chromium (III) salt with manganese metal, samarium (II) iodide, tin (II) chloride, and a chromium (II) salt, optionally wherein the metal and / or metal salt is chromium (II) bromide or, more particularly, chromium (II) chloride;(bi) the solvent is selected from one or more of the group consisting of tetrahydrofuran, 2- methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1 ,2-dimethoxyethane, 1,1- dimethoxyethane, dimethylsulfoxide, dimethylacetamide, and, more particularly, dimethyl formamide; and(ci) the temperature is about 10 °C.

4. A process to generate an intermediate in the total synthesis of (+)-molephantin or a derivative thereof, the process comprising:(aii) providing a compound of formula IV:where Prot1represents an acid-labile protecting group; and(bii) subjecting the compound of formula IV for a period of time to reaction conditions involving a catalytic amount of a nickel (II) salt or a palladium (II) salt, a stoichiometric excess of one or both of a metal and a metal salt relative to the compound of formula IV, in a solvent, and at a temperature of from 5 to 60 °C to provide a compound of formula V:where R is Prot1and Prot1is as defined above.

5. The process according to Claim 4, wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p- methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1- (2-chloroethoxy)ethyl ether, 1-methyl-1 -methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1 -methyl- 1 -phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

6. The process according to Claim 4 or Claim 5, wherein one or more of the following apply:(aiii) the metal and / or metal salt is selected from one or more of a chromium (III) salt with manganese metal, samarium (II) iodide, and a chromium (II) salt, optionally wherein the metal and / or metal salt is chromium (II) bromide or, more particularly, chromium (II) chloride;(biii) the solvent is selected from one or more of the group consisting of tetrahydrofuran, 2- methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,1- dimethoxyethane, dimethyl formamide, dimethylacetamide, and, more particularly, dimethyl sulfoxide;(ciii) the temperature is about 25 °C; and(diii) the catalytic nickel (II) salt or palladium (II) salt is selected from one or more of the group consisting of nickel (II) chloride, nickel (II) bromide, nickel(ll) iodide, nickel(ll) chloride ethylene glycol dimethyl ether complex, 1 ,2-bis(diphenylphosphino)ethane nickel (II) chloride, bis(1,5-cyclooctadiene)nickel(0), 1,3-bis(diphenylphosphino)propane]dichloronickel(ll), tetrakis(triphenylphosphine)nickel, palladium (II) chloride, palladium (II) acetate, and nickel (II) bis(acetylacetonate), optionally wherein the catalytic nickel (II) salt or palladium (II) salt is nickel (II) bis(acetylacetonate).

7. A total synthesis of (+)-molephantin or a derivative thereof, the process comprising the synthetic process according to any one of Claims 1 to 3 and the synthetic process according to any one of Claims 4 to 6.

8. The process according to Claim 7, wherein the compound of formula IV:where Prot1represents an acid-labile protecting group, is prepared by:(aiv) providing a compound of formula III:where Prot1is as defined above; and(biv) subjecting the compound of formula III to an oxidation reaction to provide the compound of formula IV, optionally wherein the oxidation conditions comprise a stoichiometric excess of manganese dioxide in a solvent (e g. methylene chloride) and at a temperature of from 5 to 35 °C (e.g. about 25 °C), optionally wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t- butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

9. The process according to Claim 7 or Claim 8, wherein the compound of formula I:where Prot1represents an acid-labile protecting group, is provided by:(av) providing a compound of formula la:; and(bv) protecting the free hydroxyl of the compound of formula la with an acid-labile protecting group using suitable conditions for a selected protecting group, optionally wherein the acid-labile protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2- (trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, 1 -ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1- methoxyethyl ether, 1 -methyl- 1 -benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1 ,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-labile protecting group is methoxymethyl ether.

10. The process according to Claim 9, wherein the protecting group is methoxymethyl ether and the reaction conditions involve reaction of the compound of formula la with dimethoxymethane as a solvent and reagent and a catalytic amount of a suitable acidic catalyst (e.g. triflic acid).

11. The process according to Claim 9 or Claim 10, wherein the compound of formula la is provided by reaction of a compound of formula VI:with a stoichiometric excess of hydrobromic acid in a solvent (e.g. ethyl acetate) at a suitable temperature (e g. about 25 °C).

12. The process according to Claim 11, wherein the compound of formula VI is provided by reaction of a compound of formula VII:with methyl acrylate, a suitable base (e.g. 1 ,4-diazabicyclo[2.2.2]octane), and at a suitable temperature (e g. about 25 °C).

13. The process according to Claim 12, wherein the compound of formula VII is provided by reaction of a compound of formula VIII:with a reducing agent (e.g. diisobutylaluminium hydride), in a suitable solvent (e.g. methylene chloride), and at a suitable temperature (e.g. about -78 °C).

14. The process according to Claim 13, wherein the compound of formula VIII is provided by reaction of a compound of formula IX:with (iodomethyl)triphenylphosphonium iodide, and a suitable base (e.g. sodium hexamethyldisilazide) in a suitable solvent (e.g. tetrahydrofuran), and at a suitable temperature (e.g. about -78 °C).

15. The process according to Claim 14, wherein the compound of formula IX is provided by reaction of a compound of formula X:with methyl lithium in a suitable solvent (e.g. methylene chloride), and at a suitable temperature (e.g. about -78 °C).

16. The process according to any one of Claims 7 to 15, wherein the compound of formulaV:where R is Prot1and Prot1is as defined in Claim 8, is subjected to an oxidation reaction to provide a compound of formula XI:where R is as defined above, optionally wherein the oxidation reaction involves a stoichiometric excess of manganese dioxide and a solvent (e.g. methylene chloride) at a suitable temperature (e.g. 25 °C).

17. The process according to Claim 16, wherein the compound of formula XI is reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g. triethylamine), a catalytic base (e.g. dimethylaminopyridine) in a suitable solvent (e.g. tetra hydrofuran) and at a suitable temperature (e.g. 25 °C), to provide a compound of formula XII:where R is Prot1and Prot1is as defined in Claim 8 and R’ is H or CH3.

18. The process according to Claim 17, wherein the compound of formula XII is reacted with an acid (e.g. trifluoroacetic acid) in a suitable solvent (e.g. methylene chloride) and at a suitable temperature (e.g. 25 °C), to provide a compound of formula XIII:where R’ is H or CH3.

19. A method of forming a compound of formula XIVwhere R’ is H or CH3, by a cyclisation reaction of a compound of formula XIII:where R’ is as defined above, through the application of ultraviolet light to the compound of formula XIII in a suitable solvent (e.g. methylene chloride) at a suitable temperature (e.g. about 25 °C), optionally wherein the ultraviolet light is provided at a wavelength of from 200 to 400 nm (e.g. about 370 nm) at a suitable power (e.g. from 10 to 100 Watts, such as about 40 Watts) and using a light source at a suitable distance from a reaction vessel including the compound of formula XIII (e.g. from 1 to 10 cm, such as about 4 cm).

20. A method of forming a compound of formula XV:where R” is selected from C1to C10alkyl or C2to C10alkenyl, from a compound of formula XIV,where R’ is H or CH3, through reacting the compound of formula XIV with an alcohol of formulaXVI:R”-OH XVI in the presence of an acid catalyst (e.g. the catalyst is para-toluene sulfonic acid).

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