Collective synthesis of the vantrumomycin family via the total synthesis of the sesquiterpene lactone peltatumin

Abstract

This document discloses a method for generating intermediates in the total synthesis of (+)-daunoglobin or its derivatives, and the total synthesis of (+)-daunoglobin or its derivatives. This document also discloses methods for forming compounds of formula XIV and XV, wherein compounds of formula XIV and XV are as defined in the specification.

Description

[0001] Invention Field

[0002] This invention relates generally to the synthesis of the phantomolin family, and more specifically, to a process and method for the collective synthesis of the phantomolin family via the total synthesis of the sesquiterpene lactone molephantin. Background Technology

[0003] The listing or discussion of previously published literature in this specification does not necessarily imply an admission that such literature is prior art or common general knowledge.

[0004] For many years, the diverse family of sesquiterpene lactones (gemmacolides), as plant secondary metabolites, has received widespread attention in the fields of natural product chemistry, medicinal chemistry, and synthetic chemistry. Epimedium (1) is a highly oxidized gemmacolide, first discovered in 1973 by Lee from the medicinal plant *Epimedium pubescens* (…). Elephantopus mollis Separation in (K.-H. Lee et al., J. Chem. Soc. Chem. Commun. 1973, 476-477), then in 2012 by Liu and Dai from *Elephantopus scabra* ( Elephantopus tomentosus (W.-L. Mei et al., Phytochem. Lett. 2012, 5, 800-803) Figure 1 A). It is known that trochophorein (1) has strong in vivo antitumor activity against Ehrlich and Walker 256 carcinosarcoma (IH Hall et al., J. Pharm. Sci. 1978, 67, 1235-1239), and also possesses anti-inflammatory and leishmanic activities (Z.-N. Wu et al., Phytochemistry 2017, 137, 81-86; and H. Fuchino et al., ...). Planta Med. 2001, 67, 647-653). The molecular structure of velutin (1) consists of a ten-membered macrocycle core with an (E,Z)-dienone moiety (C10-1-4), which is fused with α-methylene-γ-butyrolactone and connected to four consecutive stereocenters (C5-8). In 2012, Liu and Dai obtained velutin from *Elephantopus scabra* (… Elephantopus tomentosus Tomenphantopin F(2) isolated from ) is structurally similar to trompetrodin(1) (B. Wang et al., Chin. J. Chem.2012, 30, 1320-1322). Its structure is based on the same ten-membered macrocyclic core, with an α-(S)-methyl-γ-butyrolactone moiety and a free hydroxyl group at C8. In *Elephantopus pubescens* (… Elephantopus mollis ) and white-flowered ground ivy ( Elephantopus tomentosus Other topology-related components found in the study include furanogermacranolides, such as EM-2 (2-deethoxy-2β-methoxyvantothromycin) (3) (S. Banerjee et al., Planta Med. 1986, 52, 29–32), Vantomo Spirit (4) (K.-H. Lee et al., J. Pharm. Sci. 1980, 68, 1050-1056), 2- O -DemethyltomenphantopinC (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, when EM-2 (3) was used in combination with epirubicin, it was observed that EM-2 (3) made breast cancer cells more sensitive to epirubicin, mainly by inhibiting the protective autophagy pathway of cells (J. Li et al., 2022, 85, 2433-2444). Phytomedicine 2023, 116, 154878). Their ten-membered macrocyclic core contains a (Z,Z)-spaced diene centered on the C2 (hemi)ketal carbon. Although the biosynthetic pathway of these highly oxidized (furan)germaline lactones is unclear, we hypothesize that velutin (1) may be a biosynthetic precursor of EM-2 (3) and other furan macrocyclic lactones. This hypothesis is based on the interesting topological similarities between them, suggesting a potential synthetic route involving E / Z isomerization of the C1-C10 double bond of velutin (1) to generate (Z,Z)-dienone homologue A, and its subsequent (hemi)ketalization with the C5-hydroxyl group.

[0005] Despite the presence of highly oxidized gemmaconidine lactones (e.g., eremantholide) isolated from different plant species, J. Am. Chem. Soc. 1991, 113, 9682-9684) and goyazensolide ( ACS Cent. Sci. There have been landmark studies on the synthesis of *Gnaphalium* (2021, 7, 954-962), but to our knowledge, there are no studies on the synthesis of *Gnaphalium* (2021, 7, 954-962). ElephantopusReport on the total synthesis of (furan)gemaline lactone from plants ( Figure 1 B). The only exception is the synthesis of nordeoxyelephantopin, a compound derived from *Elephantopus spp.* (B). Elephantopus scaber Non-natural analogues of deoxygestilbene (R. Lagoutte et al.) Nat. Commun. 2016, 7, 12470; and R. Lagoutte et al., J. Antibiot. 2018, 71, 248–256.

[0006] Therefore, new synthetic routes are needed to obtain sesquiterpene lactones. Invention Overview

[0008] Various aspects and embodiments of the present invention are provided in the following numbered entries.

[0009] 1. A method for generating an intermediate in the total synthesis of (+)-dulodophorin or its derivatives, the method comprising:

[0010] (a) Provides compound of formula I:

[0011]

[0012] in:

[0013] Prot 1 Represents an acid-instable protecting group;

[0014] X represents Cl or, more specifically, Br;

[0015] and

[0016] (b) Comparing compound I with compound II:

[0017]

[0018] Among them Prot 2 Selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or more particularly trimethylsilyl.

[0019] Reacting for a period of time under reaction conditions involving a stoichiometric excess of a metal salt and / or metal relative to the compound of formula I, a solvent, and a temperature of 0 to 25°C, yields the compound of formula III:

[0020]

[0021] Among them Prot 1 As defined above.

[0022] 2. The method according to item 1, wherein the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-unstable protecting group is a methoxymethyl ether.

[0023] 3. The method according to item 1 or item 2, wherein one or more of the following apply:

[0024] (ai) The metal and / or metal salt is selected from one or more of zinc metal, indium metal, chromium(III) salt used in combination with manganese metal, samarium(II) iodide, tin(II) chloride and chromium(II) salt, optionally, wherein the metal and / or metal salt is chromium(II) bromide, or more particularly chromium(II) chloride;

[0025] (bi) The solvent is selected from one or more of the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethyl sulfoxide, dimethylacetamide, and more particularly dimethylformamide; and

[0026] (ci) The temperature is approximately 10 °C.

[0027] 4. A method for generating an intermediate in the total synthesis of (+)-dulodophorin or its derivatives, the method comprising:

[0028] (aii) Provides compounds of formula IV:

[0029]

[0030] Among them Prot 1 Represents an acid-instable protecting group; and

[0031] (bii) Reacting compound IV in a catalytic amount of a nickel(II) or palladium(II) salt, in stoichiometric excess of a metal and / or metal salt relative to the compound IV, in a solvent, and at a temperature of 5 to 60 °C for a period of time to provide compound V:

[0032]

[0033] Where R is Prot 1 And Prot 1 As defined above.

[0034] 5. The method according to item 4, wherein the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-unstable protecting group is a methoxymethyl ether.

[0035] 6. The method described according to item 4 or item 5, wherein one or more of the following apply:

[0036] (aiii) The metal and / or metal salt is selected from one or more of chromium(III) salts, samarium(II) iodide and chromium(II) salts used in combination with manganese metal, optionally, wherein the metal and / or metal salt is chromium(II) bromide, or more particularly chromium(II) chloride;

[0037] (biii) The solvent is selected from one or more of the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethylformamide, dimethylacetamide, and more particularly dimethyl sulfoxide;

[0038] (ciii) The temperature is approximately 25°C; and

[0039] (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(II) iodide, nickel(II) chloride ethylene glycol dimethyl ether complex, 1,2-bis(diphenylphosphine)ethane nickel(II) chloride, bis(1,5-cyclooctadiene) nickel(O), 1,3-bis(diphenylphosphine)propane dichloro nickel(II), tetra(triphenylphosphine) nickel, palladium(II) chloride, palladium(II) acetate and bis(acetylacetone) nickel(II), optionally wherein the catalytic nickel(II) salt or palladium(II) salt is bis(acetylacetone) nickel(II).

[0040] 7. Total synthesis of (+)-hygroscopicin or its derivatives, comprising the synthetic method according to any one of entries 1 to 3 and the synthetic method according to any one of entries 4 to 6.

[0041] 8. The method according to item 7, wherein the compound of formula IV is:

[0042]

[0043] Among them Prot 1 The acid-instable protecting group is prepared by the following method:

[0044] (aiv) Provides compounds of formula III:

[0045]

[0046] Among them Prot 1 As defined above; and

[0047] (biv) Oxidating the compound of formula III to provide the compound of formula IV, optionally wherein the oxidation conditions include a stoichiometric excess of manganese dioxide in a solvent (e.g., dichloromethane) at a temperature of 5 to 35 °C (e.g., about 25 °C).

[0048] Optionally, the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal, wherein the acid-unstable protecting group is methoxymethyl ether.

[0049] 9. The method according to item 7 or 8, wherein the compound of formula I is:

[0050]

[0051] Among them Prot 1 The acid-instable protecting group is obtained through the following method:

[0052] (av) Provides compound Ia:

[0053] ;and

[0054] (bv) Using suitable conditions applicable to the selected protecting group, protect the free hydroxyl group of compound Ia with an acid-unstable protecting group.

[0055] Optionally, the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal. Optionally, the acid-unstable protecting group is a methoxymethyl ether.

[0056] 10. The method according to item 9, wherein the protecting group is a methoxymethyl ether, and the reaction conditions involve the reaction of the compound of formula Ia with dimethoxymethane as a solvent and reagent and a suitable amount of acidic catalyst (e.g., trifluoromethanesulfonic acid).

[0057] 11. The method according to item 9 or 10, wherein the compound of formula Ia is prepared by reacting the compound of formula VI in a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25 °C):

[0058]

[0059] It is obtained by reacting with an excess of stoichiometric hydrobromic acid.

[0060] 12. The method according to item 11, wherein the compound of formula VI is obtained by heating at a suitable temperature (e.g., about 25°C). C) The following compounds of formula VII:

[0061]

[0062] It is obtained by reacting methyl acrylate with a suitable base (e.g., 1,4-diazabicyclo[2.2.2]octane).

[0063] 13. The method according to item 12, wherein the compound of formula VII is prepared by reacting the compound of formula VIII in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., about -78°C):

[0064]

[0065] It is obtained by reacting with a reducing agent (such as diisobutylaluminum hydride).

[0066] 14. The method according to item 13, wherein the compound of formula VIII is prepared by reacting the compound of formula IX in a suitable solvent (e.g., tetrahydrofuran) and at a suitable temperature (e.g., about -78°C):

[0067]

[0068] It is obtained by reacting (iodomethyl)triphenylphosphonium iodide with a suitable base (e.g., sodium bis(trimethylsilyl)amino).

[0069] 15. The method according to Item 14, wherein the compound of formula IX is prepared by reacting the compound of formula X in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., about -78°C):

[0070]

[0071] It is obtained by reacting with methyllithium.

[0072] 16. The method according to any one of items 7 to 15, wherein the compound of formula V:

[0073]

[0074] Where R is Prot 1 And Prot 1 As defined in entry 8, the compound of formula XI is obtained by oxidation reaction:

[0075]

[0076] Where R is as defined above, optionally, the oxidation reaction involves a stoichiometric excess of manganese dioxide and a solvent (e.g., dichloromethane) at a suitable temperature (e.g., 25°C).

[0077] 17. The method according to item 16, wherein the compound of formula XI is reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g., triethylamine), and a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) and at a suitable temperature (e.g., 25°C) to give the compound of formula XII:

[0078]

[0079] Where R is Prot 1 And Prot 1 As defined in entry 8, and R' is H or CH3.

[0080] 18. The method according to item 17, wherein the compound of formula XII is reacted with an acid (e.g., trifluoroacetic acid) in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., 25°C) to give the compound of formula XIII:

[0081]

[0082] Where R' is H or CH3.

[0083] 19. A method for forming a compound of formula XIV,

[0084]

[0085] Where R' is H or CH3, compound XIII is prepared by reacting it in a suitable solvent (e.g., dichloromethane) at a suitable temperature (e.g., about 25 °C):

[0086]

[0087] Wherein R' is as defined above, ultraviolet light is applied to induce a cyclization reaction, wherein the ultraviolet light is provided at a wavelength of 200 to 400 nm (e.g., about 370 nm), with a suitable power (e.g., 10 to 100 watts, such as about 40 watts), and a light source is used with a suitable distance (e.g., 1 to 10 cm, such as about 4 cm) between the reaction vessel containing the compound XIII.

[0088] 20. A compound of formula XIV

[0089]

[0090] Where R' is H or CH3

[0091] Methods for forming XV compounds

[0092]

[0093] Where R” is C1 to C 10 Alkyl or C2 to C 10 Alkenyl groups, through compounds of formula XIV and alcohols of formula XVI:

[0094] R”-OH XVI

[0095] The reaction is carried out in the presence of an acidic catalyst (such as p-toluenesulfonic acid). Attached Figure Description

[0096] Figure 1 shows A) from *Elephantopus pubescens* (… Elephantopus mollis ) and white-flowered ground ivy ( Elephantopus tomentosus Gemmaline lactone and furanogemmaline lactone isolated from 1. B) Highly oxidized gemmaline lactones derived from different plants.

[0097] Figure 2 The crude residue containing aldehyde 12 was shown. 1 H nuclear magnetic resonance (NMR) spectrum.

[0098] Figure 3 Crude residue containing methyl ketone 13 was shown. 1 H NMR spectrum.

[0099] Figure 4 The purified iodoolefin 14 was shown. 1 H NMR spectrum.

[0100] Figure 5 X-ray crystallographic data for compound 17 are shown (CCDC-2312148).

[0101] Figure 6 X-ray crystallographic data of compound 17' are shown (CCDC-2312149).

[0102] Figure 7 It showed 18. 1 H- 1 Correlation between H COSY and HMBC.

[0103] Figure 8 The reaction progress was monitored by liquid chromatography-mass spectrometry (LC-MS).

[0104] Figure 9 X-ray crystallographic data of compound 20 are shown (CCDC-2312151).

[0105] Figure 10 The origin of diastereoselectivity in the formation of compound 20 is shown.

[0106] Figure 11 The leucotrogenin (1) was shown to be 1 H- 1 Correlation between H COSY and HMBC.

[0107] Figure 12 X-ray crystallographic data of compound 23 are shown (CCDC-2312152).

[0108] Figure 13 The tomenphantopin F(2) was shown.1 H- 1 Correlation between H COSY and HMBC.

[0109] Figure 14 The photochemical reaction apparatus is shown (the fan has been removed from the photo for clarity). The distance between the lamp and the reaction tube is set to 4 cm.

[0110] Figure 15 The UV-Vis absorption spectrum of hygroscopicin (1) (0.5 mM, in CH2Cl2) is shown.

[0111] Figure 16 This demonstrates the photoinduced response in CDCl3. 1 H NMR monitoring.

[0112] Figure 17 The photoinduced ring isomerization of 25 (dumbulin (1)) was shown. 1 H- 1 Correlation between H COSY and HMBC.

[0113] Figure 18 X-ray crystallographic data (CCDC-2324191) of EM-2 (3) are shown.

[0114] Figure 19 The image shows EM-2 (3). 1 H- 1 Correlation between H COSY and HMBC.

[0115] Figure 20 It shows the spirit of Vantor (4) 1 H- 1 Correlation between H COSY and HMBC.

[0116] Figure 21 Showing 2- O -Demethyltomenphantopin C (5) 1 H- 1 Correlation between H COSY and HMBC.

[0117] Figure 22 shows the X-ray crystallographic data (CCDC-2312153) of Tomenphantopin C (6).

[0118] Figure 23 The results of Tomenphantopin C(6) were displayed. 1 H- 1 Correlation between H COSY and HMBC.

[0119] Figure 24 Retrosynthetic analysis of hygroscopicin (1) is shown.

[0120] Figure 25 shows the synthetic route of A) aldehyde fragment 12. B) 3-bromomethyl-5H-furan-2-one 17. C) trochodermatin (1). D) tomenphantopin F (2).

[0121] Figure 26 The collective synthesis of furanylgermaline lactone is shown.

[0122] Figure 27 The stereoselective synthetic route of (+)-hymenole is shown.

[0123] Figure 28 The synthetic route of synthon 9 is shown.

[0124] Figure 29 The synthetic route for aldehyde 12 is shown.

[0125] Figure 30 The En pathway of (+)-hygroscopicin is shown.

[0126] Figure 31 Examples of (+ / -)-hymenoletin are shown. Detailed Implementation

[0127] A surprising discovery was made: the collective synthesis of (furan)gemaline lactones can be derived from *Elephantopus pubescens* (…). Elephantopus mollis ) and white-flowered ground ivy ( Elephantopus tomentosus ).

[0128] Therefore, a first aspect of the present invention provides a method for generating an intermediate in the total synthesis of (+)-hymenole or its derivatives, the method comprising:

[0129] (a) Provides compound of formula I:

[0130]

[0131] in:

[0132] Prot 1 Represents an acid-instable protecting group;

[0133] X represents Cl or, more specifically, Br;

[0134] and

[0135] (b) Comparing compound I with compound II:

[0136]

[0137] Among them Prot 2 Selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or more particularly trimethylsilyl.

[0138] Reacting for a period of time under reaction conditions involving a stoichiometric excess of a metal salt and / or metal relative to the compound of formula I, a solvent, and a temperature of 0 to 25°C, yields the compound of formula III:

[0139]

[0140] Among them Prot 1 As defined above.

[0141] The word "comprising" in this document can be interpreted as requiring the presence of the mentioned features, but not limiting the presence of other features. Alternatively, the word "comprising" may also refer to situations where the listed components / features are intended to be present only (e.g., the word "comprising" can be replaced by the phrases "consisting of" or "substantially consisting of"). It is clearly contemplated that both broader and narrower interpretations are applicable to all aspects and embodiments of the invention. In other words, the word "comprising" and its synonyms can be replaced by the phrases "consisting of" or "substantially consisting of" or their synonyms, and vice versa.

[0142] The phrase “consistently made of” and its synonyms can be interpreted in this text as referring to materials that may contain small amounts of impurities. For example, the purity of the material may be greater than or equal to 90%, such as greater than 95%, greater than 97%, greater than 99%, greater than 99.9%, greater than 99.99%, greater than 99.999%, or 100%.

[0143] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” used herein include the plural referent. For example, when referring to “a composition,” it includes a mixture of two or more such compositions; when referring to “the catalyst,” it includes a mixture of two or more such catalysts, and so on.

[0144] The term "halogen" as used in this article includes fluorine, chlorine, bromine, and iodine.

[0145] In a first aspect of the invention, any suitable acid-insecure protecting group may be used.

[0146] In certain embodiments of the first aspect of the invention mentioned herein, the acid-unstable protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal.

[0147] In a further embodiment of the first aspect of the invention mentioned herein, the acid-unstable protecting group may be a methoxymethyl ether.

[0148] In the first aspect of the invention, any suitable time period can be used. For example, the time period could be 3 hours.

[0149] In a first aspect of the invention, any suitable metal and / or metal salt may be used.

[0150] In some embodiments of the first aspect of the invention that may be mentioned herein, the metal and / or metal salt may be selected from one or more of zinc metal, indium metal, chromium(III) salt used in combination with manganese metal, samarium(II) iodide, tin(II) chloride and chromium(II) salt (e.g. chromium(II) bromide and chromium(II) chloride).

[0151] In a further embodiment of the first aspect of the invention that may be mentioned herein, the metal and / or metal salt may be chromium(II) chloride.

[0152] In a first aspect of the invention, any suitable solvent may be used.

[0153] In certain embodiments of the first aspect of the invention mentioned herein, the solvent may be selected from one or more of the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethyl sulfoxide, dimethylacetamide, and dimethylformamide.

[0154] In a further embodiment of the first aspect of the invention mentioned herein, the solvent may be dimethylformamide.

[0155] In some embodiments of the first aspect of the invention, the temperature may be about 10. C.

[0156] In a first aspect of the invention, any suitable stoichiometric excess of a metal salt and / or metal relative to a compound of formula I may be used.

[0157] In a second aspect of the invention, a method for generating an intermediate in the total synthesis of (+)-hymenole or its derivatives is provided, the method comprising:

[0158] (aii) Provides compounds of formula IV:

[0159]

[0160] Among them Prot 1 Represents an acid-instable protecting group; and

[0161] (bii) Reacting compound IV in a catalytic amount of a nickel(II) or palladium(II) salt, in stoichiometric excess of a metal and / or metal salt relative to the compound IV, in a solvent, and at a temperature of 5 to 60 °C for a period of time to provide compound V:

[0162]

[0163] Where R is Prot 1 And Prot 1 As defined above.

[0164] In a second aspect of the invention, any suitable acid-insecure protecting group may be used.

[0165] In certain embodiments of the second aspect of the invention mentioned herein, the acid-unstable protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal.

[0166] In a further embodiment of the second aspect of the invention mentioned herein, the acid-unstable protecting group may be a methoxymethyl ether.

[0167] In a second aspect of the invention, any suitable time period can be used. For example, the time period could be 16 hours.

[0168] In a second aspect of the invention, any suitable amount of nickel(II) salt or palladium(II) salt may be used.

[0169] In a second aspect of the invention, any suitable stoichiometric excess of a metal and / or metal salt relative to the compound of formula IV may be used.

[0170] In a second aspect of the invention, any suitable metal and / or metal salt may be used.

[0171] In some embodiments of the second aspect of the invention that may be mentioned herein, the metal and / or metal salt may be selected from one or more of chromium (III) salts, samarium (II) iodide and chromium (II) salts (e.g., chromium (II) bromide and chromium (II) chloride) used in combination with manganese metal.

[0172] In a further embodiment of the second aspect of the invention that may be mentioned herein, the metal and / or metal salt may be chromium(II) chloride.

[0173] In a second aspect of the invention, any suitable solvent may be used.

[0174] In certain embodiments of the second aspect of the invention mentioned herein, the solvent may be selected from one or more of the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide. For example, the solvent may be dimethyl sulfoxide.

[0175] In some embodiments of the second aspect of the invention that may be mentioned herein, the temperature may be about 25°C.

[0176] In a second aspect of the invention, any suitable catalytic nickel(II) salt or palladium(II) salt may be used.

[0177] In certain embodiments of the second aspect of the invention mentioned herein, 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(II) iodide, nickel(II) chloride ethylene glycol dimethyl ether complex, 1,2-bis(diphenylphosphine)ethane nickel(II) chloride, bis(1,5-cyclooctadiene) nickel(II), 1,3-bis(diphenylphosphine)propane dichloronickel(II), tetra(triphenylphosphine) nickel, palladium(II) chloride, palladium(II) acetate, and bis(acetylacetone) nickel(II). For example, the catalytic nickel(II) salt or palladium(II) salt may be bis(acetylacetone) nickel(II).

[0178] A third aspect of the present invention provides a total synthesis of (+)-hygroscopicin or its derivatives, the method comprising the synthesis method according to the first aspect of the present invention and the synthesis method according to the second aspect of the present invention.

[0179] In some embodiments of the third aspect of the invention that may be mentioned herein, the compound of formula IV is:

[0180]

[0181] Among them Prot 1 The acid-instable protecting group can be prepared by the following method:

[0182] (aiv) Provides compounds of formula III:

[0183]

[0184] Among them Prot 1 As defined above; and

[0185] (biv) Oxidize the compound of formula III to provide the compound of formula IV.

[0186] In such embodiments of the third aspect of the invention that may be mentioned herein, the oxidation conditions may include a stoichiometric excess of manganese dioxide in a solvent (e.g., dichloromethane) and at a temperature of 5 to 35 °C (e.g., about 25 °C).

[0187] In such embodiments of the third aspect of the invention mentioned herein, the acid-instable protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal. For example, the acid-instable protecting group may be methoxymethyl ether.

[0188] In certain embodiments of the third aspect of the invention that may be mentioned herein, the compound of formula I is:

[0189]

[0190] Among them Prot 1The protecting group representing acid instability can be obtained through the following methods:

[0191] (av) Provides compound Ia:

[0192] ;and

[0193] (bv) Using suitable conditions applicable to the selected protecting group, protect the free hydroxyl group of compound Ia with an acid-unstable protecting group.

[0194] In such embodiments of the third aspect of the invention mentioned herein, the acid-instable protecting group may be selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal. For example, the acid-instable protecting group may be methoxymethyl ether.

[0195] In such embodiments of the third aspect of the invention mentioned herein, the protecting group may be a methoxymethyl ether, and the reaction conditions may involve the reaction of a compound of formula Ia with dimethoxymethane (as a solvent and reagent) and a suitable amount of an acidic catalyst (e.g., trifluoromethanesulfonic acid).

[0196] In a third aspect of the invention, any suitable amount of a suitable acidic catalyst can be used.

[0197] In some embodiments of the third aspect of the invention that may be mentioned herein, the compound of formula Ia can be prepared by reacting the compound of formula VI in a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25 °C):

[0198]

[0199] It is obtained by reacting with an excess of stoichiometric hydrobromic acid.

[0200] In a further embodiment of the third aspect of the invention that may be mentioned herein, the compound of formula VI can be produced by heating at a suitable temperature (e.g., about 25°C). C) The following compounds of formula VII:

[0201]

[0202] It is obtained by reacting methyl acrylate with a suitable base (e.g., 1,4-diazabicyclo[2.2.2]octane).

[0203] In a third aspect of the invention, any suitable base may be used.

[0204] In other embodiments of the third aspect of the invention that may be mentioned herein, the compound of formula VII can be produced by reacting the compound of formula VIII in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., about -78°C):

[0205]

[0206] It is obtained by reacting with a reducing agent (such as diisobutylaluminum hydride).

[0207] In a third aspect of the invention, any suitable reducing agent may be used.

[0208] In a further embodiment of the third aspect of the invention that may be mentioned herein, the compound of formula VIII can be prepared by reacting the compound of formula IX in a suitable solvent (e.g., tetrahydrofuran) and at a suitable temperature (e.g., about -78°C):

[0209] It is obtained by reacting (iodomethyl)triphenylphosphonium iodide with a suitable base (e.g., sodium bis(trimethylsilyl)amino).

[0210] In a further embodiment of the third aspect of the invention that may be mentioned herein, the compound of formula IX can be prepared by reacting the compound of formula X in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., about -78°C):

[0211]

[0212] It is obtained by reacting with methyllithium.

[0213] In certain embodiments of the third aspect of the invention that may be mentioned herein, the compound of formula V is:

[0214]

[0215] Where R is Prot 1 And Prot 1 As defined in the third aspect of this invention, the compound of formula XI can be obtained by an oxidation reaction:

[0216]

[0217] R is defined above.

[0218] In such embodiments of the third aspect of the invention, the oxidation reaction may involve a stoichiometric excess of manganese dioxide and a solvent (e.g., dichloromethane) at a suitable temperature (e.g., 25°C).

[0219] In such embodiments of the third aspect of the invention, the compound of formula XI can be reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g., triethylamine), and a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) and at a suitable temperature (e.g., 25°C) to give the compound of formula XII:

[0220]

[0221] Where R is Prot 1 And Prot 1 As defined in the third aspect of the present invention, and R' is H or CH3.

[0222] In a third aspect of the invention, any suitable catalytic base may be used.

[0223] In such embodiments of the third aspect of the invention, the compound of formula XII can be reacted with an acid (e.g., trifluoroacetic acid) at a suitable solvent (e.g., dichloromethane) and a suitable temperature (e.g., 25°C) to give the compound of formula XIII:

[0224]

[0225] Where R' is H or CH3.

[0226] In a third aspect of the invention, any suitable acid may be used.

[0227] In a fourth aspect of the invention, a method for forming a compound of formula XIV is provided:

[0228]

[0229] Where R' is H or CH3,

[0230] The cyclization reaction of compound XIII is carried out by applying ultraviolet light to compound XIII in a suitable solvent (e.g., dichloromethane) at a suitable temperature (e.g., about 25°C), optionally wherein the ultraviolet light is provided at a wavelength of 200 to 400 nm (e.g., about 370 nm), a suitable power (e.g., 10 to 100 watts, such as about 40 watts), and a light source with a suitable distance (e.g., 1 to 10 cm, such as about 4 cm) between the light source and the reaction vessel containing compound XIII.

[0231] The application of ultraviolet light can be provided by any suitable light source. For example, the light source can be an LED light source.

[0232] In a fifth aspect of the invention, a compound of formula XIV is provided.

[0233]

[0234] Where R' is H or CH3

[0235] Methods for forming XV compounds

[0236]

[0237] Where R” is C1 to C 10 Alkyl or C2 to C 10 alkenyl,

[0238] Through compounds of formula XIV and alcohols of formula XVI:

[0239] R”-OH XVI

[0240] The reaction is carried out in the presence of an acidic catalyst (such as p-toluenesulfonic acid).

[0241] In a fifth aspect of the invention, any suitable acid catalyst may be used.

[0242] Unless otherwise stated, the term "alkyl" refers to a saturated, unbranched or branched, acyclic or cyclic group that may be unsubstituted. For example, when the term "alkyl" refers to an acyclic group, it can refer to a C14 group. 1-10 Alkyl, more preferably C 1-6 Alkyl groups (e.g., ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., branched or unbranched butyl), pentyl, or more preferably methyl). When the term "alkyl" refers to a cyclic group, it can be C10. 3-12 Cycloalkyl, and more preferably C 5-10 (e.g. C) 5-7 Cycloalkyl groups. In embodiments of the invention that may be mentioned, the alkyl group may be acyclic.

[0243] Unless otherwise stated, the term "alkenyl" refers to an unsaturated, unbranched or branched, acyclic or cyclic group, which may be unsubstituted. For example, when the term "alkenyl" refers to an acyclic group, it can be C10 ... 2-10 alkenyl, and more preferably C 2-6 Alkenyl (e.g., propenyl), butenyl (e.g., branched or unbranched butenyl), pentenyl, or more preferably vinyl). When the term "alkenyl" refers to a cyclic group, it can be C10-3 ... 3-12 Cycloalkenyl, and more preferably C5-10 (e.g., C) 5-7 Cyclic alkenyl groups. In embodiments of the invention that may be mentioned, the alkenyl group may be acyclic.

[0244] Compounds of formula X and XVI may be known and / or commercially available. Other compounds of formulas I to IX and XI to XV, as well as certain compounds of formula XVI (e.g., not commercially available), may be prepared according to techniques well known to those skilled in the art, such as those described below.

[0245] The compounds of the present invention can be separated from their reaction mixtures using conventional techniques (e.g., recrystallization, column chromatography, preparative high-performance liquid chromatography, etc.). Of particular note is that compounds of formula XIII, such as linalool and linaloolin, can be crystallized (or recrystallized) in ethanol (EtOH), methanol (MeOH), diethyl ether (Et2O) or dichloromethane (CH2Cl2).

[0246] In the processes described above and below, the functional groups of the intermediate compounds may need to be protected with protecting groups.

[0247] The protection and deprotection of functional groups can be carried out before or after the reaction described above.

[0248] Protecting groups can be removed using techniques well known to those skilled in the art and described below. For example, the protected compounds / intermediates described herein can be chemically converted into unprotected compounds using standard deprotection techniques.

[0249] The type of chemistry involved will determine the need for and type of protecting groups, as well as the order in which the synthesis is completed.

[0250] The use of protective bases in " Protective Groups in Organic Chemistry ", edited by J WF McOmie, Plenum Press (1973), and " Protective Groups in Organic Synthesis ”,3 rd A detailed description can be found in the edition, TW Greene & PGM Wutz, Wiley-Interscience (1999).

[0251] The term "functional group" used in this article refers to unprotected functional groups such as hydroxyl, thiol, amino, and carboxylic acid, and protected functional groups such as lower alkoxy, N-acetyl, O-acetyl, S-acetyl, and carboxylic acid esters.

[0252] (+)-Derivatives of tomentosuside include, but are not limited to: tomentosuside, tomentosuside F, tomentosuside K, tomenphantopin C, tomenphantopin H, 2-O-demethyltomenphantopin C, 2-deethoxy-2β-methoxytomentosuside-8-O-tiglinate, and 2-deethoxy-2β-methoxytomentosuside.

[0253] Other aspects and embodiments of the invention will be discussed below with reference to non-limiting examples.

[0254] Example

[0255] Material

[0256] The n-butyllithium (Kanto Chemical-04937-25) was purchased from Kanto Chemical. Trimethyl phosphonoacetate (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). Diisobutylaluminum hydride (Sigma Aldrich-214949), trimethylsilyl trifluoromethanesulfonate (Sigma Aldrich-225649), 2,6-dimethylpyridine (Sigma Aldrich-336106), lithium methyl (Sigma Aldrich-514330), sodium bis(trimethylsilyl)amino (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(II) acetylacetonate (Strem Chemicals-28-1130) was purchased from StremChemicals.

[0257] Notes

[0258] The carbon atom numbers marked on the compound correspond to the carbon atom numbers of hygroscopicin (1).

[0259] Analytical techniques

[0260] Nuclear magnetic resonance (NMR) spectroscopy

[0261] Recording on a Jeol-ECA series 400 MHz spectrometer 1 1H NMR spectrum (400 MHz), solvent was CDCl3 (in TMS). 1 H, δ = 0.00) is an internal standard) or CD3OD ( 1 H, δ = 3.31). 13 C10 NMR spectra (100 MHz) were recorded on a Jeol-ECA series 400 MHz spectrometer, using CDCl3 as the solvent. 13 C, δ = 77.16) is an internal standard) or CD3OD ( 13 C, δ = 49.00). The following abbreviations are used to denote peak multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, dddd = double double double doublet, qd = double quartet, qt = triplet and quartet, m = multipeak, br s = broad singlet, br m = broad multipeak.

[0262] Mass spectrometry and infrared (IR) spectroscopy

[0263] High-resolution mass spectrometry (HRMS) spectra were obtained using a Xevo G2 Tof Premier mass spectrometer (ionization mode: ESI positive ion mode; mobile phase: methanol, flow rate 100 μL / min). Infrared spectra were recorded using a Shimadzu IR Prestige-21 FT-IR spectrometer.

[0264] Optical rotation

[0265] Optical rotation was recorded at a wavelength of 589 nm using an OMNI Lab JASCO P-1030 polarimeter. The results are expressed as [α]. T D (Concentration is expressed in g / 100 mL solvent).

[0266] Melting point

[0267] The melting point was not corrected and was recorded on the MPA 100 OptiMelt Automated Melting Point System.

[0268] Absorption spectrum

[0269] Steady-state absorption spectra were recorded using a UV-Vis absorption spectrometer (YV3600 Plus, SHIMADZU).

[0270] LED light source

[0271] Using Kessil PR160 series (λ) max = 370 nm) as an LED light source for photochemical reactions.

[0272] Analytical thin-layer chromatography (TLC) and silica gel chromatography

[0273] TLC was performed using 0.25 mm thick silica gel 60-F254 plates (Merck), visualized using 254 nm UV light, and stained with potassium permanganate solution. Rapid column chromatography was performed using Merck silica gel 60 and distilled solvent.

[0274] X-ray diffraction spectrum

[0275] X-ray diffraction data were acquired using CuKα radiation (λ = 1.54184 Å) on an Agilent Supernova diffractometer equipped with an ATLAS CCD detector.

[0276] Liquid chromatography-mass spectrometry (LC-MS)

[0277] LC-MS analysis was performed using an Agilent 1260 Infinity Prime LC coupled with a 6475 triple quadrupole mass spectrometer (ionization mode: ESI positive ion mode, column: Agilent Zorbax EclipsePlus C18 RRHD 1.8 μM, 2.1 x 50 mm).

[0278] Gel permeation chromatography (GPC)

[0279] GPC analysis was performed on a GPC LaboACE with a Jaigel-2HR-40 column (chloroform, 30 mL / min).

[0280] Example 1. Synthesis of Compound 10

[0281]

[0282] At -20 °C (dry ice-acetone bath), n-butyllithium (1.5 M hexane solution, 183 mL, 275 mmol) was added dropwise to a solution of trimethyl phosphonoacetate 7 (50.0 g, 275 mmol) in THF (600 mL), and the mixture was stirred for 30 min at the same temperature. 4,4-Dimethoxy-2-butanone (8) (40 mL, 39.8 g, 301 mmol) was added dropwise to the above mixture, and the reaction mixture was heated to 4 °C (ice-water bath) and stirred for 4 h. The ice-water bath was then removed, and the mixture was stirred at 25 °C for 16 h. The mixture was cooled to 4 °C and quenched with a saturated aqueous solution of NH4Cl (500 mL). The organic material was extracted twice with Et2O (500 mL × 2), the combined organic phases were dried over MgSO4, and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, hexane / ethyl acetate (EtOAc) = 100:0 to 80:20) to give compound 7 (41.5 g, 221 mmol) in 80% yield at a ratio of 71:29 (based on...). 1 The E / Z mixture was analyzed by 1H NMR. E-10 and Z-10 were partially separated for characterization by rapid column chromatography (silica gel, hexane / EtOAc = 95:5 to 90:10).

[0283] For E-10 :

[0284] Appearance: Pale yellow oily substance.

[0285] TLC:R f = 0.60 (20% EtOAc / hexane).

[0286] FTIR (pure, cm) -1 ) 2949 [ν(C=C)], 1714 [ν(C=O)], 1651 [ν(C=C)], 1225 [ν(C–O)], 1082 [ν(CO)], 813 [ν(C=C)].

[0287] 1 H NMR (400 MHz, CDCl3) δ 5.74 (q, J = 1.2 Hz, 1H, H1), 4.54 (t, J =5.6 Hz, 1H, H8), 3.68 (s, 3H, CO2 Me ), 3.33 (s, 6H, O Me ), 2.44 (d,J = 5.6 Hz, 2H, H9), 2.20 (d, J = 1.2 Hz, 3H, H 15 ).

[0288] 13 C NMR (100 MHz, CDCl3) δ 167.1, 155.1, 117.9, 102.9, 53.2, 51.0, 44.1, 19.4.

[0289] HRMS (ESI) for C9H 17 O5 + [M+H] + Calculated value: 189.1127; Measured value: 189.1126.

[0290] For Z-10

[0291] Appearance: Pale yellow oily substance.

[0292] TLC: R f = 0.62 (20% EtOAc / hexane).

[0293] FTIR (pure, cm) -1 ) 2949 [ν(C=C)], 1714 [ν(C=O)], 1643 [ν(C=C)], 1269 [ν(CO)], 1082 [ν(CO)], 735 [ν(C=C)].

[0294] 1 H NMR (400 MHz, CDCl3) δ 5.77-5.75 (m, 1H, H1), 4.55 (t, J = 6.0 Hz,1H, H8), 3.69 (s, 3H, CO2 Me ), 3.37 (s, 6H, O Me ), 2.96 (dd, J = 6.0, 0.8 Hz,2H, H9), 1.96 (d, J = 1.2 Hz, 3H, H 15 ).

[0295] 13 C NMR (100 MHz, CDCl3) δ 166.7, 156.3, 117.4, 104.5, 53.8, 51.0, 37.2, 26.6.

[0296] HRMS (ESI) for C9H 17 O5 + [M+H] + Calculated value: 189.1127; Measured value: 189.1113.

[0297] Example 2. Synthesis of Compound 11

[0298]

[0299] Diisobutylaluminum hydride (DIBAL, 1 M cyclohexane solution, 463 mL, 463 mmol) was added dropwise to a CH₂Cl₂ (800 mL) solution of compound 10 (71:29 E / Z mixture, 39.5 g, 210 mmol) at -50 °C (dry ice-acetone bath), and the reaction was stirred for 30 min. The mixture was heated to -20 °C, quenched with EtOAc (30 mL), and diluted with a saturated Rochelle salt solution (500 mL). The mixture was heated to 25 °C and stirred for 3 h. The organic matter was extracted once from the separated aqueous phase with CH₂Cl₂ (400 mL), the combined organic phases were washed with brine (500 mL), dried over MgSO₄, and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 80:20 to 50:50) to obtain the following four fractions containing compound 11.

[0300] Class 1: m = 3.98 g, E / Z = 22 : 88

[0301] Grade 2: m = 7.70 g, E / Z = 49 : 51

[0302] Grade 3: m = 4.9 g, E / Z = 90 : 10

[0303] Classification 4: m = 11.9 g, E / Z = 100 : 0

[0304] Based on the calculated mass (m = 20.7 g), the yield of E-11 was 62%, while the yield of Z-11 was 24% (m = 7.92 g).

[0305] Regarding E-11:

[0306] Appearance: Colorless oily substance.

[0307] TLC: R f = 0.25 (40% EtOAc / hexane).

[0308] FTIR (pure, cm) -1 ) 3410 [ν(OH)], 2920 [ν(C=C)], 1666 [ν(C=C)], 1122 [ν(CO)], 1065 [ν(CO)].

[0309] 1 H NMR (400 MHz, CDCl3) δ 5.49 (qt, J = 1.2, 6.8 Hz, 1H, H1), 4.51 (t, J = 6.0 Hz, 1H, H8), 4.16 (d, J = 6.8 Hz, 2H, H2), 3.33 (s, 6H, O Me ), 2.34 (d, J = 6.0 Hz, 2H, H9), 1.72 (d, J = 1.2 Hz, 3H, H 15 ).

[0310] 13 C NMR (100 MHz, CDCl3) δ 134.9, 126.7, 103.4, 59.3, 52.9, 42.6,16.9.

[0311] HRMS (ESI) for C8H 17 O3 + [M+H] + Calculated value: 161.1178; Measured value: 161.1180.

[0312] For Z-11 (a mixture of Z-11 and E-11) :

[0313] Appearance: Colorless oily substance.

[0314] TLC: R f = 0.30 (40% EtOAc / hexane).

[0315] FTIR (pure, cm) -1 ) 3388 [ν(OH)], 2934 [ν(C=C)], 1668 [ν(C=C)], 1126 [ν(CO)], 1045 [ν(CO)].

[0316] 1H NMR (400 MHz, CDCl3) δ 5.69 (mt, J = 7.6 Hz, 1H, H1), 4.43 (t, J =5.6 Hz, 1H, H8), 4.04 (d, J = 7.6 Hz, 2H, H2), 3.37 (s, 6H, O Me ), 2.49 (s, 1H,O H ), 2.44 (d, J = 5.6 Hz, 2H, H9), 1.82-1.80 (m, 3H, H 15 ).

[0317] 13 C NMR (100 MHz, CDCl3) δ 135.8, 127.4, 103.0, 58.2, 53.8, 36.0,24.4.

[0318] HRMS for C8H 17 O3 + [M+H] + Calculated value: 161.1178; Measured value: 161.1156.

[0319] Example 3. Synthesis of Compound 12

[0320]

[0321] Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 41.6 mL, 228 mmol) was added dropwise to a CH2Cl2 (550 mL) solution of E-11 (9.15 g, 57.1 mmol) and 2,6-dimethylpyridine (39.8 mL, 343 mmol) at -5°C (ice-NaCl-water bath), and the reaction mixture was stirred for 15 minutes. The reaction was then quenched by the slow addition of water (250 mL), and the organic phase was washed four times with an aqueous CuSO4 solution (1 M, 4 × 300 mL) to thoroughly remove 2,6-dimethylpyridine (inadequate washing at this stage would lead to contamination of aldehyde 12 with 2,6-dimethylpyridine, thus hindering the subsequent Barbier allylation reaction). The mixture was dried over MgSO4 and concentrated under vacuum. The resulting crude residue containing aldehyde 12 as the major component (m = 9.45 g) (see [link to relevant documentation]). Figure 2 In 1 (H NMR spectrum). Since aldehyde 12 is unstable, no further purification is required, and it can be directly used for the coupling reaction with compound 17 in Example 9.

[0322] A portion of the crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 95:5 to 70:30) for characterization of compound 12.

[0323] Appearance: Pale yellow oily substance.

[0324] TLC: R f = 0.5 (5% EtOAc / hexane).

[0325] FTIR (pure, cm) -1 ) 2924 [ν(C=C)], 1720 [ν(C=O)], 1439 [ν(C=O)], 1045 [ν(OTMS)].

[0326] 1 H NMR (400 MHz, CDCl3) δ 9.64 (t, J = 2.0 Hz, 1H, H8), 5.50 (qt, J =1.2, 6.4 Hz, 1H, 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, H 15 ), 0.14 (s, 9H, OSi Me3 ).

[0327] 13 C NMR (100 MHz, CDCl3) δ 200.0, 130.2, 128.9, 59.3, 54.2, 17.3, -0.3.

[0328] HRMS (ESI) for C9H 19 O2Si + [M+H] + Calculated value: 187.1154; Measured value: 187.1159.

[0329] Example 4. Synthesis of (Z)-iodoolefin 14

[0330]

[0331] Methyllithium (MeLi, 3.1 M diethoxymethane solution, 75 mL, 232 mmol) was added dropwise to a CH2Cl2 (380 mL) solution of compound 9 (38.0 g, 174 mmol) at -78 °C (dry ice-acetone bath). After stirring the reaction mixture for 2 hours, the reaction was quenched with a saturated NH4Cl aqueous solution (150 mL) while maintaining an internal temperature below -65 °C. The solution was heated to 25 °C, diluted with water (400 mL), and stirred for another 5 minutes. The organic matter was extracted once with CH2Cl2 (400 mL), and the combined organic phases were washed with water (200 mL) and brine (200 mL), dried over MgSO4, and concentrated under vacuum. The resulting crude product (m = 25.5 g) containing methyl ketone 13 as the main component could be used for the next reaction without further purification (the crude mixture...). 1 ¹H NMR analysis showed that it contained 1, 9, and a diketone in a molar ratio of 1:0.08:0.07. Figure 3 (As shown).

[0332] At 4 °C (ice-water bath), sodium bis(trimethylsilyl)amino (NaHMDS, 2 M THF solution, 76 mL, 152 mmol) was added dropwise to (iodomethyl)triphenylphosphonium iodide [prepared from triphenylphosphine and diiodomethane (Seyferth, D. et al.)] under light-protected conditions (flask covered with aluminum foil). J. Organomet. Chem. [1966, 5, 267-274] 80.0 g, 151 mmol] in a THF (700 mL) solution. The solution was stirred for 30 minutes and then cooled to -78 °C (dry ice-acetone bath). A THF (75 mL) solution of crude product 13 (25.5 g) was added dropwise to the mixture, and the mixture was stirred at the same temperature for 30 minutes, then heated to 0 °C (ice-water bath). The reaction was quenched with a saturated NH4Cl aqueous solution (100 mL), and the solids were removed by filtration through a diatomaceous earth pad. The filtrate was diluted with water (600 mL) and Et2O (600 mL) to separate the aqueous phase. The organic phase was extracted once with Et2O (400 mL), and the combined organic phases were dried over MgSO4 and concentrated under vacuum. The crude product was purified by rapid column chromatography (silica gel, hexane / EtOAc = 100:0 to 90:10) to give (Z)-iodoolefin 14 (25.8 g, 79.1 mmol, two-step 45% yield). The purified product... 1 1H NMR analysis showed that the purity of compound 14 was approximately 98%. Figure 4 ).

[0333] Appearance: Pale yellow oily substance.

[0334] TLC: R f = 0.5 (5% EtOAc / hexane).

[0335] [α]20 D +69.9° (C = 1, CHCl3).

[0336] FTIR (pure, cm) -1 ) 2989 [ν(C=C)], 1759 [ν(C=O)], 1207 [ν(CO)], 1103 [ν(CO)], 509 [ν(CI)].

[0337] 1 H NMR (400 MHz, CDCl3) δ 6.26 (q, J = 1.2 Hz, 1H, H3), 5.08 (d, J =8.4 Hz, 1H, H5), 4.20 (d, J = 8.4 Hz, 1H, H6), 3.80 (s, 3H, CO2 Me ), 1.93 (d, J = 1.2 Hz, 3H, H 14 ), 1.53 (s, 3H, Me 缩醛(酮) ), 1.52 (s, 3H, Me 缩醛(酮) ).

[0338] 13 C NMR (100 MHz, CDCl3) δ 170.6, 141.8, 112.2, 82.8, 79.0, 76.5, 52.9, 26.9, 26.0, 19.0.

[0339] HRMS (ESI) for C 10 H 16 IO4 + [M+H] + Calculated value: 327.0094; Measured value: 327.0090.

[0340] Example 5. Synthesis of Compound 15

[0341]

[0342] Diisobutylaluminum hydride (DIBAL, 1 M cyclohexane solution, 91 mL, 91 mmol) was added to a CH₂Cl₂ (260 mL) solution of compound 14 (25.8 g, 79.1 mmol) at -78 °C (dry ice-acetone bath), and the reaction mixture was stirred for 30 min at the same temperature. The reaction was then quenched with ethyl acetate (EtOAc, 30 mL) at -78 °C and diluted with a saturated Rochelle salt aqueous solution (500 mL). The mixture was heated to 25 °C and stirred for 3 h. The organic matter was extracted once with CH₂Cl₂ (400 mL), the combined organic phases were washed with brine (300 mL), dried over MgSO₄, and concentrated under vacuum. The resulting crude residue containing the corresponding aldehyde (m = 27.2 g) was used directly for the next reaction without further purification.

[0343] 1,4-diazabicyclo[2.2.2]octane (DABCO, 22.2 g, 198 mmol) was added to a solution of the crude aldehyde in methyl acrylate (540 mL, 5.96 mol). The reaction mixture was stirred for 40 hours at 25 °C in the dark (flask wrapped with aluminum foil). The reaction was quenched with saturated NH4Cl aqueous solution (500 mL) and diluted with CH2Cl2 (600 mL). The organic compound was extracted twice with CH2Cl2 (300 mL), and the combined organic extracts were dried over MgSO4 and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAC = 90:10 to 80:20) to give compound 15 (22.6 g, 59.1 mmol, 75% yield in two steps), a mixture of diastereomers (51:49).

[0344] The two diastereomers were partially separated by rapid column chromatography for characterization. Their C7 stereochemical configuration was not determined.

[0345] Major diastereomer 15 - major

[0346] Appearance: Pale yellow oily substance.

[0347] TLC: R f = 0.3 (20% EtOAc / hexane).

[0348] [α]20 D +5.2° (C = 1, CHCl3).

[0349] FTIR (pure, cm) -1) 3495 [ν(OH)], 2985 [ν(C=C)], 1712 [ν(C=O)], 1627 [ν(C=C)], 1242 [ν(CO)], 1060 [ν(CO)], 509 [ν(CI)].

[0350] 1 H NMR (400 MHz, CDCl3) δ 6.37 (dd, J = 0.8, 0.8 Hz, 1H, H 13a ), 6.26-6.25 (m, 1H, H3), 6.02 (dd, J = 0.8, 1.6 Hz, 1H, H 13b ), 5.00 (d, J = 8.8 Hz, 1H, H5), 4.56 (d, J = 9.6 Hz, 1H, H7), 4.05 (dd, J = 8.8, 2.0 Hz, 1H, H6),3.76 (s, 3H, CO2 Me ), 2.84 (d, J = 9.6 Hz, 1H, O H ), 1.92 (d, J = 1.6 Hz, 3H,H 14 ), 1.50 (s, 3H, Me 缩醛(酮) ), 1.46 (s, 3H, Me 缩醛(酮) ).

[0351] 13 C NMR (100 MHz, CDCl3) 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.

[0352] HRMS (ESI) for C 13 H 20 IO5 + [M+H] + Calculated value: 383.0355; Measured value: 383.0355.

[0353] Secondary diastereomer 15 - minor

[0354] Appearance: Pale yellow oily substance.

[0355] TLC: R f = 0.3 (20% EtOAc / hexane).

[0356] [α]20 D +24.6° (C = 1, CHCl3).

[0357] FTIR (pure, cm) -1 ) 3483 [ν(OH)], 2986 [ν(C=C)], 1712 [ν(C=O)], 1632 [ν(C=C)], 1242 [ν(CO)], 1060 [ν(CO)], 509 [ν(CI)].

[0358] 1 H NMR (400 MHz, CDCl3) δ 6.30 (s, 1H, H 13a ), 6.22 – 6.18 (m, 2H, H 13b +H3), 4.79 (d, J = 8.4 Hz, 1H, H5), 4.74 (dd, J = 4.4, 4.4 Hz, 1H, H7), 4.32(dd, J = 8.4, 4.4 Hz, 1H, H6), 3.76 (s, 3H, CO2 Me ), 3.04 (d, J = 4.4 Hz, 1H,O H ), 1.86 (d, J = 1.2 Hz, 3H, H 14 ), 1.46 (s, 6H, Me 缩醛(酮) ).

[0359] 13 C NMR (100 MHz, CDCl3) 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.

[0360] HRMS (ESI) for C 13 H 20 IO5 + [M+H] + Calculated value: 383.0355; Measured value: 383.0356.

[0361] Example 6. Synthesis of Compound 16

[0362]

[0363] Compound 15 (14.0 g, 36.6 mmol) was dissolved in hydrobromic acid (48% HBr aqueous solution, Sigma Aldrich-268003, 125 mL) and EtOAc (125 mL), and the reaction mixture was stirred at 25 °C for 16 hours. The solution was diluted with water (500 mL) and EtOAC (500 mL), and the separated organic phase was washed with water and brine and dried over MgSO4. The solvent was removed under vacuum to obtain a crude product, which was purified by rapid column chromatography (silica gel, hexane / EtOAc = 90:10 to 70:30) to give an inseparable mixture of compounds 16 and 16' (8.80 g). 1 ¹H NMR analysis showed a molar ratio of 85:15 (55% yield of 16 and 10% yield of 16'). Diisopropyl ether ( i Treatment of the mixture of compounds 16 and 16' with Pr2O precipitates compound 16, thus separating compound 16 (6.10 g, 16.4 mmol). The mixture of compounds 16 and 16' obtained from the filtrate was used to convert compound 16' to MOM ether 17', thereby confirming the structure of compound 16' (see Example 8).

[0364] Appearance: White solid.

[0365] Melting point: 112 °C.

[0366] TLC: R f = 0.2 (30% EtOAc / hexane).

[0367] [α]20 D +77.0° (C = 1, CHCl3).

[0368] FTIR (pure, cm) -1 ) 3437 [ν(OH)], 2985 [ν(C=C)], 1764 [ν(C=O)], 1745 [ν(C=C)], 1265 [ν(C–Br)], 1076 [ν(C–O)], 632 [ν(C-Br)].

[0369] 1 H NMR (400 MHz CDCl3) δ 7.34 (dt, J= 1.6, 1.6 Hz, 1H, H7), 6.26 (q, J = 1.2 Hz, 1H, H3), 5.05 (ddt, J = 6.4, 1.6, 1,6 Hz, 1H, H6), 4.65 (d, J =6.4 Hz, 1H, H5), 4.12 (dd, J = 1.6, 1.6 Hz, 2H, H 13 ), 2.53 (s, 1H, O H ), 2.00(d, J = 1.2 Hz, 3H, H 14 ).

[0370] 13 C NMR (100 MHz, CDCl3) δ 170.6, 149.3, 144.1, 132.5, 83.2, 78.4,77.2, 20.7, 20.2.

[0371] HRMS (ESI) for C9H 11 BrIO3 + [M+H] + Calculated value: 372.8936; Measured value: 372.8944.

[0372] Example 7. Synthesis of Compound 17

[0373]

[0374] At 25 °C, trifluoromethanesulfonic acid (TfOH, TCI-T0751, 740 µL, 8.40 mmol) was added dropwise to a solution of compound 16 (15.7 g, 42.1 mmol) in dimethoxymethane (700 mL). The mixture was stirred for 2 hours and then diluted with 700 mL of water and 500 mL of diethyl ether. After separation of the aqueous phase, the organic matter was extracted twice with Et2O (500 mL x 2). The combined extracts were dried over MgSO4 and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (silica gel, hexane / EtOAc = 100:0 to 80:20) to give compound 17 (14.0 g, 33.6 mmol, 80% yield). From diisopropyl ether ( iCompound 17 was recrystallized from diethyl ether (Et2O) and diethyl ether (Pr2O) to obtain single crystals, which were characterized by X-ray crystallography to confirm their structure and stereochemical configuration (CCDC-2312148). Figure 5 ).

[0375] Table 1. X-ray crystallographic data of compound 17 (CCDC-2312148)

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382] Appearance: Pale yellow solid / colorless crystals after recrystallization.

[0383] Melting point: 114 °C.

[0384] TLC: R f = 0.4 (30% EtOAc / hexane).

[0385] [α]20 D +92.2° (C = 1, CHCl3).

[0386] FTIR (pure, cm) -1 ) 2924 [ν(C=C)], 1755 [ν(C=O)], 1616 [ν(C=C)], 1280 [ν(C-Br)], 1064 [ν(CO)], 621 [ν(C-Br)].

[0387] 1 H NMR (400 MHz, CDCl3) δ 7.31 (dt, J = 1.2, 1.2 Hz, 1H, H7), 6.35-6.33 (m, 1H, H3), 5.11 (ddt, J = 6.0, 1.2, 1.2 Hz, 1H, H6), 4.67 (d, J = 6.0Hz, 1H, H5), 4.59 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 4.55 (d, J = 6.8 Hz, 1H,O CH2 OCH3), 4.12 (dd, J = 1.2. 1.2 Hz, 2H, H 13 ), 3.39 (s, 3H, OCH2O CH3 ), 1.95(d, J = 1.2 Hz, 3H, H 14 ).

[0388] 13 C NMR (100 MHz, CDCl3) δ 170.6, 149.1, 143.0, 132.7, 94.9, 82.1, 80.0, 79.8, 56.2, 20.8, 20.7.

[0389] HRMS (ESI) for C 11 H 15 BrIO4 + [M+H] + Calculated value: 416.9198; Measured value: 416.9196.

[0390] Example 8. Synthesis of compound 17'

[0391]

[0392] At 25 °C, the filtrate containing compounds 16 and 16' (1.50 g, molar ratio approximately 1:1) obtained in Example 6 was treated with TfOH (125 mL) in dimethoxymethane (50 mL) to give a mixture of MOM ethers 17 and 17'. They could be separated by rapid column chromatography (silica gel, hexane / EtOAc = 95:5 to 70:30) (the yield of this process was not determined). From diisopropyl ether ( i Compound 17' was recrystallized from (-Pr₂O) to obtain a single crystal, which was characterized by X-ray crystallography to confirm its structure and stereochemistry (CCDC-2312149). Figure 6 ).

[0393] Table 2. X-ray crystallographic data of compound 17' (CCDC-2312149)

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400] Appearance: White solid / colorless crystals after recrystallization.

[0401] Melting point: 92 °C.

[0402] TLC: R f = 0.45 (30% EtOAc / hexane).

[0403] [α]20 D +160.1° (C = 1, CHCl3).

[0404] FTIR (pure, cm) -1 ) 2951 [ν(C=C)], 1714 [ν(C=O)], 1614 [ν(C=C)], 1236 [ν(C-Br)], 1111 [ν(CO)], 650 [ν(C-Br)].

[0405] 1 H NMR (400 MHz, CDCl3) δ 7.12 (dt, J = 6.0, 1.2 Hz, 1H, H7), 6.17(qd, J = 1.6 Hz, 1H, H3), 5.27 (d, J = 3.2 Hz, 1H, H5), 4.63 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 4.61 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 4.46 (dd, J = 6.0, 3.2 Hz,1H, H6), 4.28 (dd, J = 11.6, 1.2 Hz, 2H, H 13a ), 4.16 (dd, J = 11.6, 1.2 Hz, 2H, H 13b ), 3.33 (s, 3H, OCH2O CH3 ), 2.10 (d, J = 1.6 Hz, 3H, H 14 ).

[0406] 13 C NMR (100 MHz, CDCl3) δ 161.9, 143.7, 140.7, 131.7, 96.5, 83.8,75.8, 66.9, 55.9, 27.4, 22.3.

[0407] HRMS for C 11 H 15 BrIO4 + [M+H] + Calculated value: 416.9198; Measured value: 416.9203.

[0408] Example 9. Synthesis of Compound 18

[0409]

[0410] Crude aldehyde 12 (from Example 3, 9.45 g, about 50.7 mmol, about 1.95 equivalents) was added to a DMF (180 mL) solution of compound 17 (10.8 g, 26.0 mmol), followed by a DMF (110 mL) solution of chromium chloride (CrCl2, Sigma Aldrich-450782, 8.95 g, 72.8 mmol) at 10 °C (ice-water bath). The reaction mixture was heated to 25 °C and stirred for 3 hours. The mixture was diluted with a saturated aqueous solution of NH4Cl (600 mL) and p-toluenesulfonic acid (494 mg, 2.60 mmol). The mixture was stirred for 30 minutes until the TMS ether intermediate was completely eliminated (as monitored by TLC: R of the silyl ether intermediate in 30% EtOAc / hexane). f Value = 0.35). The organic matter was extracted three times with EtOAc (400 mL × 3), and the combined organic phases were washed with saturated NH4Cl aqueous solution (400 mL) and brine (400 mL), dried over MgSO4, and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 50:50 to 20:100) to give compound 18 (9.22 g, 20.4 mmol) in 79% yield (dr = > 99:1).

[0411] Appearance: Pale yellow oily substance.

[0412] TLC: Rf = 0.25 (70% EtOAc / Hexane).

[0413] [α]20 D +61.5° (C = 1, CHCl3).

[0414] FTIR (neat, cm -1 ) 3402 [ν(O-H)], 2928 [ν(C=C)], 1759 [ν(C=O)], 1662 [ν(C=C)], 1276 [ν(C-O)], 1018 [ν(C-O)].

[0415] 1 1H NMR (400 MHz CDCl3) δ 6.38 (d, J = 2.4 Hz, 1H, H 13a ), 6.28 (qd, J =1.6, 0.8 Hz, 1H, H3), 5.76 (d, J = 2.0 Hz, 1H, H 13b ), 5.55 (t, J = 6.8 Hz, 1H,H1), 4.62 (dd, J = 4.8, 2.4 Hz, 1H, H6), 4.56 (d, J = 6.8 Hz, 1H, O CH2 OCH3),4.53 (d, J = 4.8 Hz, 1H, H5), 4.50 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 4.18 (d, J =6.8 Hz, 1H, H2), 3.91 – 3.81 (m, 1H, H8), 3.39 (s, 3H, OCH2O CH3 ), 3.14 – 3.06(m, 1H, H7), 2.29 (dd, 13.6, 3.2 Hz, 1H, H 9b ), 2.20 – 2.10 (dd, 13.6, 3.2, 1H,H 9a ), 2.12 (br s, 1H, O H ), 1.94 (d, J = 1.6 Hz, 3H, H[[ID=5^0]] 14), 1.70 (s, 3H, H 15 ).

[0416] 13 C NMR (100 MHz, CDCl3) 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.

[0417] HRMS (ESI) for C 17 H 26 IO6 + [M+H] + Calculated value: 453.0774; Measured value: 453.0775. Figure 7 ).

[0418] Example 10. Synthesis of Compound 19

[0419]

[0420] Manganese dioxide (MnO2, 21.1 g, 243 mmol) was added to a CH2Cl2 (380 mL) solution of compound 18 (11.0 g, 24.3 mmol), and the suspension was stirred at 25°C for 3 hours. Solids were removed by filtration through a diatomaceous earth mat, and the filtrate was concentrated under vacuum. The resulting crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 70:30 to 30:70) to give compound 19 (9.32 g, 20.7 mmol) in 85% yield.

[0421] Appearance: Pale yellow oily substance.

[0422] TLC: R f = 0.25 (50% EtOAc / hexane).

[0423] [α]20 D +130.6° (C = 1, CHCl3).

[0424] FTIR (pure, cm) -1 ) 3441 [ν(OH)], 2947 [ν(C=C)], 1766 [ν(C=O)], 1666 [ν(C=O)], 1273 [ν(CO)], 1122 [ν(CO)].

[0425] 1H NMR (400 MHz CDCl3) δ 9.98 (d, J = 8.0 Hz, 1H, H2), 6.41 (d, J =2.0 Hz, 1H, H 13a ), 6.29 (s, 1H, H3), 5.97 (d, J = 8.0 Hz, 1H, H1), 5.78 (d, J =2.0 Hz, 1H, H 13b ), 4.61 (dd, J = 4.4, 2.0 Hz, 1H, H6), 4.55 (d, J = 6.8 Hz,1H, O CH2 OCH3), 4.53 (d, J = 4.4 Hz, 1H, H5), 4.49 (d, J = 6.8 Hz, 1H,O CH2 OCH3), 4.00 – 3.92 (m, 1H, H8), 3.38 (s, 3H, OCH2O CH3 ), 3.09 (dddd, J =2.0, 2.0, 2.0, 2.0 Hz, 1H, H7), 2.57 (d, J = 4.4 Hz, 1H, O H ), 2.45 (dd, J =14.0, 3.2 Hz, 1H, H 9a ), 2.37 (dd, J = 14.0, 10.0 Hz, 1H, H 9b ), 2.23 (s, 3H,H 15 ), 1.94 (d, J = 1.6 Hz, 3H, H 14 )。

[0426] 13 C NMR (100 MHz, CDCl3) 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。

[0427] HRMS (ESI) for C 17 H 24 IO6 + [M+H] + Calculated value: 451.0618; Measured value: 451.0617.

[0428] Example 11. Synthesis of Compound 20

[0429] Anhydrous chromium chloride (CrCl2, 2.46 g, 20.0 mmol) was slowly dissolved in anhydrous dimethyl sulfoxide (DMSO, 950 mL, degassed by argon for 30 min before use) at 4 °C (ice-water bath) to avoid violent exothermic reactions. A degassed anhydrous DMSO (40 mL) solution of compound 19 (2.25 g, 5.00 mmol) was added, followed by a degassed anhydrous DMSO (10 mL) solution of nickel(II) acetylacetonate (Ni(acac)2, 25.7 mg, 0.04 mmol). The mixture was stirred at 25 °C for 16 h (the reaction progress was monitored by LC-MS, see Note 3, Figure 8 and Table 3). The reaction mixture was diluted with saturated aqueous NH4Cl solution (1 L) and brine (1 L), and stirred at 25 °C for 30 min. Organic compounds were extracted seven times from the separated aqueous phases using EtOAC (500 mL × 7), and the combined organic phases were washed with brine (1 L). The residual organic compounds in the brine phase were extracted once with EtOAc (500 mL × 1), and the combined organic phases were dried over MgO4 and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, CH2Cl2 / EtOAc ester = 50:50 to 0:100) to give compound 20 (820 mg, 2.55 mmol) in 51% yield (dr = > 99:1). Compound 20 was recrystallized from diethyl ether (Et2O) and dichloromethane (CH2Cl2) to obtain single crystals, which were characterized by X-ray crystallography (CCDC-2312151). Figure 9 ).

[0430] Note 1: Anhydrous chromium chloride (CrCl2) from several different suppliers (Sigma Aldrich-450782, TCI-C3788 and Fluorochem-101514) were tested, and no significant differences in reactivity were observed (see Table 4 for optimized reaction conditions).

[0431] Note 2: Adding brine to the aqueous phase helps in the extraction of compound 20.

[0432] Note 3: LC-MS monitoring of the reaction process revealed the formation of an organochromium compound. This compound could be protonated by an LC column to form the reduced olefin intermediate 19-H, which was detected by mass spectrometry as [M+Na]. + = 347.1 ( Figure 8 19-H gradually transforms into cyclized product 20, while simultaneously generating byproducts. Based on mass spectrometry data ([M+Na)... + = 671.3), we speculate that the byproduct may be a dimer (19-dimer) produced by the intermolecular NHK reaction.

[0433] Table 3. LC-MS monitoring of reaction progress

[0434]

[0435] Table 4. Optimization of Reaction Conditions

[0436]

[0437]

[0438] Table 5. X-ray crystallographic data of compound 20 (CCDC-2312151)

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445] Appearance: White solid / colorless crystals after recrystallization.

[0446] Melting point: 124 °C.

[0447] TLC: R f = 0.25 (70% EtOAc / CH2Cl2).

[0448] [α]20 D +132.6° (C = 1, CHCl3).

[0449] FTIR (pure, cm) -1) 3381 [ν(O-H)], 2914 [ν(C=C)], 1728 [ν(C=O)], 1651 [ν(C=C)], 1267[ν(C-O)], 1020 [ν(C-O)]。

[0450] 1 H NMR (400 MHz CDCl3) δ 6.40 (dd, J = 2.4, 0.8 Hz, 1H, H 13a ), 5.91(dd, J =2.4, 0.8 Hz, 1H, H 13b ), 5.81 (d, J = 7.2 Hz, 1H, H1), 5.74 (qd, J =1.2, 6.8 Hz, 1H, H3), 5.17 (s, 1H, H5), 4.91-4.86 (br m, 1H, H2), 4.51 (s, 2H,O CH2 OCH3), 3.93 (d, J = 2.8 Hz, 1H, H6), 3.77 (dddd, J = 10.8, 10.0, 5.2, 4.0Hz, 1H, H8), 3.30 (s, 3H, OCH2O CH3 ), 2.91 (dddd, J = 10.0, 2.8, 2.4, 2.4 Hz,1H, H7), 2.67 (dd, J = 12.4, 4.0 Hz, 1H, H 9b ), 2.40 (dd, J = 12.4, 10.8 Hz,1H, H 9a ), 2.21 (d, J = 4.4 Hz, 1H, O H ), 1.97 (d, J = 5.2 Hz, 1H, O H ), 1.79 (d, J = 1.2 Hz, 3H, H 14 ), 1.63 (s, 3H, H 15 )。

[0451] 13C NMR (100 MHz, CDCl3) 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.

[0452] HRMS (ESI) for C 17 H 25 O6 + [M+H] + Calculated value: 325.1651; Measured value: 325.1644.

[0453] Sources of diastereoselectivity: As shown in Figure 10, the alkenyl chromium species 19-Cr can be obtained via C... 7-8 Bond rotation results in two conformations: a 19-Cr major conformation and a 19-Cr minor conformation. The 19-Cr major conformation has a C8 linker opposite in orientation to the α-ethylidene-γ-butyrolactone moiety, leading to a nucleophilic attack of the alkenylchromium species from the top face of the C2 carbonyl group, generating compound 20. On the other hand, the 19-Cr minor conformation (which may lead to another stereoisomer of compound 20) suffers from severe steric hindrance between the C8 linker and the α-ethylidene-γ-butyrolactone moiety, thus exhibiting an energy disadvantage.

[0454] Example 12. Synthesis of Compound 21

[0455]

[0456] At 25 °C, manganese dioxide (MnO2, 3.36 g, 38.7 mmol) was added to a CH2Cl2 (40 mL) solution of compound 20 (1.25 g, 3.87 mmol), and the suspension was stirred for 3 hours. The solid was removed by filtration through a diatomaceous earth mat, and the filtrate was concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, CH2Cl2 / EtOAc = 80:20 to 50:50) to give compound 21 (1.01 g, 3.14 mmol) in 81% yield.

[0457] Appearance: Pale yellow oily substance.

[0458] TLC: R f = 0.3 (50% EtOAc / CH2Cl2).

[0459] [α]20 D +136.5° (C = 1, CHCl3).

[0460] FTIR (neat, cm -1 ) 3518 [ν(O-H)], 2945 [ν(C=C)], 1755 [ν(C=O)], 1643 [ν(C=O)], 1633 [ν(C=C)], 1070 [ν(C-O)].

[0461] 1 1H NMR (400 MHz, CDCl3) δ 6.45 (d, J J = 2.8 Hz, 1H, H 13a ), 6.20 (s, 1H,H1), 6.06 (s, 1H, H3), 5.98 (d, J J = 2.8 Hz, 1H, H 13b ), 5.39 (s, 1H, H5), 4.53(d, J J = 6.8 Hz, 1H, O CH2 OCH3), 4.48 (d, J J = 6.8 Hz, 1H, O CH2 OCH3), 4.16 (d, J J = 2.8 Hz, 1H, H6), 3.93 (dddd, J J = 10.8, 10.8, 4.2, 3.8 Hz, 1H, H8), 3.31 (s,3H, OCH2O CH3 ), 3.02 (dddd, J J = 10.8, 2.8, 2.8, 2.8 Hz, 1H, H7), 2.79 (dd, J J =12.4, 3.8 Hz, 1H, H 9b ), 2.47 (dd, J J = 12.4, 10.8 Hz, 1H, H 9a ), 2.29 (d, J J =4.2 Hz, 1H, O H ), 1.99 (d, J J = 1.6 Hz, 3H, H 14 ), 1.73 (s, 3H, H 15 ).

[0462] 13C NMR (100 MHz, CDCl3) 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.

[0463] HRMS (ESI) for C 17 H 22 O6Na + [M+Na] + Calculated value: 345.1314; Measured value: 345.1310.

[0464] Example 13. Synthesis of Compound 22

[0465]

[0466] Methacrylic anhydride (560 µL, 3.74 mmol) was added to a solution of compound 21 (1.00 g, 3.11 mmol), triethylamine (Et3N, 1.3 mL, 9.3 mmol), and 4-dimethylaminopyridine (DMAP, 75.9 mg, 0.62 mmol) in tetrahydrofuran (THF, 30 mL), and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with CH2Cl2 (80 mL) and 0.1 M HCl aqueous solution (80 mL). The organic matter was extracted twice from the separated aqueous phase with dichloromethane (CH2Cl2, 40 mL × 2), the combined organic phases were dried over MgSO4, and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 70:30 to 50:50) to give compound 22 (1.02 g, 2.62 mmol) in 84% yield.

[0467] Appearance: Pale yellow oily substance.

[0468] TLC: R f = 0.3 (50% EtOAc / hexane).

[0469] [α]20 D +162.9° (C = 1, CHCl3).

[0470] FTIR (pure, cm) -1) 2954 [ν(C=C)], 1769 [ν(C=O)], 1717 [ν(C=O)], 1643 [ν(C=C)], 1269 [ν(C-O)], 1155 [ν(C-O)]。

[0471] 1 H NMR (400 MHz, CDCl3) δ 6.36 (d, J = 2.4 Hz, 1H, H 13a ), 6.23 (s, 1H,H1), 6.16 (qd, J = 1.2, 1.2 Hz, 1H, H 18a ), 6.08 (q, J = 1.2 Hz, 1H, H3), 5.78(d, J = 2.4 Hz, 1H, H 13b ), 5.67 (qd, J = 1.2, 1.2 Hz, 1H, H 18b ), 5.41 (s, 1H,H5), 5.23 (ddd, J = 10.8, 10.8, 4.0 Hz, 1H, H8), 4.55 (d, J = 6.8 Hz, 1H,O CH2 OCH3), 4.49 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 4.25 (d, J = 3.2 Hz, 1H, H6),3.32 (s, 3H, OCH2O CH3 ), 3.28 (dddd, J = 10.8, 3.2, 2.4, 2.4 Hz, 1H, H7), 2.78(dd, J = 12.4, 4.0 Hz, 1H, H 9b ), 2.53 (dd, J = 12.4, 10.8 Hz, 1H, H 9a ), 2.01(d, J = 1.2 Hz, 3H, H 14 ), 1.96 (dd, J = 1.2, 1.2 Hz, 3H, H 19 ), 1.79 (s, 3H,H15 ).

[0472] 13 C NMR (100 MHz, CDCl3) 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.

[0473] HRMS (ESI) for C 21 H 27 O7 + [M+H] + Calculated value: 391.1757; Measured value: 391.1759.

[0474] Example 14. Synthesis of hygroscopicin (1)

[0475]

[0476] MOM ether 22 (1.02 g, 2.62 mmol) was treated in trifluoroacetic acid (CF3CO2H) and CH2Cl2 (1:1 v / v, 30 mL), and the mixture was stirred at 25°C for 4 hours. The reaction was slowly quenched with a saturated aqueous solution of NaHCO3 (150 mL), and the organic matter was extracted three times from the separated aqueous phase with CH2Cl2 (50 mL × 3). The combined organic phases were dried over MgSO4 and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 80:20 to 40:60) to give leucotrodin 1 (690 mg, 1.99 mmol) in 76% yield.

[0477] Appearance: White solid.

[0478] Melting point: 217 °C.

[0479] TLC: R f = 0.2 (50% EtOAc / hexane).

[0480] [α]20 D +158.2° (C = 1, CHCl3).

[0481] FTIR (pure, cm) -1) 3437 [ν(O-H)], 2924 [ν(C=C)], 1759 [ν(C=O)], 1730 [ν(C=O)], 1697 [ν(C=O)], 1639 [ν(C=C)], 1263 [ν(C-O)]。

[0482] 1 H NMR (400 MHz, CDCl3) δ 6.38 (d, J = 2.8 Hz, 1H, H 13a ), 6.22 (s, 1H,H1), 6.15 (s, 1H, H 18a ), 6.02 (s, 1H, H3), 5.84 (d, J = 2.0 Hz, 1H, H 13b ), 5.68(s, 1H, H 18b ), 5.46 (d, J = 12.0 Hz, 1H, H5), 5.24 (ddd, J = 10.8, 10.8, 4.0Hz 1H, H8), 4.25 (d, J = 4.0 Hz, 1H, H6), 3.40 (dddd, J = 10.8, 4.0, 2.4, 2.0Hz, 1H, H7), 2.78 (dd, J = 12.0, 4.0 Hz, 1H, H 9a ), 2.51 (dd, J = 12.0, 10.8Hz, 1H, H 9b ), 2.39 (d, J = 12.0 Hz, 1H, O H ), 2.02 (s, 3H, H 14 ), 1.96 (s, 3HH 19 ), 1.80 (s, 3H, H 15 )。

[0483] 13C NMR (100 MHz, CDCl3) δ 195.3 (C2), 169.5 (C12), 165.7 (C16), 159.2(C4), 137.0 (C10), 135.8 (C17), 133.5 (C1), 133.2 (C11), 129.3 (C3), 128.3(C13), 126.7 (C18), 81.4 (C6), 73.8 (C5), 72.5 (C8), 49.6 (C7), 45.5 (C9), 20.2 (C14), 19.0 (C15), 18.4 (C19).

[0484] HRMS for C 19 H 23 O6 + [M+H] + Calculated value: 347.1495; Measured value: 347.1490.

[0485] ( Figure 11 ).

[0486] Example 15. Synthesis of Compound 23

[0487]

[0488] Sodium borohydride (NaBH4, 585 µL, 0.155 mmol, 10 mg / mL MeOH solution) was added to a MeOH (2 mL) solution of compound 20 (50 mg, 0.154 mmol) at 0 °C (ice-water bath), and the reaction mixture was stirred for 0.5 h at the same temperature. The mixture was quenched with saturated NH4Cl aqueous solution (2 mL) and diluted with brine (20 mL). The organic matter was extracted three times from the aqueous phase with EtOAC (20 mL × 3). The combined organic phases were dried over MgSO4 and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, CH2Cl2 / EtOAc = 50:50 to 0:100) to give compound 23 (37 mg, 0.113 mmol) in 73% yield. Compound 23 was spontaneously crystallized from deuterated chloroform (CDCl3) to obtain a colorless single crystal, which was analyzed by X-ray crystallography (CCDC-2312152). Figure 12 ).

[0489] Table 6. X-ray crystallographic data of compound 23 (CCDC-2312152)

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496] Appearance: White solid / colorless crystals after recrystallization.

[0497] Melting point: 158 °C.

[0498] TLC: R f = 0.25 (70% EtOAc / CH2Cl2).

[0499] [α]20 D +38.5° (C = 1, CHCl3).

[0500] FTIR (pure, cm) -1 ) 3439 [ν(OH)], 2918 [ν(C=C)], 1755 [ν(C=O)], 1643 [ν(C=C)], 1273 [ν(CO)], 1018 [ν(CO)].

[0501] 1 H NMR (400 MHz, CDCl3) δ 5.80 (d, J = 7.6 Hz, 1H, H1), 5.73 (d, J =6.8 Hz, 1H, H3), 5.29 (s, 1H, H5), 4.91-4.83 (br m, 1H, H2), 4.60 (d, J = 6.8Hz, 1H, O CH2 OCH3), 4.56 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 3.91 – 3.82 (m, 1H, H8), 3.84 (d, J = 5.2 Hz, 1H, H6), 3.44 (s, 3H, OCH2O CH3 ), 2.72 (qd, J = 7.2, 7.2Hz, 1H, H11 ), 2.62 (dd, J = 12.0, 3.2 Hz, 1H, H 9b ), 2.37 (dd, J = 12.0, 12.0Hz, 1H, H 9a ), 2.06 (ddd, J = 5.2, 7.2, 10.0 Hz, 1H, H7), 1.89 (d, J = 6.4 Hz, O H ), 1.77 (s, 3H, H 14 ), 1.62 (s, 3H, H 15 ), 1.41 (d, J = 7.2 Hz, 3H, H 13 ).

[0502] 13 C NMR (100 MHz, CDCl3) 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.

[0503] HRMS for C 17 H 26 O6Na + [M+Na] + Calculated value: 349.1627; Measured value: 349.1630.

[0504] Example 16. Synthesis of Compound 24

[0505]

[0506] At 25°C, MnO2 (80 mg, 0.92 mmol) was added to a CH2Cl2 (2 mL) solution of compound 23 (30 mg, 0.092 mmol), and the reaction suspension was stirred for 3 hours. Solids were removed by filtration through a diatomaceous earth filter, and the filtrate was concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, CH2Cl2 / EtOAc = 80:20 to 50:50) to give compound 24 (23 mg, 0.071 mmol) in 77% yield.

[0507] Appearance: Colorless oily substance.

[0508] TLC R f = 0.3 (50% EtOAc / CH2Cl2).

[0509] [α]20 D +84.6° (C = 1, CHCl3).

[0510] FTIR (neat, cm -1 ) 3458 [ν(O-H)], 2938 [ν(C=C)], 1768 [ν(C=O)], 1643 [ν(C=O)], 1633 [ν(C=C)], 1238 [ν(C–O)], 1192 [ν(C-O)], 1018 [ν(C-O)].

[0511] 1 1H NMR (400 MHz, CDCl3) δ 6.18 (s, 1H, H1), 6.06 (s, J = 1H, H3), 5.53(s, 1H, H5), 4.63 (d, J = 6.8 Hz, 1H, O CH2 OCH3), 4.52 (d, J = 6.8 Hz, 1H,O CH2 OCH3), 4.04 (d, J = 5.6 Hz, 1H, H6), 4.05 – 3.96 (m, 1H, H8), 3.45 (s, 3H,OCH2O CH3 ), 2.78 – 2.70 (m, 2H, H 11 +H 9b ), 2.45 (dd, J = 12.0, 11.2 Hz, 1H, H 9a ),2.18 (ddd, J = 10.4, 6.8, 5.6 Hz, 1H, H7), 2.11 (d, J = 5.2 Hz, 1H, O H ), 1.99(d, J = 1.6 Hz, 3H, H 14 ), 1.71 (s, 3H, H 15 ), 1.43 (d, J = 7.6 Hz, 3H, H 13).

[0512] 13 C NMR (100 MHz, CDCl3) 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.

[0513] HRMS for C 17 H 24 O6Na + [M+H] + Calculated value: 347.1471; Measured value: 347.1472.

[0514] Example 17. Synthesis of Tomenphantopin F (2)

[0515]

[0516] MOM ether 24 (20 mg, 0.062 mmol) was dissolved in CF3CO2H and CH2Cl2 (1:1 v / v, 2 mL), and the mixture was stirred at 25 °C for 3 hours. The reaction was quenched with saturated NaHCO3 aqueous solution (50 mL), and the organic matter was extracted three times from the separated aqueous phase with EtOAc (20 mL × 3). The combined organic phases were dried over MgSO4 and concentrated under vacuum. The crude residue was purified by rapid column chromatography (silica gel, CH2Cl2 / EtOAc = 70:30 to 10:90) to give tomenphantopin F (2) (13 mg, 0.046 mmol) in 74% yield.

[0517] Appearance: White solid.

[0518] Melting point: 184 °C.

[0519] TLC: R f = 0.3 (70% EtOAc / CH2Cl2).

[0520] [α]20 D +34.8° (C = 1, MeOH).

[0521] FTIR (pure, cm) -1) 3388 [ν(OH)], 2949 [ν(C=C)], 1753 [ν(C=O)], 1631 [ν(C=O)], 1203 [ν(CO)], 1018 [ν(CO)]

[0522] 1 H NMR (400 MHz; d 4) δ 6.31(s,1H,H1), 5.92(s,1H,H3), 5.56(s,1H,H5), 4.08(d, J = 5.4 Hz, 1H, H6), 3.97 (ddd, J = 10.8, 10.8, 4.0 Hz, 1H, H8, 2.73 (qd, J = 7.6, 6.0 Hz 1H, H 11 ), 2.68 (dd, J = 12.0, 4.0 Hz, 1H,H 9a ), 2.42 (dd, J = 12.0, 10.8 Hz, 1H, H 9b ), 2.21 (ddd, J = 10.8, 6.0, 5.4 Hz, 1H, H7, 2.01 (d, J = 1.2 Hz, 3H, H 14 ), 1.69 ( s , 3H , H 15 ), 1.36 (d, J = 7.6 Hz,3H,H 13 )。 。

[0523] 13 C NMR (100 MHz; d 4) 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 for C5 andC8), 57.7(C7), 49.8(C9), 40.6 (C11), 21.0 (C14), 18.6 (C15), 18.4 (C13).

[0524] HRMS and C 15 H 20O5Na + [M+H] + Calculated value: 303.1208; Measured value: 303.1205.

[0525] (Figure 13).

[0526] Example 18. Synthesis of Compound 25—Photoinduced cycloisomerization of hygroscopicin (1)

[0527]

[0528] Gluconin (1) (50 mg, 0.144 mmol) was dissolved in degassed CH2Cl2 (5 mL, purged with argon for 30 min), and the solution was irradiated with 370 nm light (40 W × 2) for 100 min at room temperature (29 °C, fan cooled) (see Figure 14). The solvent was removed under vacuum to give compound 25 (50 mg, yield >99%), which was pure enough to be characterized and used in the next reaction.

[0529] Note 1: Compound 25 is unstable on silica gel.

[0530] Note 2: Through CDCl3 1 H NMR spectroscopy monitoring of this photochemical reaction showed the rapid formation of multiple intermediates with different olefin peaks, which gradually transformed into 25 ( Figure 16 ).

[0531] Appearance: Pale yellow oily substance.

[0532] TLC: R f = 0.4 (50% EtOAc / hexane).

[0533] [α]20 D +42.2° (C = 1, CHCl3).

[0534] FTIR (pure, cm) -1 ) 3441 [ν(OH)], 2924 [ν(C=C)], 1767 [ν(C=O)], 1713 [ν(C=O)], 1658 [ν(C=C)], 1273 [ν(CO)], 1153 [ν(CO)], 1033 [ν(CO)].

[0535] 1 H NMR (400 MHz, CDCl3) δ 6.32 (d, J = 3.2 Hz, 1H, H 13a), 6.16 (q, J =0.8 Hz, 1H, H 18a ), 5.79 (d, J = 2.8 Hz, 1H, H 13b ), 5.78-5.75 (m, 1H, H3), 5.71(q, J = 0.8 Hz, 1H, H 18b ), 5.58 (s, 1H, H1), 5.26 (d, J = 4.0 Hz, 1H, H5), 5.24(ddd, J = 10.8, 4.4, 2.0 Hz, 1H, H8), 4.65 (dd, J = 6.0, 4.0 Hz, 1H, H6), 3.77(dd, J = 14.4, 2.0 1H, H 9b ), 3.13 (dddd, J = 10.8, 6.0, 3.2, 2.8 Hz, 1H, H7),2.83 (s, 1H, O H ), 2.23 (dd, J = 14.4, 4.4 Hz, 1H, H 9a ), 1.99 (dd, J = 0.8, 0.8Hz, 3H, H 19 ), 1.78 (s, 3H, H 15 ), 1.72 (qd, J = 0.8, 0.8 Hz, 3H, H 14 )。

[0536] 13 C NMR (100 MHz, CDCl3) 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)。

[0537] HRMS for C 19 H 23 O6 + [M+H] + Calculated value: 347.1495; Measured value: 347.1490.

[0538] (Figure 17).

[0539] Example 19. Synthesis of EM-2 (3)

[0540]

[0541] p-Toluenesulfonic acid (TsOH·H2O, 160 µL, 8.4 µmol, 10 mg / mL MeOH solution) was added to a MeOH (1 mL) solution of compound 25 (30 mg, 0.087 mmol), and the reaction mixture was stirred at 25 °C for 10 min. The solvent was removed under vacuum, and the crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 95:5 to 70:30) to give EM-2 (3) (29 mg, 0.081 mmol) in 93% yield. From diisopropyl ether ( i Compound 3 was recrystallized from Pr2O to obtain a single crystal, which was characterized by X-ray crystallography to confirm its structure and stereochemistry (CCDC-2324191, Figure 18).

[0542] Table 7. X-ray crystallographic data of EM-2 (3) (CCDC-2324191)

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549] Appearance: White solid / colorless crystals after recrystallization.

[0550] Melting point: 102 °C.

[0551] TLC: R f = 0.4 (20% EtOAc / hexane).

[0552] [α]20 D +48.6° (C = 1, CHCl3).

[0553] FTIR (neat, cm -1 ) 2928 [ν(C=C)], 1767 [ν(C=O)], 1713 [ν(C=O)], 1659 [ν(C=C)], 1635 [ν(C=C)], 1273 [ν(C-O)], 1153 [ν(C-O)], 1092 [ν(C-O)], 1045 [ν(C-O)].

[0554] 1 1H NMR (400 MHz, CDCl3) δ 6.32 (d, J J = 3.2 Hz, 1H, H 13a ), 6.16 (qd, J J=1.2, 1.2 Hz 1H, H 18a ), 5.79 (d, J J = 2.8 Hz, 1H, H 13b ), 5.71 (qd, J J = 1.2, 1.2Hz, 1H, H 18b ), 5.63 (qd, J J = 1.6, 1.6 Hz, 1H, H3), 5.49 (s, 1H, H1), 5.26 –5.21 (m, 2H, H8+H5), 4.66 (dd, J J = 6.4, 4.0 Hz, 1H, H6), 3.73 (qd, J J = 1.2,14.4 Hz, 1H, H 9b ), 3.22 (s, 3H, O CH3 ), 3.15 (dddd, J J = 11.2, 6.4, 3.2, 2.8 Hz,1H, H7), 2.23 (dd, J J = 14.4, 4.4 Hz, 1H, H 9a ), 1.99 (dd, J J = 1.2, 1.2 Hz, 3H,H 19 ), 1.78 (d, J J = 1.2 Hz, 3H, H 15 ), 1.74 (dd, 3H,J = 1.6, 0.8 Hz, H 14 ).

[0555] 13 C NMR (100 MHz, CDCl3) 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 (O Me ), 39.1 (C7), 32.8 (C9), 28.7 (C15), 18.6 (C19), 13.3 (C14).

[0556] HRMS for C 20 H 25 O6 + [M+H] + Calculated value: 361.1651; Measured value: 361.1651.

[0557] (Figure 19).

[0558] Example 20. Synthesis of Vantomol (4)

[0559]

[0560] Gluconin (1) (50 mg, 0.144 mmol) was dissolved in degassed CH2Cl2 (0.5 mL) and irradiated at 29 °C with 370 nm light (40 W × 2, 4 cm) for 100 min. The solvent was removed under vacuum, and the residue was dissolved in EtOH (2 mL), followed by the addition of p-toluenesulfonic acid (TsOH·H2O, 160 µL, 8.4 µmol, 10 mg / mL EtOH solution). After stirring at 25 °C for 10 min, the solvent was removed under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (silica gel, hexane / EtOAc = 95:5 to 70:30) to obtain vaprolin (4) (46 mg, 0.123 mmol), with a yield of 85%.

[0561] Appearance: Colorless oily substance.

[0562] TLC: R f= 0.4 (20% EtOAc / Hexane).

[0563] [α]20 D +55.2° (C = 1, CHCl3).

[0564] FTIR (neat, cm -1 ) 2924 [ν(C=C)], 1771 [ν(C=O)], 1717 [ν(C=O)], 1659 [ν(C=C)], 1635 [ν(C=C)], 1273 [ν(C-O)], 1153 [ν(C-O)], 1092 [ν(C-O)], 1045 [ν(C-O)].

[0565] 1 1H NMR (400 MHz, CDCl3) δ 6.32 (d, J = 3.2 Hz, 1H, H 13a ), 6.16 (s, 1H,H 18a ), 5.79 (d, J = 2.8 Hz, 1H, H 13b ), 5.70 (qd, J = 1.6, 1.6 Hz, 1H, H 18b ),5.66 (qd, J = 1.6, 1.6 Hz, 1H, H3), 5.50 (s, 1H, H1), 5.26 – 5.21 (m, 2H, H8+H5), 4.64 (dd, J = 6.0, 4.0 Hz, 1H, H6), 3.74 (qd, J = 1.6, 14.4 Hz, 1H, H 9b ),3.54 – 3.41 (m, 2H, O CH2 CH3), 3.15 (dddd, J = 11.6, 6.0, 3.2, 2.8 Hz, 1H, H7),2.22 (dd, J = 14.4, 4.4 Hz, 1H, H 9a ), 1.99 (s, 3H, H 19 ), 1.78 (d, J = 1.6 Hz,3H, H 15 ), 1.73 (s, 3H, H 14 ), 1.20 (t,J = 7.2 Hz, 3H, OCH2 CH3 ).

[0566] 13 C NMR (100 MHz, CDCl3) 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 (O CH2 CH3), 39.1 (C7), 32.8 (C9), 28.8 (C15), 18.6 (C19), 15.6 (OCH2 CH3 ), 13.3 (C14).

[0567] (Figure 20)

[0568] Example 21.2- O Synthesis of -demethylated tomenphantopin C(5)

[0569]

[0570] Sodium methoxide (MeONa, 50 µL, 9.3 μmol, 10 mg / mL MeOH solution: MeONa powder was prepared fresh from MeONa and MeOH) was added to a MeOH (1 mL) solution of compound 25 (30 mg, 0.087 mmol), and the reaction mixture was stirred at 25 °C for 3 h. 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 under vacuum. The crude residue was purified by rapid column 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.

[0571] Appearance: White solid.

[0572] Melting point: 272 °C (decomposes).

[0573] TLC: R f= 0.4 (50% EtOAc / Hexane).

[0574] [α]20 D -15.1° (C = 1, CHCl3).

[0575] FTIR (neat, cm -1 ) 3444 [ν(O-H)], 2924 [ν(C=C)], 1782 [ν(C=O)], 1713 [ν(C=O)], 1666 [ν(C=C)], 1635 [ν(C=C)], 1296 [ν(C-O)], 1165 [ν(C-O)], 1034 [ν(C-O)].

[0576] 1 1H NMR (400 MHz, CDCl3) δ 6.11 (qd, J = 1.6, 1.6 Hz, 1H, H 18a ), 5.72(qd, J = 1.6, 1.6 Hz, 1H, H 18b ), 5.66 (qd, J = 1.6, 1.6 Hz, 1H, H3), 5.57 (s,1H, H1), 5.27 (ddd, J = 11.2, 4.0, 1.6 Hz, H8), 5.24 (dd, 1H, J = 4.4, 1.6 Hz,H5), 4.58 (dd, J = 7.6, 4.4 Hz, 1H, H6), 3.82 (qd, J = 1.2, 14.4 Hz, 1H, H 9β ),3.76 (dd, J = 9.2, 2.4 Hz, 1H, H 13a ), 3.42 (dd, J = 9.2, 2.8 Hz, 1H, H 13b ),3.30 (s, 3H, O CH3 ), 2.81 (ddd, J = 11.2, 9.2, 7.6 Hz, 1H, H7), 2.78 (br s, 1H,O H ), 2.56 (ddd, J = 9.2, 2.8, 2.4 Hz, 1H, H11 ), 2.15 (dd, J = 14.4, 4.0 Hz,1H, H 9α ), 1.97 (dd, J = 1.6, 1.6 Hz, 3H, H 19 ), 1.79 (dd, J = 1.6, 0.8 Hz, 3H,H 14 ), 1.76 (d, J = 1.2 Hz, 3H, H 15 )。

[0577] 13 C NMR (100 MHz, CDCl3) 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。

[0578] 1 H NMR (400 MHz, CD3OD) δ 6.10 (qd, J = 1.2, 1.6 Hz, 1H, H 18a ), 5.72(qd, J = 1.6, 1.6 Hz, 1H, H 18b ), 5.70 (qd, J = 1.6, 1.2 Hz, 1H, H3), 5.52 (s,1H, 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, 1H, H6), 3.85 (qdd, J = 1.2, 2.4, 14.4 Hz, 1H,H 9b ), 3.73 (dd, J = 9.2, 2.4 Hz, 1H, H 13a ), 3.45 (dd, J = 9.2, 2.8 Hz, 1H,H 13b), 3.28 (s, 3H, O CH3 ), 2.83 (ddd, J = 10.8, 9.2, 7.6 Hz, 1H, H7), 2.72(ddd, J = 9.2, 2.8, 2.4 Hz, 1H, H 11 ), 2.16 (dd, J = 14.4, 4.4 Hz, 1H, H 9a ),1.96 (dd, J = 1.6, 1.2 Hz, 3H, H 19 ), 1.76 (dd, J = 1.6, 0.8 Hz, 3H, H 14 ), 1.74(d, J = 1.2 Hz, 1H, H 15 ).

[0579] 13 C NMR (100 MHz, CD3OD) δ 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 (O Me ), 48.2 (C11), 38.5 (C7), 33.5 (C9), 28.7 (C15), 18.6 (C19), 13.5 (C14).

[0580] HRMS for C 20 H 27 O7 + [M+H] + Calculated value: 379.1757; Measured value: 379.1773.

[0581] (Figure 21)

[0582] Example 22. Synthesis of Tomenphantopin C (6)

[0583]

[0584] Sodium methoxide (MeONa, 50 µL, 9.3 mmol, 10 mg / mL MeOH solution) was added to a MeOH (1 mL) solution of compound 25 (30 mg, 0.087 mmol), and the mixture was stirred at 25 °C for 3 hours. p-Toluenesulfonic acid (TsOH·H₂O, 32 µL, 16.8 mmol, 10 mg / mL MeOH solution) was added, and the mixture was stirred at 25 °C for 10 minutes. The solvent was then removed under vacuum, and the crude residue was purified by rapid column chromatography (silica gel, hexane / EtOAc = 95:5 to 80:20) to give tomenphantopin C(6) (26 mg, 0.066 mmol) in 76% yield. From diisopropyl ether ( i Compound 6 was recrystallized from -Pr₂O to obtain a single crystal, which was then subjected to X-ray crystallography analysis (CCDC-2312153). Figure 22 ).

[0585] Table 8. X-ray crystallographic data of Tomenphantopin C (6) (CCDC-2312153)

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] Appearance: White solid / colorless crystals after recrystallization.

[0593] Melting point: 272 °C (decomposes).

[0594] TLC: R f = 0.4 (30% EtOAc / hexane).

[0595] [α]20 D -27.0° (C = 1, CHCl3).

[0596] FTIR (pure, cm) -1) 2924 [ν(C=C)], 1778 [ν(C=O)], 1712 [ν(C=O)], 1664 [ν(C=C)], 1634 [ν(C=C)], 1265 [ν(C-O)], 1161 [ν(C-O)], 1037 [ν(C-O)]。

[0597] 1 H NMR (400 MHz, CDCl3) δ 6.11 (qd, J = 1.2, 1.2 Hz, H 18a ), 5.67 (qd, J = 1.2, 1.2 Hz, 1H, H 18b ), 5.58 (s, 1H, H3), 5.47 (s, 1H, H1), 5.28 (ddd, J =11.2, 4.4, 2.4 Hz, 1H, H8), 5.22 (d, J = 4.0 Hz, 1H, H5), 4.60 (dd, J = 8.0,4.0 Hz, 1H, H6), 3.82 – 3.73 (m, 2H, H 9b +H 13a ), 3.43 (dd, J = 9.6, 2.8 Hz, 1H,H 13b ), 3.30 (s, 3H, C 13 O CH3 ), 3.21 (s, 3H, C2O CH3 ), 2.87 – 2.78 (m, 1H, H7),2.57 (ddd, J = 8.8, 2.8, 2.8 Hz, 1H, H 11 ), 2.15 (dd, J = 14.4, 4.4 Hz, 1H,H 9a ), 1.97 (s, 3H, H 19 ), 1.82 (s, 3H, H 14 ), 1.77 (s, 3H, H 15 )。

[0598] 13C NMR (100 MHz, CDCl3) 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-O Me ), 49.6(C2-O Me ), 47.1 (C11), 37.4 (C7), 33.1 (C9), 28.6 (C15), 18.5 (C19), 13.3 (C14).

[0599] HRMS for C 21 H 29 O7 + [M+H] + Calculated value: 393.1913; Measured value: 393.1906.

[0600] (Figure 23)

[0601] Comparative Example 1

[0602] Table 9. Comparison of natural and synthetic hygroscopicin (1) (CDCl3)

[0603]

[0604]

[0605] Comparative Example 2

[0606] Table 10. Comparison of natural and synthetic tomenphantopin F (2) (CD3OD)

[0607]

[0608]

[0609] Comparative Example 3

[0610] Table 11. Comparison of natural and synthetic EM-2 (3) (CDCl3)

[0611]

[0612]

[0613] Comparative Example 4

[0614] Table 12. Comparison of natural and synthetic vastatin (4) (CDCl3)

[0615]

[0616]

[0617] Comparative Example 5

[0618] Table 13. Natural and Synthetic 2- O Comparison of -demethylated tomenphantopin C (5) (CD3OD)

[0619]

[0620]

[0621] Comparative Example 6

[0622] Table 14. Comparison of natural and synthetic tomenphantopin C (6) (CDCl3)

[0623]

[0624]

[0625] Comparative Example 7

[0626] Table 15. Comparison of natural and synthetic compound 25 (CDCl3)

[0627]

[0628]

[0629] Example 23. Retrosynthesis of hygroscopicin (1)

[0630] Our retrosynthetic method for tufted gentianin (1) begins with the construction of a highly strained, C(sp²)-rich ten-membered ring skeleton. This involves the Nozaki-Hiyama-Kishi (NHK) synthesis of an E-enal I linked to a Z-iodoalkene (A. Gil et al.). Chem. Rev.(2017, 117, 8420–8446) Macrocyclization, constructing C2-C3 bonds, followed by oxidation of the resulting secondary alcohol (Fig. 24). Stereoselective construction of the α-methylene-γ-butyrolactone moiety in compound I is achieved by constructing C7-C8 bonds via the Barbier allylation reaction of β,γ-unsaturated aldehyde II with optically active 3-bromomethyl-5H-furan-2-one III (DM Hodgson et al., Org. Lett. 2011, 13, 2594–2597). We envision that the preparation of aldehyde II can be initiated from commercially available trimethyl phosphonoacetate (7) and 4,4-dimethoxy-2-butanone (8), while 3-bromomethyl-5H-furan-2-one III is expected to be derived from the 2,3-... O -Isopropylidene-L-dimethyl tartrate (9) synthesis, thereby ensuring the potential scale-up of the developed synthetic route.

[0631] We first synthesized aldehyde II containing the C8-10-1-2 fragment (Figure 25A). This was achieved through three steps: (i) a Horner-Wadsworth-Emmons reaction of ketone 8 with phosphonoacetate 7 to give a trisubstituted alkene 10, which is an E / Z mixture (71:29); (ii) reduction of the ester moiety of 10 by DIBAL to give allyl alcohol 11, wherein the desired ester moiety is obtained from the alkene. E -11 can be obtained by silica gel column chromatography. Z -11 Separation; (iii) E-11 was treated with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the presence of 2,6-dimethylpyridine (H. Fujioka et al., J. Am. Chem. Soc. 2004, 126, 11800–11801) to obtain β,γ-unsaturated aldehyde 12 with a trimethylsilyl ether moiety. Since aldehyde 12 is unstable, it was used directly in the next step without purification (Fig. 25C). Meanwhile, from 2,3- O Starting with dimethyl isopropylidene-L-tartrate (9), an optically active 3-bromomethyl-5H-furan-2-one III was synthesized via a five-step reaction (Figure 25B). Methyl ketone 13 was constructed by nucleophilic substitution of one methoxycarbonyl group of compound 9 with MeLi, followed by a stereoselective Wittig iodoalkenylation reaction to yield the desired (Z)-iodoalkene 14 (purity >98%) (G. Stork & K. Zhao, Tetrahedron Lett.1989, 30, 2173–2174). This two-step reaction can be scaled up to tens of grams. After monohydride reduction of the ester moiety of compound 14 with diisobutylaluminum hydride (DIBAL), the resulting crude aldehyde was treated with methyl acrylate in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO) to give α-methylene-β-hydroxy ester 15, which is a mixture of insignificant diastereomers (D. Basavaiah et al., Chem. Rev. 2010, 110, 5447–5674). Following the scheme developed by Winssinger (R. Lagoutte et al., Tetrahedron (2018, 74, 6012–6021) Treatment of compound 15 with aqueous HBr solution yielded an optically active 3-bromomethyl-5H-furan-2-one 16 as the major product and 3-bromomethyl-5,6-dihydro-2H-pyran-2-one 16' as the minor component. After separating pure compound 16 by reprecipitation from diisopropyl ether, its free hydroxyl group was protected to a methoxymethyl ether to give compound 17.

[0632] After obtaining the two key fragment moieties, β,γ-unsaturated aldehyde 12 and 3-bromomethyl-5H-furan-2-one 17, a mixture of aldehyde 12 (approximately 2 equivalents) and ketone 17 was treated with chromium chloride (CrCl2) in dimethylformamide (DMF) to achieve their coupling via an intermolecular Barbier allylation reaction, yielding α-methylene-γ-butyrolactone 18 (dr > 99:1, at 400 MHz) with excellent selectivity and the desired stereochemistry at the C7 and C8 positions. 1 No other diastereomers were detected at the 1H NMR spectral scale (Fig. 25C). Acid-water posttreatment caused simultaneous deprotection of the C2-position trimethylsilyl ether. This stereochemical control can be reasonably explained by the Zimmerman-Traxler pseudochair transition state B between aldehyde 12 and the 17-derived allyl chromium species, where aldehyde 12 is primarily derived from sp... 2 The top surface of the hybrid C7 is close to, opposite to, the C5-C6 bond (HE Zimmerman & MD Traxler, J. Am. Chem. Soc.1957, 79, 1920–1923). Then, the C2-allyl moiety of compound 18 was chemiselectively oxidized with manganese dioxide (MnO2) to give α,β-unsaturated aldehyde 19. Extensive screening of NHK macrocyclization reaction conditions for compound 19 (see the examples above) showed that treatment of compound 19 with CrCl2 and Ni(acac)2 in DMSO (5 mM) at 25°C yielded the desired ten-membered macrocycle 20 in 51% yield, as a single diastereomer (dr > 99:1). The structure of compound 20 was clearly confirmed by single-crystal X-ray crystallography (see Example 11). The dielyl moiety of compound 20 was oxidized with manganese dioxide to give diene 21, followed by acylation of the remaining C8 hydroxyl group with methacrylic anhydride to give compound 22. Finally, the methoxymethyl ether at the C5 position was deprotected with trifluoroacetic acid (TFA) to obtain hygroscopicin (1), the spectral data of which were consistent with the reported values ​​(B. Wang et al., Chin. J. Chem. 2012, 30, 1320–1322).

[0633] Furthermore, we synthesized tomenphantopin F (2) using the ten-membered macrocyclic intermediate 20 (Figure 25D). Treatment of compound 20 with sodium borohydride (NaBH4) in MeOH enabled diastereoselective reduction of the ex-methylene moiety, yielding a single stereoisomer, α-(S)-methyl-γ-butyrolactone 23. The stereochemical configuration of compound 23 was verified by X-ray diffraction analysis (see Example 15). Subsequently, compound 23 was oxidized with MnO2 to successfully construct diene 24, followed by MOM deprotection with TFA to obtain tomenphantopin F (2).

[0634] Example 24. Method for converting hygroscopicin (1) into furanogelmalide lactone

[0635] Our next goal is to explore a method for converting gentianin (1) into furanogelmaline lactone. The hypothesized skeletal transformation can be achieved by isomerizing the (E,Z)-dienone moiety of compound 1 to (Z,Z)-dienone [(Z,Z)-1], followed by a hemiketalization reaction with the C5-hydroxy group, yielding 2-deethoxy-2β-hydroxyvantothromycin (25), a compound previously obtained from gentianin (Gentianin) Elephantopus mollis Separation of (PP-H. But et al.) Planta Med . 1996, 62, 474–476).

[0636] We investigated a similar photochemical diene isomerization reaction of leucovorin (1). Indeed, we observed a weak absorption band at λmax = 348 nm in the UV / Vis spectrum of leucovorin (1) in CH₂Cl₂ solution (0.5 mM), which was identified as the n-π junction of the diene partial carbonyl group. Transition (see the above examples) (VN Gutrov et al., J. Photochem. Photobiol. A 2022, 425, 113678). We found that irradiation of a degassed CH2Cl2 solution of compound 1 with ultraviolet A light (λmax = 370 nm) can generate multiple olefin isomers within minutes, which has been verified by... 1 ¹H NMR analysis confirmed the formation of dienone isomers (E,E)-1, (Z,E)-1, and (Z,Z)-1 under light equilibrium conditions. We observed that these dienone analogs could ultimately be converted to compound 25 in quantitative yield via hemiketalization of (Z,Z)-1.

[0637] Hemiketal 25 can serve as the main skeleton, and a series of other furanomeric lactones, such as EM-2(3) and vaprolin(4), can be synthesized by ketalization of compound 25 with the corresponding alcohol in the presence of a catalytic amount of p-toluenesulfonic acid (TsOH) (Figure 26). On the other hand, treatment of compound 25 in methanol with sodium methoxide (NaOMe) allows for chemoselective and diastereoselective addition of methanol to the p-methylene-γ-butyrolactone moiety, yielding 2- O -Demethylated tomenphantopin C (5). Subsequently, under alkaline reaction conditions, methanol was added to compound 25, and the solution was acidified to initiate a continuous C2 ketalization reaction to obtain tomenphantopin C (6).

[0638] Example 25. Stereoselective Synthesis Route

[0639] Figure 27 illustrates the synthetic route using MOM as an alcohol protecting group.

[0640] Example 26. Bromolactone synthon (Figure 28)

[0641]

[0642] 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). After stirring the mixture for 36 hours, the solvent was removed to obtain 234 g of (+)-L-tartaric acid dimethyl ester (yield = 99%). The crude product was ready for use without further purification.

[0643] TLC: R f = 0.2 (40% EtOAc / hexane).

[0644] [α]20 D +1.0° (C = 1, CHCl3).

[0645] FTIR (pure, cm) -1 ) 3458, 1748, 1439, 1277, 1240, 1128, 1090, 908, 735,650.

[0646] 1 H NMR (396 MHz, CDCl3) δ 4.59 (s, 2H), 3.86 (s, 6H).

[0647] 13 C NMR (100 MHz, CDCl3) δ 172.06, 72.21, 53.24.

[0648] HRMS for C6H 11 O6 + [M+H] + Calculated value: 179.0556; Measured value: 179.0557.

[0649]

[0650] p-Toluenesulfonic acid (PTSA) (1.6 g, 9 mmol) was added to a solution of (+)-L-dimethyl tartrate (20 g, 112 mmol) and 2,2-dimethoxypropane (80 mL, 672 mmol) in CH2Cl2 (280 mL). The mixture was refluxed for 4 hours and cooled to room temperature. The organic phase was washed with saturated sodium bicarbonate solution (NaHCO3sat), dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 95 / 5 to 60 / 40) to give 19.3 g of (-)-2,3- O -Dimethyl isopropylidene-L-tartrate 9(Yield = 79%).

[0651] TLC: R f = 0.3 (20% EtOAc / hexane).

[0652] [α]20 D -46° (C = 1, CHCl3).

[0653] FTIR (pure, cm) -1 ) 2994, 2957, 1759, 1375, 1254, 1211, 1161, 1113, 1014,858, 748.

[0654] 1 H NMR (396 MHz, CDCl3) δ 4.81 (s, 2H), 3.83 (s, 6H), 1.50 (s, 6H).

[0655] 13 C NMR (100 MHz, CDCl3) δ. 170.21, 114.00, 77.11, 52.94, 26.41.

[0656] HRMS for C9H 15 O6 + [M+H] + Calculated value: 219.0869; Measured value: 219.0863.

[0657]

[0658] At -78 °C, lithium methyl (60 mL, 180 mmol, 3 M DME solution) was added dropwise to dimethyl isopropylidene-L-tartrate 9 (24 g, 720 mmol) in CH₂Cl₂ (250 mL). The mixture was stirred for 2 hours and then quenched with saturated NH₄Cl solution. The mixture was heated to room temperature and stirred for 5 minutes. The aqueous phase was extracted with CH₂Cl₂, and the organic phases were combined, washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 95 / 5 to 60 / 40) to give 16.1 g of methyl ketone 13 (72% yield). Note the presence of an inseparable diketone.

[0659] TLC: R f = 0.3 (20% EtOAc / hexane).

[0660] [α]20 D -3.5° (C = 1, CHCl3).

[0661] FTIR (pure, cm) -1 ) 2993, 2954, 1759, 1724, 1439, 1377, 1358, 1254, 1211,1157, 1107, 1022, 860, 806, 737, 579, 513.

[0662] 1 H NMR (396 MHz, CDCl3) δ 4.74 (d, J = 5.6 Hz, 1H), 4.64 (d, J = 5.5Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H), 1.49 (d, J = 0.7 Hz, 3H), 1.46 (d, J =0.8 Hz, 3H).

[0663]

[0664] At 0 °C, NaHMDS (111 mL, 111 mmol, 1 M THF solution) was added dropwise to (iodomethyl)triphenylphosphonium iodide (58.8 g, 111 mmol) in THF (500 mL) and stirred for 30 minutes. The mixture was cooled to -78 °C, and then compound 13 (18.7 g, 92.5 mmol) was added dropwise. The mixture was stirred at -78 °C for 30 minutes, and then heated to 0 °C. The solution was then mixed with saturated ammonium chloride solution (NH4Cl). sat The reaction was quenched and diluted with Et2O. The aqueous phase was extracted with Et2O, the organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 60 / 40) to give 15.8 g of trisubstituted olefin 14 (yield 52%). Considering the presence of diketones in the starting material, the yield should be 70%.

[0665] TLC: R f = 0.6 (5% ether / hexane).

[0666] [α]20 D +69.9° (C = 1, CHCl3).

[0667] FTIR (pure, cm) -1) 3059, 2990, 2920, 2851, 1759, 1620, 1439, 1377, 1292,1258, 1207, 1165, 1103, 1057, 1026, 984, 887, 856, 806, 756, 694, 509.

[0668] 1 H NMR (396 MHz, CDCl3) δ 6.26 (dd, J = 1.5, 0.6 Hz, 1H), 5.08 (dd, J = 8.0, 0.6 Hz, 1H), 4.21 (d, J = 7.9 Hz, 1H), 3.80 (s, 3H), 1.93 (d, J = 1.5Hz, 3H), 1.53 (dd, J = 6.1, 0.7 Hz, 6H).

[0669] HRMS for C 10 H 16 IO4 + [M+H] + Calculated value: 327.0094; Measured value: 327.0090.

[0670]

[0671] At -78 °C, DIBAl-H (63 mL, 63 mmol, 1 M cyclohexane solution) was added to a CH2Cl2 (200 mL) solution of compound 14 (15.8 g, 48.5 mmol). The mixture was stirred at -78 °C for 1 hour, then quenched with EtOAc, followed by the addition of tartrate solution. The mixture was heated to room temperature and stirred for 2 hours, then filtered through diatomaceous earth. The aqueous phase was extracted with EtOAc, the organic phases were combined, washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum to give 15.7 g of aldehyde. The crude product was ready for use without further purification.

[0672] The sample partially decomposed on the silica gel.

[0673] TLC: R f = 0.3 (20% EtOAc / hexane).

[0674] [α]20 D +61.2° (C = 1, CHCl3).

[0675] FTIR (pure, cm) -1 ) 441, 3055, 2985, 2920, 1735,1618, 1438, 1377, 1285,1242, 1219, 1150, 1072, 1026, 887, 810, 783, 737, 702, 509.

[0676] 1 H NMR (396 MHz, CDCl3) δ 9.80 (d, J = 2.3 Hz, 1H), 6.23 (dd, J = 1.5, 0.7 Hz, 1H), 5.08 (dd, J = 7.9, 0.7 Hz, 1H), 4.08 (dd, J = 7.9, 2.3 Hz, 1H),1.95 – 1.92 (m, 3H), 1.54 (d, J = 0.7 Hz, 3H), 1.49 (d, J = 0.7 Hz, 3H).

[0677] 13 C NMR (100 MHz, CDCl3) δ 141.43, 133.40, 132.61, 132.60, 79.93, 63.54, 21.26.

[0678] HRMS for C9H 14 IO4 + [M+H] + Calculated value: 296.9988; Measured value: 296.9986.

[0679]

[0680] 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 at room temperature for 16 hours. The mixture was diluted with CH2Cl2 and saturated NH4Cl solution. The aqueous phase was extracted with CH2Cl2, and the organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 90 / 10 to 70 / 30) to give 10.7 g of compound 15 (two-step yield = 58%), characterized as a mixture of diastereomers.

[0681] diastereomer 1

[0682] TLC: R f = 0.3 (30% EtOAc / hexane)

[0683] HRMS for C 13 H 20 IO5 + [M+H] + Calculated value: 383.0355; Measured value: 383.0355.

[0684] diastereomer 2

[0685] TLC: R f = 0.3 (30% EtOAc / hexane).

[0686] HRMS for C 13 H 20 IO5 + [M+H] + Calculated value: 383.355; Measured value: 383.0356.

[0687]

[0688] Compound 15 (10.7 g, 28 mmol) was dissolved in HBr / EtOAc (1 / 1) (50 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and water. The organic phase was washed with H2O and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 90 / 10 to 70 / 30). The resulting yellow powder was ground in diisopropyl ether to give 5.2 g of compound 16 (yield = 50%).

[0689] TLC: R f= 0.2 (25% EtOAc / hexane).

[0690] [α]20 D +70.0° (C = 1, CHCl3).

[0691] FTIR (pure, cm) -1 ) 3437, 3082, 2916, 2357, 1748, 1643, 1431, 1350, 1277,1242, 1222, 1130, 1061, 1015, 957, 779, 676.

[0692] 1 H NMR (396 MHz CDCl3) δ 7.35 (d, J = 1.5 Hz, 1H), 6.26 (dd, J = 1.6, 0.7 Hz, 1H), 5.05 (dd, J = 6.3, 1.6 Hz, 1H), 4.66 (d, J = 6.3 Hz, 1H), 4.13(d, J = 1.4 Hz, 2H), 2.53 (s, 1H), 2.01 (d, J = 1.6 Hz, 3H).

[0693] 13 C NMR (100 MHz, CDCl3) δ 170.56, 149.35, 144.08, 132.52, 83.22, 78.39, 77.21, 20.71, 20.21.

[0694]

[0695] At room temperature, TfOH (330 µL, 3.75 mmol) was added dropwise to a solution of compound 16 (4 g, 10.7 mmol) in dimethoxymethane (150 mL), and the mixture was stirred for 2 hours. The mixture was diluted with Et2O and brine. The aqueous phase was extracted with Et2O, and the organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 80 / 20) to give 3.46 g of compound 17 (yield = 77%).

[0696] TLC: R f = 0.4 (25% EtOAc / hexane).

[0697] [α]20 D +92.2° (C = 1, CHCl3).

[0698] FTIR (pure, cm) -1 ) 3441, 3082, 2924, 2820, 1755, 1638, 1616, 1427, 1354,1281, 1211, 1150, 1096, 1065, 1015, 984, 922, 864, 779, 737, 679, 621.

[0699] 1 H NMR (396 MHz, CDCl3) δ 7.34 – 7.30 (m, 1H), 6.37 – 6.31 (m, 1H), 5.11 (ddd, J = 6.0, 1.7, 0.5 Hz, 1H), 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).

[0700] 13 C NMR (100 MHz, CDCl3) δ 170.56, 149.05, 143.03, 132.68, 94.92, 82.13, 79.98, 79.79, 56.20, 20.82, 20.67.

[0701] HRMS for C 11 H 15 BrIO4 + [M+H] + Calculated value: 416.9198; Measured value: 416.9196.

[0702] Example 27. Aldehyde synthon (Figure 29)

[0703]

[0704] At -20 °C, n-BuLi (183 mL, 275 mmol, 1.5 M hexane solution) was added dropwise to trimethyl phosphonoacetate 7 (50 g, 275 mmol) in THF (600 mL). After 30 minutes, 1,1-dimethoxypropyl-2-one 8 (40 g, 302 mmol) was added. The mixture was heated to 4 °C and stirred for 4 hours. The mixture was then heated to room temperature and stirred for 16 hours. The mixture was cooled to 4 °C and quenched with saturated NH4Cl solution. The aqueous phase was extracted twice with diethyl ether, and the organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 80 / 20) to give 41.5 g of compound 10 (yield = 80%), which was a mixture of diastereomers (E / Z ratio of 2.4 / 1), wherein the (E) isomers would be more easily separated in the next step.

[0705] Analysis of purified (E) isomer samples :

[0706] TLC: R f = 0.4 (10% EtOAc / hexane).

[0707] FTIR (pure, cm) -1 ) 2951, 2831, 1717, 1647, 1435, 1354, 1223, 1153, 1119,1080, 1065, 968, 918, 868, 814, 598.

[0708] 1 H NMR (396 MHz, CDCl3) δ 5.74 (q, J = 1.2 Hz, 1H), 4.54 (t, J = 5.7Hz, 1H), 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).

[0709] 13 C NMR (100 MHz, CDCl3) δ 167.08, 155.11, 117.95, 102.95, 53.19, 50.98, 44.08, 19.38.

[0710] HRMS for C9H14 O5 + [M+H] + Calculated value: 189.1127; Measured value: 189.1126.

[0711]

[0712] At 4 °C, DIBAl-H (530 mL, 530 mmol, 1 M cyclohexane solution) was added dropwise to a CH2Cl2 (800 mL) solution of compound 10 (41.5 g, 220 mmol) and stirred for 0.5 h. The mixture was carefully quenched with EtOAc + saturated NH4Cl solution, followed by the addition of tartrate solution. The mixture was heated to room temperature and stirred for 2 h. The aqueous phase was extracted with EtOAc, and the organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 80 / 20 to 50 / 50) to give 17.4 g of pure (E) configuration E-11 (yield = 49%).

[0713] TLC: R f = 0.3 (50% EtOAc / hexane).

[0714] FTIR (pure, cm) -1 ) 3410, 2920, 2835, 1666, 1447, 1366, 1296, 1234, 1188,1123, 1065, 1003, 964, 808, 567.

[0715] 1 H NMR (396 MHz, CDCl3) δ 5.51 – 5.43 (m, 1H), 4.49 (t, J = 5.8 Hz, 1H), 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, 1H).

[0716] 13 C NMR (100 MHz, CDCl3) δ 126.71, 103.42, 59.29, 52.86, 42.63, 16.86.

[0717] HRMS for C8H17 O3 + [M+H] + Calculated value: 161.1178; Measured value: 161.1180.

[0718]

[0719] At 4 °C, 2,6-dimethylpyridine (5 mL, 42.72 mmol) was added to E-11 (1.14 g, 7.12 mmol), followed by the dropwise addition of TMSOTf (5.2 mL, 28.46 mmol). The mixture was stirred at 4 °C for 30 min, then 33 mL of water was added, and the mixture was stirred again at 4 °C for 30 min. The mixture was diluted with CH2Cl2 and saturated NH4Cl solution. The organic phase was washed with water and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 95 / 5 to 70 / 30) to give 695 mg of compound 12 (yield = 52%).

[0720] TLC: R f = 0.5 (5% EtOAc / hexane).

[0721] FTIR (pure, cm) -1 ) 2924, 2837, 1720, 1663, 1439, 1385, 1096, 1045, 1007,880, 841, 779, 605.

[0722] 1 H NMR (396 MHz, CDCl3) δ 9.68 – 9.60 (m, 1H), 5.54 – 5.45 (m, 1H), 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).

[0723] 13 C NMR (100 MHz, CDCl3) δ 198.51, 128.66, 127.34, 57.76, 52.67, -1.81.

[0724] HRMS for C9H 19 O2Si + [M+H] + Calculated value: 187.1154; Measured value: 187.1159.

[0725] Example 28. Late-stage reaction sequence ( Figure 30 )

[0726]

[0727] At 10°C, a 30 mL solution of CrCl2 (2.65 g, 21.6 mmol) in DMF was added to a 50 mL solution of compound 17 (3.00 g, 7.19 mmol) and compound 12 (2.6 g, 14.0 mmol) in DMF. The mixture was heated to room temperature and stirred for 1 hour. The mixture was diluted with saturated NH4Cl solution and stirred at room temperature for 30 minutes. The aqueous phase was extracted three times with EtOAc, and the organic phases were combined, washed with saturated NH4Cl solution and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (CH2Cl2 / EtOAc = 70 / 30 to 20 / 80) to give 2.76 g of compound 18 (yield = 85%).

[0728] TLC: R f = 0.3 (70% EtOAc / hexane).

[0729] [α]20 D +51.3° (C = 1, CHCl3).

[0730] FTIR (pure, cm) -1 ) 3402, 2928, 2893, 2361, 1759, 1662, 1639, 1439, 1411,1277, 1238, 1153, 1099, 1061, 1018, 922, 818, 787, 733, 679.

[0731] 1 H NMR (396 MHz CDCl3) δ 6.37 (d, J = 2.0 Hz, 1H), 6.31 – 6.26 (m,1H), 5.76 (d, J = 1.7 Hz, 1H), 5.53 (t, J = 6.7 Hz, 1H), 4.63 (dd, J= 4.7,2.3 Hz, 1H), 4.58 – 4.46 (m, 3H), 4.15 (s, 2H), 3.85 (d, J = 3.7 Hz, 1H), 3.39 (s, 3H), 3.08 (dd, J = 5.3, 2.2 Hz, 1H), 2.80 (s, OH), 2.31 – 2.20 (m,1H+OH), 2.16 (d, J = 9.8 Hz, 1H), 1.94 (d, J = 1.4 Hz, 3H), 1.69 (s, 3H).

[0732] 13 C NMR (100 MHz, CDCl3) 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.

[0733] HRMS for C 17 H 26 IO6 + [M+H] + Calculated value: 453.0774; Measured value: 453.0775.

[0734]

[0735] MnO2 (2.88 g, 33.2 mmol) was added to a CH2Cl2 (30 mL) solution of compound 18 (1 g, 2.21 mmol) and stirred at room temperature for 4 hours. The mixture was filtered through diatomaceous earth to remove the solvent. The crude product was purified by rapid column chromatography (hexane / EtOAc = 80 / 20 to 50 / 50) to give 650 mg of compound 19 (yield = 71%).

[0736] TLC: R f = 0.3 (50% EtOAc / hexane).

[0737] [α]20 D +130° (C = 1, CHCl3).

[0738] FTIR (pure, cm) -1) 3441, 2947, 2924, 1767, 1666, 1439, 1408, 1273, 123,1068, 1018, 922, 818, 733, 698.

[0739] 1 H NMR (396 MHz CDCl3) δ 9.98 (d, J = 7.8 Hz, 1H), 6.41 (d, J = 2.0Hz, 1H), 6.32 – 6.24 (m, 1H), 5.97 (d, J = 7.8 Hz, 1H), 5.78 (d, J = 1.7 Hz, 1H), 4.61 (dd, J = 4.3, 2.2 Hz, 1H), 4.56 – 4.48 (m, 3H), 3.96 (d, J = 3.6Hz, 1H), 3.38 (s, 3H), 3.09 (dd, J = 5.8, 2.0 Hz, 1H), 2.57 (d, J = 4.3 Hz,1H), 2.48 – 2.35 (m, 2H), 2.23 (s, 3H), 1.94 (d, J = 1.3 Hz, 3H).

[0740] 13 C NMR (100 MHz, CDCl3) 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.

[0741] HRMS for C 17 H 24 IO6 + [M+H] + Calculated value: 451.0618; Measured value: 451.0617.

[0742]

[0743] A DMSO (5 mL) solution of compound 19 (700 mg, 1.55 mmol) was added to a DMSO (240 mL) solution of CrCl2 (1.15 g, 9.33 mmol), followed by the initial addition of Ni(acac)2 (12 mg, 0.016 mmol). The mixture was stirred at room temperature for 1 hour, followed by the addition of Ni(acac)2 (12 mg, 0.016 mmol). The mixture was stirred for 5 hours, diluted with EtOAc / saturated NH4Cl solution, and stirred at room temperature for 1 hour. The aqueous phase was extracted three times with EtOAc, and the organic phases were combined, washed with saturated NH4Cl solution and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (CH2Cl2 / EtOAc = 50 / 50 to 10 / 90) to give 245 mg of compound 20 (yield = 49%).

[0744] TLC: R f = 0.25 (70% EtOAc / CH2Cl2).

[0745] [α]20 D +132° (C = 1, CHCl3).

[0746] FTIR (pure, cm) -1 ) 3381, 2939, 2914, 2848, 2351, 1728, 1714, 1651, 1556,1267, 1153, 1099, 1064, 1020, 995, 918, 871, 815, 797, 732, 702, 615.

[0747] 1 H NMR (396 MHz CDCl3) 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 = 3.9Hz, 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).

[0748] 13 C NMR (100 MHz, CDCl3) 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.

[0749] HRMS for C 17 H 25 O6 + [M+H] + Calculated value: 325.1651; Measured value: 325.1644.

[0750]

[0751] MnO2 (964 mg, 11.1 mmol) was added to a 25 mL solution of compound 20 (240 mg, 0.74 mmol) in CH2Cl2 and stirred at room temperature for 3 hours. The mixture was filtered through diatomaceous earth to remove the solvent. The crude product was purified by rapid column chromatography (eluent: CH2Cl2 / EtOAc 80 / 20 to 50 / 50) to give 190 mg of compound 21 (yield = 80%).

[0752] TLC: R f = 0.3 (50% EtOAc / CH2Cl2).

[0753] [α]20 D +136° (C = 1, CHCl3).

[0754] FTIR (pure, cm) -1 ) 3518, 2945, 2922, 1755, 1633, 1608, 1435, 1381, 1269,1246, 1151, 1130, 1103, 1070, 1018, 933, 918, 815, 732, 704.

[0755] 1 H NMR (396 MHz, CDCl3) 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, 1H), 3.68 – 3.60 (m, 1H), 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).

[0756] 13 C NMR (100 MHz, CDCl3) 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.

[0757] HRMS for C 17 H 22 O6Na + [M+Na] + Calculated value: 345.1314; Measured value: 345.1310.

[0758]

[0759] Methacrylic anhydride (103 μL, 0.689 mmol) was added to a solution of compound 21 (185 mg, 0.574 mmol), Et3N (242 μL, 1.72 mmol), and DMAP (14 mg, 0.115 mmol) in THF (5 mL). The mixture was stirred at room temperature for 3 hours, and then the solvent was removed. The crude product was diluted with EtOAc and saturated NH4Cl solution. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 70 / 30 to 50 / 50) to give 170 mg of compound 22 (yield = 76%).

[0760] TLC: R f = 0.3 (50% EtOAc / hexane).

[0761] [α]20 D +163° (C = 1, CHCl3).

[0762] FTIR (pure, cm) -1 ) 2954, 2852, 1769, 1717, 1643, 1611, 1439, 1317, 1269,1155, 1111, 1076, 1020, 918, 814, 734, 702.

[0763] 1 H NMR (396 MHz, CDCl3) δ 6.35 (d, J = 2.4 Hz, 1H), 6.25 (s, 1H), 6.16(q, J = 1.1 Hz, 1H), 6.08 (d, J = 2.0 Hz, 1H), 5.81 – 5.76 (m, 1H), 5.70 –5.64 (m, 1H), 5.41 (s, 1H), 5.23 (td, J = 10.8, 3.9 Hz, 1H), 4.59 – 4.48 (m,2H), 4.25 (d, J = 3.2 Hz, 1H), 3.32 (d, J = 0.8 Hz, 4H), 2.76 (d, J = 3.9 Hz, 1H), 2.54 (t, J= 11.5 Hz, 1H), 2.03 – 2.00 (m, 3H), 1.99 – 1.95 (m, 3H), 1.79 (s, 3H).

[0764] 13 C NMR (100 MHz, CDCl3) δ 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.

[0765] HRMS for C 21 H 27 O7 + [M+H] + Calculated value: 391.1757; Measured value: 391.1759.

[0766]

[0767] Compound 22 (157 mg, 0.402 mmol) was dissolved in a CH2Cl2 / TFA (1 / 1, 5 mL) solution, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with NaHCO3 solution, and the aqueous phase was extracted twice with CH2Cl2. The organic phase was collected, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 80 / 20 to 40 / 60) to give 101 mg (+)-deltachophorin 1 (yield = 73%).

[0768]

[0769] TLC: R f = 0.2 (50% EtOAc / hexane).

[0770] [α]20 D +158.0° (C = 1, CHCl3).

[0771] FTIR (pure, cm) -1 ) 2955, 2924, 2851, 1759, 1730, 1697, 1639, 1462, 1377,1263, 1161, 1082, 1047, 743, 706.

[0772] 1H NMR (396 MHz, CDCl3) 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 = 6.2Hz, 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 = 0.6Hz, 3H, H18), 1.80 (d, J = 1.0 Hz, 3H, H15)。

[0773] 13 C NMR (100 MHz, CDCl3) 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)。

[0774] Table 16. 2D NMR correlation of compound 1

[0775]

[0776] 1 H- 1 H COSY related: (H9) a,b / H8), (H19 / H20), (H8 / H7), (H18 / H19 a,b ), (H7 / H6), (H3 / H14), (H1 / H15).

[0777] HMBC related: (C12 / H13) a,b ), (C16 / H18 / H19 a,b ), (C4 / H14), (C10 / H1 / H15), (C3 / H14), (C2 / H1), (C5 / H3 / H14), (C6 / H8), (C15 / H1 / H9), (C9 / H1 / H15), (C7 / H13 a,b ), (C17 / H18 / H19 a ).

[0778] NOESY related: (H5 / H1), (H6 / H15), (H5 / H7), (H6-H8).

[0779] HRMS for C 19 H 23 O6 + [M+H] + Calculated value: 347.1495; Measured value: 347.1490.

[0780] Analysis of 100g of hygroscopic gentianin

[0781]

[0782] TLC: R f = 0.2 (50% EtOAc / hexane).

[0783] [α]20 D +184.5 o (C = 1, CHCl3).

[0784] FTIR (pure, cm) -1) 3427, 3053, 2986, 2940, 1759, 1692, 1639, 1601, 1441,1265, 1238, 1138, 1084, 1047, 1022, 947, 914, 806, 737, 704.

[0785] 1 H NMR (396 MHz, CDCl3) δ 6.98 – 6.86 (m, 1H, H-19), 6.34 (s, 1H, H-13a), 6.22 (s, 1H, H-1), 6.01 (s, 1H, H-3), 5.81 (s, 1H, H-13b), 5.48 (s, 1H,H-5), 5.25 (dt, J = 10.8, 5.4 Hz, 1H, H-8), 4.25 (d, J = 3.6 Hz, 1H, H-6), 3.44 – 3.32 (m, 1H, H-7), 2.75 (dd, J = 12.1, 3.7 Hz, 2H, H-9a+OH), 2.49 (t, J = 11.5 Hz, 1H, H-9b), 2.02 (s, 3H, H-14), 1.90 – 1.82 (m, 6H, H-20+H-18), 1.79 (s, 3H, H-15).

[0786] 13 C NMR (100 MHz, CDCl3) 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).

[0787] Table 17. 2D NMR correlation of compound 100

[0788]

[0789] 1 H- 1 H COSY related: (H13) a,b / 7), (H19 / H20), (H8 / H7), (H8 / H9 a,b ), (H7 / H6), (H3 / H14), (H1 / H15).

[0790] HMBC related: (C12 / H13) a,b / H6), (C16 / H8), (C4 / H6), (C10 / H1 / H9 a,b ), (C3 / H14), (C20 / H19), (C2 / H1 / H15), (C5 / H3 / H14), (C6 / H8), (C8 / H6 / H13 a,b ), (C15 / H1 / H9), (C14H3), (C9 / H1 / H15), (C7 / H6 / H9 a,b / H13 a,b ).

[0791] NOESY related: (H5 / H1), (H6 / H15), (H9 / H15).

[0792] HRMS for C 20 H 25 O6 + [M+H] + Calculated value: 361.1652; Measured value: 361.1649.

[0793] Example 29. The Vantor Mother Spirit Family

[0794]

[0795] 10 mg of hygroscopicin 1 (0.029 mmol) was dissolved in 0.5 mL of CH2Cl2 and irradiated with 370 nM light (40 W, 4 cm) for 1 hour and 45 minutes. The solvent was removed under vacuum, and the crude product of compound 25 (10 mg, yield = 100%) was ready for use in the next step without further purification.

[0796] Analysis of purified samples

[0797]

[0798] TLC: R f= 0.4 (50% EtOAc / Hexane).

[0799] [α]20 D +42.2° (C = 1, CHCl3).

[0800] 1 1H NMR (400 MHz, C6D6) δ 6.27 (d, J = 2.9 Hz, 1H, H13 a ), 5.89 (s, 1H, H19 a ), 5.54 (d, J = 2.2 Hz, 1H, H13 b ), 5.43 (s, 1H, H1), 5.21 – 5.14 (m, 2H, H3 + H19 b ),, 5.09 (dd, J = 11.1, 2.3 Hz, 1H, H8), 4.91 (d, J = 3.6 Hz, 1H, H5), 4.00 (dd, J [[ID=​​​​​​​​​​​​​​​C 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).

[0802] Table 18. 2D NMR correlation of compound 25

[0803]

[0804] 1 H- 1 H COSY related: (H13) a,b / 7), (H19 a / H18), (H8, H7), (H8, H9 b ), (H5 / H6).

[0805] HMBC related: (C12 / H13) a,b ), (C16 / H19 a,b / H18), (C4 / H5 / H6 / H14), (C10 / H8 / H9 a,b / H15), (C3 / H5 / H14), (C1 / H15), (C2 / H1), (C5 / H7 / H14), (C6 / H14), (C8 / H13).

[0806] NOESY related: (H5 / H6), (H5 / H14), (H6 / H8), (H6 / H9) a ), (H1 / H15).

[0807] HRMS for C 19 H 23 O6 + [M+H] + Calculated value: 347.1495; Measured value: 347.1490.

[0808] 10 mg of daunogermina 100 (0.029 mmol) was dissolved in 0.5 mL of CH2Cl2 and irradiated with 370 nm light (40 W, 4 cm) for 1 hour and 45 minutes. The solvent was removed under vacuum, and the crude product 101 (10 mg, yield = 100%) was ready for use in the next step without further purification.

[0809]

[0810] TLC: R f = 0.4 (50% EtOAc / hexane).

[0811] 1 H NMR (396 MHz, C6D6) δ 6.73 (dq, J = 7.1, 1.5 Hz, 1H, H19), 6.29(dd, J = 3.2, 1.1 Hz, 1H, H13 a ), 5.57 (dd, J = 2.8, 1.1 Hz, 1H, H13 b ), 5.43(t, J = 1.3 Hz, 1H, H1), 5.18 – 5.10 (m, 2H, H3+H8), 4.92 – 4.88 (m, 1H, H5), 3.97 (dd, J = 6.2, 3.9 Hz, 1H, H6), 3.60 (ddd, J = 14.2, 2.2, 1.2 Hz, 1H,H9 a ), 3.04 – 2.97 (m, 1H, H7), 2.27 (s, 1H, OH), 2.16 (dd, J = 14.2, 4.5 Hz, 1H, H9 b ), 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, H2O).

[0812] 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).

[0813] Table 19. 2D NMR correlation of compound 101

[0814]

[0815] 1 H- 1 H COSY related: (H13) a,b / H7), (H19 / H18), (H19 / H20), (H8, H7), (H8,H9 b ), (H5 / H6), (H6 / H7), (H3 / H14), (H1 / H15).

[0816] HMBC related: (C12 / H6), (C16 / H19 / H18 / H8), (C4 / H5 / H6 / H3), (C10 / H8 / H9) a,b / H15), (C3 / H5 / H14), (C1 / H15 / H9 a,b ), (C2 / H1 / H3), (C5 / H6 / H14), (C8 / H6 / H9 b ), (C7 / H13 a,b / H5), (C9 / H1 / H15), (C15 / H9 a,b ), (C17 / H18 / H20).

[0817] NOESY related: (H5 / H6), (H1 / H8), (H6 / H9) a ).

[0818] HRMS for C 20 H 25 O6 + [M+H]+ Calculated value: 361.1651; Measured value: 361.1651.

[0819]

[0820] PTSA (50 mg, 0.29 mmol) was added to compound 25 (200 mg, 0.5 mmol) / EtOH (5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 80 / 0) to give 143 mg of vaprolin 4 (yield = 66%).

[0821] TLC: R f = 0.4 (30% EtOAc / hexane).

[0822] [α]20 D +55.2° (C = 1, CHCl3).

[0823] FTIR (pure, 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.

[0824] 1 H NMR (396 MHz, CDCl3) 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).

[0825] 13 C NMR (100 MHz, CDCl3) 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.

[0826] HRMS for C 21 H 27 O6 + [M+H] + Calculated value: 375.1808; Measured value: 375.1794.

[0827]

[0828] PTSA (25 mg, 0.15 mmol) was added to compound 25 (100 mg, 0.25 mmol) / MeOH (3 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 80 / 0) to give 68 mg of 2-deethoxy-2β-methoxyvantothromycin 3 (yield = 64%).

[0829] TLC: R f = 0.4 (30% EtOAc / hexane).

[0830] [α]20 D +48.6° (C = 1, CHCl3).

[0831] FTIR (pure, cm) -1) 2974, 2928, 2886, 1767, 1713, 1659, 1636, 1443, 1404,1381, 1273, 1153, 1092, 1045, 1011, 964,841, 818, 737, 683, 664, 610.

[0832] 1 H NMR (396 MHz, CDCl3) 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).

[0833] 13 C NMR (100 MHz, CDCl3) 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.

[0834] HRMS for C 20 H 25 O6 + [M+H] + Calculated value: 361.1651; Measured value: 361.1651.

[0835]

[0836] MeONa (19 mg, 0.35 mmol) was added to compound 25 (100 mg, 0.29 mmol) / MeOH (3 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 and saturated NH4Cl solution. The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 80 / 0) followed by GPC to give 54 mg of compound 5 (yield = 51%).

[0837] TLC: R f = 0.4 (50% EtOAc / hexane).

[0838] 1 H NMR (396 MHz, CDCl3) δ 6.95 – 6.81 (m, 1H), 5.74 – 5.67 (m, 1H), 5.55 (s, 1H), 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, 1H), 3.30 (s, 3H), 3.01 (s, 1H), 2.84 – 2.72(m, 1H), 2.56 (d, J = 8.9 Hz, 1H), 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).

[0839] 13 C NMR (100 MHz, CDCl3) 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.

[0840]

[0841] MeONa (0.8 mg, 0.015 mmol) was added to compound 24 (55 mg, 0.15 mmol) / MeOH (3 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was then converted to CH2C. l2 Dilute with saturated NH4Cl solution. Dry the organic phase with magnesium sulfate and remove the solvent under vacuum. Purify the crude product by rapid column chromatography (hexane / EtOAc = 100 / 0 to 80 / 0) to give 43 mg of compound 26 (yield = 72%).

[0842] Example 30. Racemic Synthesis Route (Figure 31)

[0843]

[0844] At -10 °C, methyl magnesium bromide (240 mL, 720 mmol) was added dropwise to propargyl alcohol (20.12 g, 360 mmol), copper iodide (68 g, 360 mmol), and diethyl ether (1.2 L). The mixture was heated to room temperature and stirred for 4 hours. After cooling the mixture to -5 °C, iodine (91 g, 360 mmol) in THF (400 mL) was added dropwise. The mixture was heated to room temperature and stirred for 16 hours. At 4 °C, the mixture was quenched with saturated NH4Cl solution and filtered through diatomaceous earth. The aqueous phase was extracted with diethyl ether, and the organic phases were combined, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 95 / 5 to 60 / 40) to give 44.8 g of trisubstituted olefin 50 (yield = 63%).

[0845] 1 H NMR (396 MHz, CDCl3) δ 5.98 (d, J = 1.4 Hz, 1H), 4.24 (s, 2H), 1.98(d, J = 1.5 Hz, 3H), 1.97 – 1.92 (m, 1H).

[0846] 13 C NMR (100 MHz, CDCl3) δ 146.20, 74.99, 68.24, 21.77.

[0847]

[0848] MnO2 (225 g, 2.59 mol) was added in portions to CH2Cl2 (1.2 L) containing compound 50 (51.2 g, 259 mmol) and stirred at room temperature until the starting material was completely dissolved (TLC monitoring, approximately 36 h). The mixture was filtered through diatomaceous earth and cooled at 4 °C. Phospho (86.5 g, 259 mmol) in CH2Cl2 (500 mL) was added dropwise, and the mixture was stirred at 4 °C for 30 min. The mixture was filtered through a silica gel pad and the solvent was removed under vacuum to give 60.09 g of compound 51 (crude product yield = 92%). This crude product was ready for use without further purification.

[0849] 1 H NMR (396 MHz, CDCl3) δ 7.64 (dt, J = 15.7, 0.7 Hz, 1H), 6.64 (d, J = 0.7 Hz, 1H), 6.05 (dq, J = 15.7, 0.6 Hz, 1H), 3.80 (s, 3H), 2.00 (d, J =1.3 Hz, 3H).

[0850] 13 C NMR (100 MHz, CDCl3) δ 167.35, 145.14, 140.99, 122.36, 88.41, 51.98, 21.10.

[0851]

[0852] At -78 °C, DIBAl-H (454 mL, 454 mmol, 1 M THF solution) was added to a CH2Cl2 (500 mL) solution of compound 51 (52 g, 206 mmol). The mixture was heated to 4 °C and stirred for 15 min. The mixture was cooled to -10 °C and quenched with tartrate solution. The mixture was warmed to room temperature and then diluted with EtOAC and tartrate solution. The aqueous phase was extracted with EtOAc, the organic phases were combined, washed with brine, dried over magnesium sulfate, and the solvent was removed under pressure to give 47 g of compound 52 (88% crude yield). This crude product was ready for use without further purification.

[0853] 1 H NMR (396 MHz, CDCl3) δ 6.64 (dd, J= 15.7, 1.7 Hz, 1H), 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, 1H).

[0854] 13 C NMR (100 MHz, CDCl3) δ 141.43, 133.40, 132.61, 132.60, 79.93, 63.54, 21.26.

[0855]

[0856] At 4 °C, a solution of TBSCl (31.5 g, 209 mmol) in CH₂Cl₂ (300 mL) was added dropwise to a solution of compound 52 (47 g, 209 mmol) and imidazole (21.4 g, 315 mmol) in CH₂Cl₂ (500 mL). The mixture was heated to room temperature and stirred for 1 hour. The mixture was diluted with 0.1 M HCl, and the organic phase was washed with 0.1 M hydrochloric acid and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was dissolved in a small amount of CH₂Cl₂ and filtered through a silica gel pad. The solvent was removed to give compound 53 (51.3 g, crude product yield 72%). This crude product could be used without further purification.

[0857] 1 H NMR (396 MHz, CDCl3) δ 6.74 – 6.61 (m, 1H), 6.09 (tq, J = 1.4, 0.7Hz, 1H), 6.00 – 5.92 (m, 1H), 4.32 – 4.29 (m, 2H), 1.96 (d, J = 1.2 Hz, 3H), 0.95 (s, 10H), 0.11 (s, 6H).

[0858] 13 C NMR (100 MHz, CDCl3) δ 141.61, 134.07, 131.02, 78.87, 63.52, 26.13, 25.80, 21.22, -5.04.

[0859]

[0860] Compound 53 (24 g, 70.94 mmol) was added dropwise to K2OsO2(OH)4 (1 g, 2.71 mmol) and NMO·H2O (9.14 g, 78.03 mmol, 50%). wt The mixture was dissolved in an aqueous solution of tBuOH / H2O (1 / 1, 500 mL). The mixture was stirred at room temperature for 24 hours. The mixture was quenched with sodium sulfite, stirred for 20 minutes, filtered through diatomaceous earth, and extracted three times with CH2Cl2. The organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 95 / 5 to 70 / 30) to give 18.1 g of compound 54 (yield = 68%).

[0861] 1 H NMR (396 MHz, CDCl3) δ 6.03 (dt, J = 2.1, 1.0 Hz, 1H), 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, 1H), 2.79 – 2.73 (m, 1H), 1.94 (d, J = 1.5 Hz, 3H), 0.92 (s, 10H), 0.11 (dd, J = 2.2, 1.2 Hz, 6H).

[0862] 13 C NMR (100 MHz, CDCl3) δ 147.12, 76.31, 75.58, 73.28, 65.28, 26.05, 20.56, 18.41, -5.21.

[0863]

[0864] Acetone (100 mL) was added to compound 54 (2.15 g, 5.77 mmol), PTSA (1.99 g, 1.55 mmol), and CuSO4 (1.84 g, 11.55 mmol), and the mixture was stirred at room temperature for 16 hours. NaHCO3 (2.13 g, 12.69 mmol) was added, and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the crude product was dissolved in CH2Cl2, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The crude product was purified by rapid column chromatography (hexane / EtOAc = 95 / 5 to 70 / 30) to give 1.08 g of compound 55 (yield = 63%).

[0865] 1 H NMR (396 MHz, CDCl3) δ 6.15 (dt, J = 1.5, 0.7 Hz, 1H), 4.82 (dd, J = 8.5, 0.7 Hz, 1H), 3.90 – 3.81 (m, 2H), 3.76 – 3.65 (m, 1H), 2.11 (t, J =6.3 Hz, 1H), 1.90 (d, J = 1.5 Hz, 3H), 1.46 (s, 6H).

[0866] 13 C NMR (100 MHz, CDCl3) δ 142.82, 110.08, 80.85, 79.72, 77.50, 61.88, 27.28, 27.23, 19.70.

[0867]

[0868] At -78°C, oxalyl chloride (1.97 mL, 22.98 mmol) was added dropwise to a solution of DMSO (2.5 mL, 35.36 mmol) in CH₂Cl₂ (80 mL). After stirring for 15 minutes, compound 55 (5.27 g, 17.68 mmol) was added dropwise, and the mixture was stirred for 15 minutes, followed by the addition of Et₃N (12.4 mL, 88.4 mmol). The mixture was heated to room temperature and stirred for 30 minutes. A hexane / Rt₂O (1 / 1) solution was added, and the mixture was filtered through a silica gel pad. The solvent was removed to give compound 56 (5.25 g, crude product >100%). This crude product was ready for use without further purification.

[0869]

[0870] DABCO (2.18 g, 19.45 mmol) was added to a methyl acrylate (60 mL) solution of compound 56 (5.23 g, 17.67 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 and saturated NH4Cl. The aqueous phase was extracted with CH2Cl2, and the organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 90 / 10 to 70 / 30) to give 3.86 g of compound 57 (overall yield = 57%), which was characterized as a mixture of diastereomers.

[0871]

[0872] Compound 57 (4.1 g, 0.060 mmol) was dissolved in HBr / EtOAc (1 / 1) (30 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and water. The organic phase was washed with H2O and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc 90 / 10 to 70 / 30) to give 2.03 g of compound 58 (yield = 51%).

[0873] 1 H NMR (396 MHz CDCl3) δ 7.35 (d, J = 1.5 Hz, 1H), 6.26 (dd, J = 1.6, 0.7 Hz, 1H), 5.05 (dd, J = 6.3, 1.6 Hz, 1H), 4.66 (d, J = 6.3 Hz, 1H), 4.13(d, J = 1.4 Hz, 2H), 2.53 (s, 1H), 2.01 (d, J = 1.6 Hz, 3H).

[0874] 13 C NMR (100 MHz, CDCl3) δ 170.56, 149.35, 144.08, 132.52, 83.22, 78.39, 77.21, 20.71, 20.21.

[0875]

[0876] At 4 °C, pyridinium p-toluenesulfonate (PPTS, 67 mg, 0.268 mmol) was added to a solution of compound 58 (1 g, 2.68 mmol) and 3,4-dihydro-2H-pyran (367 μL, 4.02 mmol) in 10 mL of CH2Cl2, and the mixture was stirred for 2 h 30 min. The mixture was diluted with brine, and the aqueous phase was extracted with CH2Cl2. The organic phases were combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 100 / 0 to 70 / 30) to give 1.11 g of compound 59 (yield = 90%) as a mixture of diastereomers.

[0877] 1 H NMR (396 MHz, CDCl3) 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, 1H), 3.68 – 3.60 (m, 1H), 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).

[0878] 13C NMR (100 MHz, CDCl3) 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.

[0879]

[0880] At 4°C, a DMF (5 mL) solution of compound 59 (449 mg, 0.982 mmol) and compound 12 (311 mg, 1.67 mmol) was added to a DMF (5 mL) solution of CrCl2 (338 mg, 2.75 mmol), and the mixture was heated to room temperature and stirred for 1 hour. The mixture was diluted with EtOAc and serine solution and stirred at room temperature for 30 minutes. The aqueous phase was extracted twice with EtOAc, and the organic phases were combined, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (hexane / EtOAc = 70 / 30 to 20 / 80) to give 299 mg of compound 60 (yield = 62%) as a mixture of diastereomers.

[0881] 1 H NMR (396 MHz, CDCl3) δ 6.34 (d, J = 2.0 Hz, 2H), 6.26 (d, J = 1.6Hz, 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= 3.3Hz, 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, 11H), 1.51 (s, 8H).

[0882] 13 C NMR (100 MHz, CDCl3) 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.

[0883]

[0884] MnO2 (702 mg, 8.08 mmol) was added to a CH2Cl2 (15 mL) solution of compound 60 (398 mg, 0.808 mmol) and stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth to remove the solvent. The crude product was purified by rapid column chromatography (hexane / EtOAc = 90 / 10 to 50 / 50) to give 321 mg of compound 61 (yield = 81%) as a mixture of diastereomers.

[0885] 1 H NMR (396 MHz, CDCl3) 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)。

[0886]

[0887] A DMSO (2 mL) solution of compound 61 (110 mg, 0.224 mmol) was added to a DMSO (38 mL) solution of CrCl2 (149 mg, 1.212 mmol) and NiCl2 (2.9 mg, 0.0224 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc and serine solution and stirred at room temperature for 30 minutes. The aqueous phase was extracted twice with EtOAc, and the organic phases were combined, washed with saturated NH4Cl solution, water, and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by rapid column chromatography (CH2Cl2 / EtOAc = 80 / 20 to 30 / 70) to give 23 mg of compound 62 (28% yield), a mixture of diastereomers.

[0888] 1 H NMR (396 MHz, CDCl3) δ 6.40 (dd, J = 2.4, 1.2 Hz, 1H), 5.89 (dq, J = 2.7, 1.2 Hz, 1H), 5.81 (d, J = 6.9 Hz, 1H), 5.76 – 5.59 (m, 1H), 5.20 (s,1H), 4.84 (t, J = 6.9 Hz, 1H), 4.50 (s, 1H), 3.88 (dd, J = 37.5, 2.9 Hz, 1H),3.80 – 3.61 (m, 2H), 3.53 (d, J = 11.2 Hz, 1H), 3.00 – 2.86 (m, 1H), 2.72 –2.61 (m, 1H), 2.46 – 2.30 (m, 2H), 1.88 (d, J = 1.5 Hz, 3H), 1.75 (d, J = 1.5Hz, 3H), 1.62 (s, 11H).

[0889]

[0890] MnO2 (79 mg, 0.906 mmol) was added to a 5 mL solution of compound 62 (33 mg, 0.091 mmol) in CH2Cl2 and stirred at room temperature for 16 hours. The mixture was filtered through diatomaceous earth to remove the solvent. The crude product was purified by rapid column chromatography (hexane / EtOAc = 90 / 10 to 50 / 50) to give 27 mg of compound 63 (82% yield) as a mixture of diastereomers.

[0891] 1 H NMR (396 MHz, CDCl3) δ 6.43 (d, J = 2.7 Hz, 1H), 6.19 (s, 1H), 6.05(t, J = 1.5 Hz, 1H), 5.99 – 5.91 (m, 1H), 5.41 (d, J = 36.3 Hz, 1H), 4.58 –4.39 (m, 1H), 4.16 (d, J = 3.1 Hz, 1H), 3.91 (s, 1H), 3.74 – 3.63 (m, 1H), 3.56 – 3.42 (m, 1H), 3.07 (dd, J = 10.1, 2.7 Hz, 1H), 2.77 (dd, J = 12.3, 3.9Hz, 1H), 2.45 (t, J = 3.6 Hz, 2H), 2.04 – 1.90 (m, 3H), 1.84 – 1.37 (m, 11H).

[0892] 13 C NMR (100 MHz, CDCl3) 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.

[0893]

[0894] Methacrylic anhydride (13 μL, 0.0894 mmol) was added to a THF (2 mL) solution of compound 63 (27 mg, 0.0745 mmol), Et3N (31 μL, 0.223 mmol), and dimethylaminopyridine (DMAP, 1.8 mg, 0.0149 mmol). The mixture was stirred at room temperature for 16 hours, and the solvent was removed. The crude product was diluted with EtOAc and saturated NH4Cl solution. The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum to give 29 mg of compound 64 (yield = 91%). This crude product was ready for use without further purification.

[0895]

[0896] PTSA (5.8 mg, 0.034 mmol) was added to compound 64 (29 mg, 0.067 mmol) / MeOH (1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, and the crude product was purified by rapid column chromatography (hexane / EtOAc 80 / 20 to 40 / 60) to give 15 mg (+ / -)-deltachophorin 65 (two-step yield = 60%). The sample was purified by gel permeation chromatography (GPC) for bioassay.

[0897] 1 H NMR (396 MHz, CDCl3) δ 6.37 (s, 1H), 6.21 (s, 1H), 6.18 – 6.10 (m,1H), 6.04 – 5.98 (m, 1H), 5.83 (s, 1H), 5.68 (d, J = 1.8 Hz, 1H), 5.45 (d, J = 11.6 Hz, 1H), 5.23 (dd, J = 3.9, 1.8 Hz, 1H), 4.24 (d, J = 3.7 Hz, 1H), 3.45 – 3.33 (m, 1H), 2.76 (d, J = 3.9 Hz, 1H), 2.56 – 2.44 (m, 1H), 2.36 (dd, J = 11.7, 1.8 Hz, 1H), 2.01 (s, 3H), 1.96 (s, 3H), 1.79 (s, 3H).

[0898] in conclusion

[0899] In this study, we achieved for the first time the extraction of *Elephantopus pubescens* (a type of plant) from *Elephantopus pubescens*. Elephantopus mollis ) and white-flowered ground ivy ( Elephantopus tomentosus The collective synthesis of (furan)gemaline lactones. The key to the stereoselective assembly of the highly oxidized strained ten-membered macrocyclic core of boudin (1) and tomenphantopin F (2) lies in the use of diastereoselective intermolecular Barbier allylation reaction combined with Nozaki-Hiyama-Kishi (NHK) macrocyclization reaction. In addition, by photo-induced isomerization of the (E,Z)-dienone portion of boudin (1) to (Z,Z)-dienone, followed by hemiketylation, four furan gemmaline lactone compounds can be concisely synthesized: EM-2 (3), vasomonol (4), 2-O-demethyl tomenphantopin C (5) and tomenphantopin C (6). This suggests that boudin (1) is likely a product of *Eleutherococcus senticosus* ( Elephantopus mollis ) and white-flowered ground ivy ( Elephantopus tomentosus Biosynthetic precursors of furanylgermaline lactones in ).

Claims

1. A method for generating an intermediate in the total synthesis of (+)-hymenole or its derivatives, the method comprising: (a) Provides compound of formula I: in: Prot 1 Represents an acid-instable protecting group; X represents Cl or, more specifically, Br; and (b) Comparing compound I with compound II: Among them Prot 2 Selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or more particularly trimethylsilyl. Reacting for a period of time under reaction conditions involving a stoichiometric excess of a metal salt and / or metal relative to the compound of formula I, a solvent, and a temperature of 0 to 25°C, yields the compound of formula III: Among them Prot 1 As defined above.

2. The method according to claim 1, wherein the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-unstable protecting group is methoxymethyl ether.

3. The method according to claim 1 or claim 2, wherein one or more of the following are applicable: (ai) The metal and / or metal salt is selected from one or more of zinc metal, indium metal, chromium(III) salt used in combination with manganese metal, samarium(II) iodide, tin(II) chloride and 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-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethyl sulfoxide, dimethylacetamide, and more particularly dimethylformamide; and (ci) The temperature is approximately 10 °C.

4. A method for generating an intermediate in the total synthesis of (+)-dulodophorin or its derivatives, the method comprising: (aii) Provides compounds of formula IV: Among them Prot 1 Represents an acid-instable protecting group; as well as (bii) Reacting compound IV in a catalytic amount of a nickel(II) or palladium(II) salt, in stoichiometric excess of a metal and / or metal salt relative to the compound IV, in a solvent, and at a temperature of 5 to 60 °C for a period of time to provide compound V: Where R is Prot 1 And Prot 1 As defined above.

5. The method according to claim 4, wherein the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal, optionally wherein the acid-unstable protecting group is methoxymethyl ether.

6. The method according to claim 4 or claim 5, wherein one or more of the following are applicable: (aiii) The metal and / or metal salt is selected from one or more of chromium(III) salts, samarium(II) iodide and chromium(II) salts used in combination with manganese metal, 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-methyltetrahydrofuran, 3-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethylformamide, dimethylacetamide, and more particularly dimethyl sulfoxide; (ciii) The temperature is approximately 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(II) iodide, nickel(II) chloride ethylene glycol dimethyl ether complex, 1,2-bis(diphenylphosphine)ethane nickel(II) chloride, bis(1,5-cyclooctadiene) nickel(O), 1,3-bis(diphenylphosphine)propane dichloro nickel(II), tetra(triphenylphosphine) nickel, palladium(II) chloride, palladium(II) acetate and bis(acetylacetone) nickel(II), optionally wherein the catalytic nickel(II) salt or palladium(II) salt is bis(acetylacetone) nickel(II).

7. Total synthesis of (+)-hygroscopicin or its derivatives, comprising the synthesis method according to any one of claims 1 to 3 and the synthesis method according to any one of claims 4 to 6.

8. The method according to claim 7, wherein the compound of formula IV: Among them Prot 1 The acid-instable protecting group is prepared by the following method: (aiv) Provides compounds of formula III: Among them Prot 1 As defined above; and (biv) Oxidating the compound of formula III to provide the compound of formula IV, optionally wherein the oxidation conditions include a stoichiometric excess of manganese dioxide in a solvent (e.g., dichloromethane) at a temperature of 5 to 35 °C (e.g., about 25 °C). Optionally, the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal. Optionally, the acid-unstable protecting group is a methoxymethyl ether.

9. The method according to claim 7 or claim 8, wherein the compound of formula I: Among them Prot 1 The acid-instable protecting group is obtained through the following method: (av) Provides compound Ia: ;and (bv) Using suitable conditions applicable to the selected protecting group, protect the free hydroxyl group of compound Ia with an acid-unstable protecting group. Optionally, the acid-unstable protecting group is selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacol methyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-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, tert-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiopentane-2-yl ether, and benzyloxymethyl acetal. Optionally, the acid-unstable protecting group is a methoxymethyl ether.

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

11. The method according to claim 9 or claim 10, wherein the compound of formula Ia is prepared by reacting the compound of formula VI in a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25°C): It is obtained by reacting with an excess of stoichiometric hydrobromic acid.

12. The method of claim 11, wherein the compound of formula VI is obtained by heating at a suitable temperature (e.g., about 25°C). C) The following compounds of formula VII: It is obtained by reacting methyl acrylate with a suitable base (e.g., 1,4-diazabicyclo[2.2.2]octane).

13. The method of claim 12, wherein the compound of formula VII is prepared by reacting the compound of formula VIII in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., about -78°C): It is obtained by reacting with a reducing agent (such as diisobutylaluminum hydride).

14. The method of claim 13, wherein the compound of formula VIII is prepared by reacting the compound of formula IX in a suitable solvent (e.g., tetrahydrofuran) and at a suitable temperature (e.g., about -78°C): It is obtained by reacting (iodomethyl)triphenylphosphonium iodide with a suitable base (e.g., sodium bis(trimethylsilyl)amino).

15. The method of claim 14, wherein the compound of formula IX is prepared by reacting the compound of formula X in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., about -78°C): It is obtained by reacting with methyllithium.

16. The method according to any one of claims 7 to 15, wherein the compound of formula V: Where R is Prot 1 And Prot 1 As defined in claim 8, the compound of formula XI is obtained by oxidation reaction: Where R is as defined above, optionally, the oxidation reaction involves a stoichiometric excess of manganese dioxide and a solvent (e.g., dichloromethane) at a suitable temperature (e.g., 25°C).

17. The method 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), and a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) and at a suitable temperature (e.g., 25°C) to give the compound of formula XII: Where R is Prot 1 And Prot 1 As defined in claim 8, and R' is H or CH3.

18. The method of claim 17, wherein the compound of formula XII is reacted with an acid (e.g., trifluoroacetic acid) in a suitable solvent (e.g., dichloromethane) and at a suitable temperature (e.g., 25°C) to give the compound of formula XIII: Where R' is H or CH3.

19. A method for forming a compound of formula XIV, Where R' is H or CH3, and the compound of formula XIII is reacted in a suitable solvent (e.g., dichloromethane) at a suitable temperature (e.g., about 25°C): Wherein R' is as defined above, ultraviolet light is applied to carry out the cyclization reaction of the compound of formula XIII, wherein the ultraviolet light is provided at a wavelength of 200 to 400 nm (e.g., about 370 nm), with a suitable power (e.g., 10 to 100 watts, such as about 40 watts), and a light source is used with a suitable distance (e.g., 1 to 10 cm, such as about 4 cm) between the reaction vessel containing the compound of formula XIII and the light source.

20. A compound of formula XIV Where R' is H or CH3 Methods for forming XV compounds Where R” is selected from C1 to C 10 Alkyl or C2 to C 10 Alkenyl groups, through compounds of formula XIV and alcohols of formula XVI: R”-OH XVI The reaction is carried out in the presence of an acidic catalyst (such as p-toluenesulfonic acid).

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