Collective synthesis of the phantomorine family by total synthesis of sesquiterpene lactone morephantines

Abstract

Disclosed herein are methods for producing intermediates in the total synthesis of (+)-molefantine or its derivatives, and the total synthesis of (+)-molefantine or its derivatives. Methods for forming the compound of formula XIV and the compound of formula XV are also disclosed herein, where the compound of formula XIV and the compound of formula XV are as defined herein.

Description

[Technical Field]

[0001] This invention generally relates to the synthesis of the phantomorine family, and more particularly to processes and methods for the collective synthesis of the phantomorine family by the total synthesis of the sesquiterpene lactone morephantine. [Background technology]

[0002] The list or discussion of prior art in this specification should not necessarily be taken as an acknowledgment that such art is part of the state of the art or universal general knowledge.

[0003] The diverse family of sesquiterpene lactones (germacranolides), which are plant secondary metabolites, has attracted considerable attention from the fields of natural product chemistry, medicinal chemistry, and synthetic chemistry for many years. Morephantin (1), a highly oxygenated germanolide, was first isolated in 1973 from the herb Elephantopus mollis by Lee (K.-H. Lee et al., J. Chem. Soc. Chem. Commun. 1973, 476-477), and subsequently discovered in 2012 from Elephantopus tomentosus by Liu and Dai (W.-L. Mei et al., Phytochem. Lett. 2012, 5, 800-803) (Figure 1A). Morephantin (1) is known to have strong in vivo antitumor activity against Ehrlich and Walker 256 carcinosarcoma tumors (IH Hallet al., J. Pharm. Sci. 1978, 67, 1235-1239), as well as anti-inflammatory and leishmania-killing activity (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 morephantin (1) consists of a 10-membered macrocyclic core (C10-1-4) with an (E,Z)-dienone moiety, which is condensed with α-methylene-γ-butyrolactone and decorated with four consecutive stereocenters (C5-8). Tomenphantopine F(2), isolated from Elephantopus tomentosus by Liu and Dai in 2012, is structurally similar to morephantin(1) (B. Wanget al., Chin. J. Chem. 2012, 30, 1320-1322). Its structure is based on the same 10-membered macrocyclic core, with an α-(S)-methyl-γ-butyrolactone moiety and a free hydroxyl group at C8.Other topologically related components found in Elephantopus mollis and Elephantopus tomentosus include furanogelmacranolides, e.g., EM-2(2-deethoxy-2β-methoxyphantomorine)(3)(S. Banerjee et al., Planta Med. 1986, 52, 29~32), phantomorine(4)(K.-H. Leeet al., J. Pharma. Sci. 1980, 68, 1050~1056), 2-O-demethyltomenphantopine C(5)(Z.-N. Wu et al., Phytochemistry 2017, 137, 81~86) and tomenphantopine C(6)(W.-L. Mei et al., Phytochem. Lett. 2012, 5, 800~803; and M. Baiet (J. Liet al., J.Nat.Prod. 2022, 85, 2433~2444). In particular, when EM-2(3) and epirubicin are co-administered, EM-2(3) has been observed to increase the sensitivity of breast cancer cells to epirubicin, mainly by inhibiting the cellular protective autophagy pathway (J. Liet al., Phytomedicine 2023, 116, 154878). The 10-membered macrocyclic core contains a (Z,Z)-skipped diene centered on a C2 (hemi)ketal carbon. Although the biosynthetic routes of these highly oxygenated (furanogencranolides) remain unclear, the inventors hypothesized that morephantin(1) could be a biosynthetic precursor of EM-2(3) and other furanogermacranolides. This hypothesis, based on the intriguing topological similarities of morephantin(1), suggests a potential synthetic route involving E / Z isomerization of morephantin(1) from the C1-C10 double bond to the (Z,Z)-dienone homolog A, followed by successive (hemi)ketalization via the C5-hydroxyl group.

[0004] Despite groundbreaking research in the synthesis of highly oxygenated germanolides isolated from different plant species, such as elemans solid (J. Am. Chem. Soc. 1991, 113, 9682-9684) and goyazen solid (ACS Cent. Sci. 2021, 7, 954-962), to the best of our knowledge, the total synthesis of (furanose)germanolides derived from Elephantopus species has not been reported (Figure 1B). An exception to this gap is the synthesis of nordeoxyelephantopin, a non-natural analog of deoxyelephantopin derived from Elephantopus scaber (R. Lagoutte et al., Nat. Commun. 2016, 7, 12470; and R. Lagoutte et al., J. Antibiot. 2018, 71, 248-256). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] K.-H.Lee et al., J.Chem.Soc.Chem.Commun.1973, 476~477 [Non-Patent Document 2] W.-L.Mei et al., Phytochem.Lett.2012, 5, 800~803 [Non-Patent Document 3] IHHall et al., J.Pharm.Sci.1978, 67, 1235~1239 [Non-Patent Document 4] Z.-N.Wu et al., Phytochemistry 2017, 137, 81~86 [Non-Patent Document 5] H.Fuchino et al., Planta Med.2001, 67, 647~653 [Non-Patent Document 6] B.Wang et al., Chin.J.Chem.2012, 30, 1320~1322 [Non-Patent Document 7] S. Banerjee et al., Planta Med.1986, 52, 29~32 [Non-Patent Document 8] K.-H.Lee et al., J.Pharma.Sci.1980, 68, 1050~1056 [Non-Patent Document 9] M.Baiet al., J.Nat.Prod.2022, 85, 2433~2444 [Non-Patent Document 10] J. Liet al., Phytomedicine 2023, 116, 154878 [Non-Patent Document 11] J.Am.Chem.Soc.1991, 113, 9682~9684 [Non-Patent Document 12] ACS Cent.Sci.2021, 7, 954~962 [Non-Patent Document 13] R. Lagoutte et al., Nat.Commun.2016, 7, 12470 [Non-Patent Document 14] R. Lagoutte et al., J. Antibiot.2018, 71, 248~256 [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, there is a need for new synthetic routes that will make sesquiterpene lactones available. [Means for solving the problem]

[0007] Aspects and embodiments of the present invention are provided in the following numbered clauses.

[0008] 1. A method for producing an intermediate in the total synthesis of (+)-molefantine or its derivatives, (a) Compounds of formula I:

[0009] [ka]

[0010] [In the formula, Prot 1 [where represents an acid-unstable protecting group, and X represents Cl or especially Br] The process of obtaining, (b) Compound I is a compound of formula II:

[0011] [ka]

[0012] [In the formula, Prot 2 [This group is selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups, or in particular, trimethylsilyl.] Then, the compound of formula I is reacted with a stoichiometrically excess metal salt and / or the metal, under reaction conditions with a solvent and at a temperature of 0-25°C for a certain period of time to obtain the compound of formula III:

[0013] [ka]

[0014] [In the formula, Prot 1 This is as defined above. The process of obtaining Methods that include...

[0015] 2. A method according to Clause 1, wherein the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally the acid-instability protecting group is methoxymethyl ether.

[0016] 3. One or more of the following apply: (ai) The metal and / or metal salt is selected from one or more of the following: zinc metal, indium metal, manganese metal, chromium(III) salt, samarium(II) iodide, tin(II) chloride, and chromium(II) salt, and optionally the metal and / or metal salt is chromium(II) bromide or, in particular, 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, and dimethylacetamide, and is particularly dimethylformamide, and (ci) A method according to clause 1 or clause 2, where the temperature is approximately 10°C.

[0017] 4. A method for producing an intermediate in the total synthesis of (+)-molefantine or its derivatives, Compounds of formula IV (aii):

[0018] [ka]

[0019] [In the formula, Prot 1 This represents an acid-unstable protecting group. The process of obtaining, (bii) The compound of formula IV is subjected to reaction conditions in a solvent at a temperature of 5-60°C for a certain period of time, with a catalytic amount of nickel(II) salt or palladium(II) salt, and one or both of the metal and metal salt in a stoichiometric excess relative to the compound of formula IV, to obtain the compound of formula V:

[0020] [ka]

[0021] [In the formula, R is Prot 1 And, Prot 1 This is as defined above. A method including the step of obtaining

[0022] 5. A method according to Clause 4, wherein the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally the acid-instability protecting group is methoxymethyl ether.

[0023] 6. One or more of the following apply: (aiii) The metal and / or metal salt is selected from one or more of the following: chromium(III) salts with added manganese metal, samarium(II) iodide, and chromium(II) salts, and optionally the metal and / or metal salt is chromium(II) bromide or, in particular, 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, and dimethylacetamide, and is particularly dimethyl sulfoxide. (ciii) The temperature is approximately 25°C, and (diii) The nickel(II) salt catalyst or palladium(II) salt catalyst 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(diphenylphosphino)ethanenickel(II) chloride, bis(1,5-cyclooctadiene)nickel(0), 1,3-bis(diphenylphosphino)propane]dichloronickel(II), tetrakis(triphenylphosphine)nickel, palladium(II) chloride, palladium(II) acetate, and nickel(II)bis(acetylacetonate), and optionally the nickel(II) salt catalyst or palladium(II) salt catalyst is nickel(II)bis(acetylacetonate). A method in accordance with Clause 4 or Clause 5.

[0024] 7. Total synthesis of (+)-molefantine or a derivative thereof, comprising a synthesis method according to any one of clauses 1 to 3 and a synthesis method according to any one of clauses 4 to 6.

[0025] 8. Compounds of formula IV:

[0026] [ka]

[0027] [In the formula, Prot 1 This represents an acid-unstable protecting group. , (aiv) a compound of formula III:

[0028] [Chemical Formula]

[0029] [wherein, Prot 1 is as defined above] obtaining, and (biv) subjecting the compound of formula III to an oxidation reaction to obtain a compound of formula IV, which is prepared by optionally, the oxidation conditions comprise a stoichiometric excess of manganese dioxide in a solvent (e.g., methylene chloride) at a temperature of 5°C to 35°C (e.g., about 25°C), optionally, the acid-labile 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally, the acid-labile protecting group is methoxymethyl ether, A process according to clause 7.

[0030] 9. A compound of formula I:

[0031] [Chemical Formula]

[0032] [wherein, Prot 1 represents an acid-labile protecting group] is, (av) a compound of formula Ia:

[0033]

化

[0034] obtaining, and (bv) protecting the free hydroxyl of the compound of formula Ia with an acid-labile protecting group using conditions appropriate for the selected protecting group obtainable by, optionally, the acid-labile 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally, the acid-labile protecting group is methoxymethyl ether, A method according to clause 7 or clause 8.

[0035] 10. A method according to clause 9, wherein the protecting group is methoxymethyl ether, and the reaction conditions comprise reacting the compound of formula Ia with dimethoxymethane as solvent and reagent and a catalytic amount of a suitable acidic catalyst, such as triflic acid.

[0036] 11. A compound of formula Ia, which is a compound of formula VI:

[0037]

Chem.

[0038] which is obtained by reaction with a stoichiometric excess of hydrobromic acid in a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25°C), the process according to Clause 9 or Clause 10.

[0039] 12. A compound of formula VI is reacted to obtain a compound of formula VII:

[0040]

Chem.

[0041] which is obtained by reaction with methyl acrylate and a suitable base (e.g., 1,4-diazabicyclo[2.2.2]octane) at a suitable temperature (e.g., about 25°C), the process according to Clause 11.

[0042] 13. A compound of formula VII is reacted to obtain a compound of formula VIII:

[0043]

Chem.

[0044] which is obtained by reaction with a reducing agent (e.g., diisobutylaluminum hydride) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C), the process according to Clause 12.

[0045] 14. A compound of formula VIII is reacted to obtain a compound of formula IX:

[0046]

Chem.

[0047] The method according to Clause 13, obtained by reacting (iodomethyl)triphenylphosphonium iodide with a suitable base (e.g., sodium hexamethyldisilazide) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., about -78°C).

[0048] 15. Compound of formula IX, compound of formula X:

[0049] [ka]

[0050] A method according to Clause 14, obtained by reaction of methyllithium with a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C).

[0051] 16. Compounds of formula V:

[0052] [ka]

[0053] [In the formula, R is Prot 1 And, Prot 1 This is as defined in Article 8. When subjected to an oxidation reaction, the compound of formula XI is obtained:

[0054] [ka]

[0055] [In the formula, R is as defined above.] Prepare the following, and optionally, the oxidation reaction will occur at a suitable temperature (e.g., 25°C) with a stoichiometrically excess of manganese dioxide and a solvent (e.g., methylene chloride). A method that complies with any one of clauses 7 through 15.

[0056] 17. The compound of formula XI is reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g., triethylamine), a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., 25°C) to obtain the compound of formula XII:

[0057] [ka]

[0058] [In the formula, R is Prot 1 And, Prot 1 [This is as defined in Article 8, where R' is H or CH3] Obtain the method described in Article 16.

[0059] 18. The compound of formula XII is reacted with an acid (e.g., trifluoroacetic acid) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., 25°C) to obtain the compound of formula XIII:

[0060] [ka]

[0061] [In the formula, R' is either H or CH3] Obtain the following method in accordance with Article 17.

[0062] 19. Compounds of formula XIV

[0063] [ka]

[0064] [In the formula, R' is either H or CH3] The compound of formula XIII:

[0065] [ka]

[0066] A method for forming [wherein R' is as defined above] by a cyclization reaction of the compound of formula XIII by applying ultraviolet light to a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about 25°C), Optionally, ultraviolet light is provided at a wavelength of 200–400 nm (e.g., approximately 370 nm) and at an appropriate power (e.g., 10–100 watts, for example, approximately 40 watts) using a light source at an appropriate distance (e.g., 1–10 cm, for example, approximately 4 cm) from the reaction vessel containing the compound of formula XIII. A method for forming the compound of formula XIV.

[0067] 20. Compounds of formula XV:

[0068] [ka]

[0069] [In the formula, R'' represents C1~C 10 Alkyl or C2-C 10 [Selected from Alkenil] The compound of formula XIV

[0070] [ka]

[0071] [In the formula, R' is either H or CH3] From this, the compound of formula XIV is given by formula XVI: R"-OH XVI A method of forming by reacting an alcohol with an acid catalyst (for example, the catalyst is p-toluenesulfonic acid). [Brief explanation of the drawing]

[0072] [Figure 1]A) A diagram showing germanolides and furanogermanolides isolated from Elephantopus mollis and Elephantopus tomentosus, and B) highly oxygenated germanolides derived from different plants. [Figure 2] Figure showing the 1H nuclear magnetic resonance (NMR) spectrum of the crude residue containing aldehyde-12. [Figure 3] Figure showing the 1H NMR spectrum of the crude residue containing methyl ketone 13. [Figure 4] Figure showing the 1H NMR spectrum of purified iodoalkene 14. [Figure 5] This figure shows the X-ray crystal structure analysis data for compound 17 (CCDC-2312148). [Figure 6] This figure shows the X-ray crystal structure analysis data for compound 17' (CCDC-2312149). [Figure 7] A diagram showing the 1H-1H COSY and HMBC correlation for item 18. [Figure 8] A diagram showing the monitoring of reaction progress using liquid chromatography-mass spectrometry (LC-MS). [Figure 9] This figure shows the X-ray crystal structure analysis data for compound 20 (CCDC-2312151). [Figure 10] A diagram illustrating the origin of diastereoselectivity in the formation of compound 20. [Figure 11] A diagram showing the correlation between morefantin (1) and 1H-1H COSY and HMBC. [Figure 12] This figure shows the X-ray crystal structure analysis data for compound 23 (CCDC-2312152). [Figure 13] A graph showing the correlation between tomenphantopine F(2) and 1H-1H COSY and HMBC. [Figure 14] A diagram showing the photochemical reaction setup (the fan has been removed from the photo for clarity). The distance between the lamp and the reaction tube was set to 4 cm. [Figure 15]A figure showing the ultraviolet-visible (UV-vis) absorption spectrum of morephantin (1) (0.5 mM in CH2Cl2). [Figure 16] A figure showing 1H NMR monitoring of a photo-induced reaction in CDCl3. [Figure 17] A figure showing the correlation between 1H-1H COSY and HMBC for 25 (photo-induced cyclization isomerization of morephantin (1)). [Figure 18] This figure shows the X-ray crystal structure analysis data for EM-2(3)(CCDC-2324191). [Figure 19] A diagram showing the correlation between 1H-1H COSY and HMBC for EM-2(3). [Figure 20] A diagram showing the correlation between phantomorin (4) and 1H-1H COSY and HMBC. [Figure 21] A diagram showing the correlation between 1H-1H COSY and HMBC for 2-O-demethyltomenphantopine C(5). [Figure 22] This figure shows the X-ray crystal structure analysis data for tomenphanthopine C(6) (CCDC-2312153). [Figure 23] A figure showing the correlation between tomenphantopine C(6) and 1H-1H COSY and HMBC. [Figure 24] A figure showing the retrosynthetic analysis of molefantin (1). [Figure 25A-B] A) A diagram showing the synthesis route to aldehyde fragment 12, and B) a diagram showing the synthesis route to 3-bromomethyl-5H-furan-2-one 17. [Figure 25C-D] A diagram showing C) the synthesis of morephanthin (1) and D) the synthesis of tomenphantopine F (2). [Figure 26] A diagram illustrating the collective synthesis of furanogermacranolide. [Figure 27] A diagram showing the stereoselective synthesis route of (+)-molefantin. [Figure 28] A diagram illustrating the synthesis root of Synton 9. [Figure 29] A diagram showing the synthesis route of aldehyde 12. [Figure 30]Diagram showing the En route to (+)-molefantin. [Figure 31] A diagram showing an example using (+ / -)-molefantine. [Modes for carrying out the invention]

[0073] Surprisingly, it was found that the co-synthesis of (furanose)germacranolide may originate from Elephantopus mollis and Elephantopus tomentosus.

[0074] Therefore, in a first aspect of the present invention, a method for producing an intermediate in the total synthesis of (+)-molefantine or its derivatives, (a) Compounds of formula I:

[0075] [ka]

[0076] [In the formula, Prot 1 [where represents an acid-unstable protecting group, and X represents Cl or especially Br] The process of obtaining, (b) Compound I is a compound of formula II:

[0077] [ka]

[0078] [In the formula, Prot 2 [This group is selected from triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl groups, or in particular, trimethylsilyl.] Then, the compound of formula I is reacted with a stoichiometrically excess metal salt and / or the metal, under reaction conditions with a solvent and at a temperature of 0-25°C for a certain period of time to obtain the compound of formula III:

[0079] [ka]

[0080] [In the formula, Prot 1 This is as defined above. A method is provided which includes the step of obtaining [something].

[0081] In this specification, the phrase “contains” is to be interpreted as requiring the described features but not limiting the presence of other features. Alternatively, the phrase “contains” may also refer to situations in which only the listed components / features are intended to be present (for example, the phrase “contains” may be replaced by “consisting of” or “essentially consisting of”). It is expressly intended that broader and narrower interpretations may apply to all aspects and embodiments of the invention. In other words, the phrase “contains” and its synonyms may be replaced by the phrase “consisting of” or “essentially consisting of” or their synonyms, and vice versa.

[0082] The phrase "essentially consisting of" and its pseudoonyms may be interpreted herein as referring to materials that may contain trace impurities. For example, the material may have a purity of 90% or higher, e.g., over 95%, e.g., over 97%, e.g., over 99%, e.g., over 99.9%, e.g., over 99.99%, e.g., over 99.999%, e.g., 100%.

[0083] As used herein, the singular forms "a," "an," and "the" refer to multiple objects unless the context clearly indicates otherwise. For example, a reference to "composition" includes mixtures of two or more compositions, and a reference to "catalyst" includes mixtures of two or more catalysts.

[0084] The term "halo," as used herein, includes references to fluoro, chloro, bromo, and iodine.

[0085] In the first embodiment of the present invention, any suitable acid-unstable protecting group can be used.

[0086] In some embodiments of the first aspect of the present invention as referred herein, the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal.

[0087] In further embodiments of the first aspect of the present invention as referred to herein, the acid-unstable protecting group may be a methoxymethyl ether.

[0088] In the first embodiment of the present invention, any suitable time can be adopted. For example, the time may be 3 hours.

[0089] In a first embodiment of the present invention, any suitable metal and / or metal salt can be used.

[0090] In some embodiments of the first aspect of the present invention as referred to herein, the metal and / or metal salt may be selected from one or more of the following: zinc metal, indium metal, chromium(III) salts with manganese metal, samarium(II) iodide, tin(II) chloride, and chromium(II) salts (e.g., chromium(II) bromide and chromium(II) chloride).

[0091] In further embodiments of the first aspect of the present invention as referred to herein, the metal and / or metal salt may be chromium(II) chloride.

[0092] In the first embodiment of the present invention, any suitable solvent can be used.

[0093] In some embodiments of the first aspect of the present invention as referred to 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.

[0094] In further embodiments of the first aspect of the present invention as referred to herein, the solvent may be dimethylformamide.

[0095] In some embodiments of the first aspect of the present invention, the temperature may be about 10°C.

[0096] In a first embodiment of the present invention, any suitable metal salt and / or metal in stoichiometric excess can be used with respect to the compound of formula I.

[0097] A second aspect of the present invention provides a method for generating an intermediate in the total synthesis of (+)-molefantine or a derivative thereof, Compounds of formula IV (aii):

[0098] [ka]

[0099] [In the formula, Prot 1 This represents an acid-unstable protecting group. The process of obtaining, (bii) The compound of formula IV is subjected to reaction conditions in a solvent at a temperature of 5-60°C for a certain period of time, with a catalytic amount of nickel(II) salt or palladium(II) salt, and one or both of the metal and metal salt in a stoichiometric excess relative to the compound of formula IV, to obtain the compound of formula V:

[0100] [ka]

[0101] [In the formula, R is Prot 1 And, Prot 1 This is as defined above. The process of obtaining A method is provided that includes this.

[0102] In a second embodiment of the present invention, any suitable acid-instability protecting group can be used.

[0103] In some embodiments of a second aspect of the present invention as referred herein, the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal.

[0104] In further embodiments of the second aspect of the present invention as referred to herein, the acid-instability protecting group may be a methoxymethyl ether.

[0105] In a second embodiment of the present invention, any suitable time may be adopted. For example, the time may be 16 hours.

[0106] Any suitable catalytic amount of nickel(II) salt or palladium(II) salt can be used in a second embodiment of the present invention.

[0107] In a second embodiment of the present invention, any suitable metal and / or metal salt in stoichiometric excess with respect to the compound of formula IV can be used.

[0108] In a second embodiment of the present invention, any suitable metal and / or metal salt can be used.

[0109] In some embodiments of a second aspect of the present invention as referred to herein, the metal and / or metal salt may be selected from one or more chromium(III) salts with added manganese metal, samarium(II) iodide, and chromium(II) salts (e.g., chromium(II) bromide and chromium(II) chloride).

[0110] In further embodiments of the second aspect of the present invention as referred to herein, the metal and / or metal salt may be chromium(II) chloride.

[0111] In a second aspect of the present invention, any suitable solvent can be used.

[0112] In some embodiments of a second aspect of the present invention as referred to 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.

[0113] In some embodiments of a second aspect of the present invention as referred to herein, the temperature may be about 25°C.

[0114] In a second aspect of the present invention, any suitable nickel(II) salt catalyst or palladium(II) salt catalyst can be used.

[0115] In some embodiments of a second aspect of the present invention as referred to herein, the nickel(II) salt catalyst or palladium(II) salt catalyst may be 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(diphenylphosphino)ethanenickel(II) chloride, bis(1,5-cyclooctadiene)nickel(0), 1,3-bis(diphenylphosphino)propane]dichloronickel(II), tetrakis(triphenylphosphine)nickel, palladium(II) chloride, palladium(II) acetate, and nickel(II)bis(acetylacetonate). For example, the nickel(II) salt catalyst or palladium(II) salt catalyst may be nickel(II)bis(acetylacetonate).

[0116] A third aspect of the present invention provides a total synthesis of (+)-molefantin or a derivative thereof, comprising a synthesis method according to a first aspect of the present invention and a synthesis method according to a second aspect of the present invention.

[0117] In some embodiments of a third aspect of the present invention as referred to herein, a compound of formula IV:

[0118] [ka]

[0119] [In the formula, Prot 1 This represents an acid-unstable protecting group. teeth, (aiv) Compounds of formula III:

[0120] [ka]

[0121] [In the formula, Prot 1 This is as defined above. To obtain, and (biv) The compound of formula III is subjected to an oxidation reaction to obtain the compound of formula IV. It is obtained by [method].

[0122] In a third embodiment of the present invention as may be referred to herein, the oxidation conditions may include a stoichiometrically excess of manganese dioxide in a solvent (e.g., methylene chloride) at a temperature of 5 to 35°C (e.g., about 25°C).

[0123] In embodiments of a third aspect of the present invention as referred to herein, the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal. For example, the acid-instability protecting group may be methoxymethyl ether.

[0124] In some embodiments of a third aspect of the present invention as referred to herein, a compound of formula I:

[0125] [ka]

[0126] [In the formula, Prot 1 This represents an acid-unstable protecting group. teeth, Compounds of formula Ia (av):

[0127] [ka]

[0128] To obtain, and (bv) Obtained by protecting the free hydroxyl of the compound of formula Ia with an acid-unstable protecting group using appropriate conditions for the selected protecting group.

[0129] In embodiments of a third aspect of the present invention as referred to herein, the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal. For example, the acid-instability protecting group may be methoxymethyl ether.

[0130] In a third embodiment of the present invention as referred to herein, the protecting group may be a methoxymethyl ether, and the reaction conditions may involve the reaction of the compound of formula Ia with dimethoxymethane as the solvent and reagent, and a catalytic amount of a suitable acidic catalyst (e.g., trifluic acid).

[0131] In a third aspect of the present invention, any appropriate catalytic amount of a suitable acidic catalyst can be used.

[0132] In some embodiments of a third aspect of the present invention as referred to herein, the compound of formula Ia is the compound of formula VI:

[0133] [ka]

[0134] It is obtained by the reaction of a stoichiometrically excess hydrobromic acid with a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25°C).

[0135] In further embodiments of a third aspect of the present invention as referred to herein, the compound of formula VI is replaced with the compound of formula VII:

[0136] [ka]

[0137] It is obtained by the reaction of methyl acrylate with a suitable base (e.g., 1,4-diazabicyclo[2.2.2]octane) at a suitable temperature (e.g., about 25°C).

[0138] In a third aspect of the present invention, any suitable base can be used.

[0139] In further embodiments of a third aspect of the present invention as referred to herein, the compound of formula VII is replaced with the compound of formula VIII:

[0140] [ka]

[0141] It is obtained by the reaction of a reducing agent (e.g., diisobutylaluminum hydride) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C).

[0142] In a third aspect of the present invention, any suitable reducing agent can be used.

[0143] In further embodiments of a third aspect of the present invention as referred to herein, the compound of formula VIII is replaced with the compound of formula IX:

[0144] [ka]

[0145] It is obtained by the reaction of (iodomethyl)triphenylphosphonium iodide and a suitable base (e.g., sodium hexamethyldisilazide) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., about -78°C).

[0146] In further embodiments of a third aspect of the present invention as referred to herein, the compound of formula IX is replaced with the compound of formula X:

[0147] [ka]

[0148] It is obtained by the reaction of methyllithium with a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C).

[0149] In some embodiments of a third aspect of the present invention as referred to herein, a compound of formula V:

[0150] [ka]

[0151] [In the formula, R is Prot 1 And, Prot 1 This is as defined in the third aspect of the present invention. When subjected to an oxidation reaction, the compound of formula XI is obtained:

[0152] [ka]

[0153] [In the formula, R is as defined above.] You can obtain this.

[0154] In a third embodiment of the present invention, the oxidation reaction can be carried out at a suitable temperature (e.g., 25°C) using a stoichiometrically excess amount of manganese dioxide and a solvent (e.g., methylene chloride).

[0155] In a third embodiment of the present invention, the compound of formula XI is reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g., triethylamine), a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., 25°C) to obtain the compound of formula XII:

[0156] [ka]

[0157] [In the formula, R is Prot 1 And, Prot 1 [where R' is defined as in the third aspect of the present invention, and R' is H or CH3] You can obtain this.

[0158] In a third aspect of the present invention, any suitable catalytic base can be used.

[0159] In a third embodiment of the present invention, the compound of formula XII is reacted with an acid (e.g., trifluoroacetic acid) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., 25°C) to obtain the compound of formula XIII:

[0160] [ka]

[0161] [In the formula, R' is either H or CH3] You can obtain this.

[0162] In a third aspect of the present invention, any suitable acid can be used.

[0163] In a fourth aspect of the present invention, the compound of formula XIV

[0164] [ka]

[0165] [In the formula, R' is either H or CH3] of, Compounds of formula XIII:

[0166] [ka]

[0167] A method for forming [wherein R' is as defined above] by a cyclization reaction by applying ultraviolet light to the compound of formula XIII in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about 25°C), Optionally, ultraviolet light is provided at a wavelength of 200–400 nm (e.g., approximately 370 nm) and at an appropriate power (e.g., 10–100 watts, for example, approximately 40 watts) using a light source at an appropriate distance (e.g., 1–10 cm, for example, approximately 4 cm) from the reaction vessel containing the compound of formula XIII. A method for forming the compound of formula XIV is provided.

[0168] Ultraviolet irradiation is performed using any suitable light source. For example, an LED light source can be used.

[0169] In a fifth aspect of the present invention, the compound of formula XV:

[0170] [ka]

[0171] [In the formula, R'' represents C1~C 10 Alkyl or C2-C 10 Compounds of formula XIV selected from alkenyls

[0172] [ka]

[0173] [In the formula, R' is either H or CH3] From this, the compound of formula XIV is given by formula XVI: R"-OH XVI A method for forming the substance is provided by reacting the alcohol with an acid catalyst (for example, the catalyst is p-toluenesulfonic acid).

[0174] In a fifth embodiment of the present invention, any suitable acid catalyst can be used.

[0175] Unless otherwise specified, the term "alkyl" refers to saturated, unbranched, or branched, acyclic, or cyclic radicals, which may be unsubstituted. For example, when the term "alkyl" refers to an acyclic group, it means C 1~10 Alkyl, more preferably C 1~6 Alkyl groups may refer to 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 means C 3~12 Cycloalkyl, more preferably C 5~10 (For example C 5~7 ) may be cycloalkyl. In embodiments of the present invention as referred to herein, the alkyl group may be acyclic.

[0176] Unless otherwise specified, the term "alkenyl" refers to an unsaturated, non-branched or branched, acyclic or cyclic radical, which may be unsubstituted. For example, when the term "alkenyl" refers to an acyclic group, it is C 2~10 Alkenil, more preferably, C 2~6This may refer to alkenyls (such as propenyl), butenyls (e.g., branched or unbranched butenyls), pentenyls, or more preferably etenyls). When the term "alkenyl" refers to a cyclic group, it means C 3~12 Cycloalkenyl, more preferably C 5~10 (For example C 5~7 )It may be a cycloalkenyl. In embodiments of the present invention as referred to herein, the alkenyl group may be acyclic.

[0177] The compounds of formula X and formula XVI may be known and / or commercially available. Other compounds of formulas I-IX and XI-XV, as well as certain compounds of formula XVI (e.g., not commercially available), can be prepared by techniques well known to those skilled in the art, such as those described below.

[0178] The compounds of the present invention can be isolated from their reaction mixtures using conventional techniques (e.g., recrystallization, column chromatography, preparative HPLC, etc.). In particular, it should be noted that compounds having formula XIII, such as morephantine and morefantinin, can be crystallized (or recrystallized) in ethanol (EtOH), methanol (MeOH), diethyl ether (Et2O), or dichloromethane (CH2Cl2).

[0179] In the methods described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups.

[0180] Protection and deprotection of functional groups can be performed before or after the reaction in the scheme described above.

[0181] Protecting groups may be removed according to techniques well known to those skilled in the art, as described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques.

[0182] The types of chemistry involved will determine the need for and type of protecting groups, as well as the sequence required to carry out the synthesis.

[0183] The use of protecting groups is well described in "Protective Groups in Organic Chemistry," edited by JWF McOmie, Plenum Press (1973), and in "Protective Groups in Organic Synthesis," 3rd edition, by TW Greene and PGMWutz, Wiley-Interscience (1999).

[0184] As used herein, the term “functional group” means, in the case of an unprotected functional group, hydroxy-, thio-, amino, and carboxylic acids, and in the case of a protected functional group, lower alkoxy, N-, O-, S-acetyl, and carboxylic acid esters.

[0185] Derivatives of (+)-morephantin may include, but are not limited to, morephantinin, phantomolin, tomentosuside F, tomentosuside K, tomenphantopine C, tomenphantopine H, 2-O-demethyltomenphantopine C, 2-deethoxy-2β-methoxyphantomolin-8-O-tigrinate, and 2-deethoxy-2β-methoxyphantomolin.

[0186] Further aspects and embodiments of the present invention will be described below with reference to the examples, but the present invention is not limited to the examples. [Examples]

[0187] material n-BuLi (Kanto Chemical Co., Ltd. - 04937-25) was purchased from Kanto Chemical Co., Ltd. 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), trimethylsilyltrifluoromethanesulfonate (Sigma Aldrich-225649), 2,6-lutidine (Sigma Aldrich-336106), methyllithium (Sigma Aldrich-514330), sodium hexamethyldisilazide (Sigma Aldrich-80631), chromium chloride (Sigma Aldrich-450782), triethylamine (Sigma Aldrich-471283), 4-dimethylaminopyridine (Sigma Aldrich-107700), methacrylic anhydride (Sigma Aldrich-276685), trifluoroacetic acid (Sigma Aldrich-T6508), sodium borohydride (Sigma Aldrich-452882), hydrobromic acid (Sigma Aldrich-268003), and methyl acrylate (Sigma Aldrich Aldrich-M27301 was 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 Strem Chemicals.

[0188] Note The number of carbon atoms indicated for the compound corresponds to that of molephanthin (1).

[0189] Analysis method Nuclear magnetic resonance (NMR) spectroscopy 1 The H NMR spectrum (400 MHz) was obtained using a JEOL Ltd. ECA series 400 MHz spectrometer, and the TMS( 1 For H, use δ=0.00) as the internal standard] or in CD3OD ( 1 For H, the data was recorded with δ=3.31). 13 The 13C NMR spectrum (100MHz) was analyzed using a JEOL Ltd. ECA series 400MHz spectrometer to determine the concentration of CDCl3 in [CDCl3( 13 For C, use δ=77.16) as the internal standard] or in CD3OD ( 13 For C, it was recorded at δ49.00). The following abbreviations were used to describe the multiplicity: s=single line, d=double line, t=triple line, q=quadruple line, dd=double double line, ddd=double double line, dddd=double double line, qd=quadruple double line, qt=quadruple triple line, m=multiple lines, brs=broad single line, brm=broad multiple lines.

[0190] Mass and infrared (IR) spectroscopy High-resolution mass spectrometry (HRMS) spectra were obtained using a Xevo G2 Tof Premier mass spectrometer (ionization mode: ESI positive polarity; mobile phase: MeOH 100 μL / min). IR spectra were recorded using a Shimadzu IR Prestige-21 FT-IR spectrometer.

[0191] optical rotation Optical rotation was recorded at 589 nm using an OMNI Lab JASCO P-1030 polarimeter, [α] T D Record the concentration as (grams / 100 mL solvent).

[0192] melting point The melting point was not corrected and was recorded using the MPA100 OptiMelt automatic melting point measurement system.

[0193] absorption spectroscopy The steady-state absorption spectrum was recorded using a UV-vis absorption spectrometer (YV3600 Plus, Shimadzu Corporation).

[0194] LED light source Kessil PR160 series (λ max A wavelength of 370 nm was used as the LED light source for the photochemical reaction.

[0195] Analytical thin-layer chromatography (TLC) and silica gel chromatography TLC was performed using a 0.25 mm silica gel 60-F254 plate (Merck) with 254 nm UV light for visualization and a potassium permanganate solution as a staining agent. Flash chromatography was performed using Merck silica gel 60 with distilled solvent.

[0196] X-ray diffraction spectroscopy X-ray diffraction data were collected using CuKα (λ=1.54184A) radiation with an Agilent supernova diffractometer equipped with an ATLAS CCD detector.

[0197] Liquid chromatography-mass spectrometry (LC-MS) LC-MS was performed using an Agilent 1260 Infinity Prime LC connected to a 6475 triple quadrupole mass spectrometer (ionization mode: ESI positive polarity, column: Agilent Solvax Eclipse Plus C18 RRHD 1.8 μM, 2.1 × 50 mm).

[0198] Gel permeation chromatography (GPC) GPC was performed using GPC Lab Ace and Column Gygel-2HR-40 (chloroform 30 mL / min).

[0199] Example 1 Synthesis of 10

[0200] [ka]

[0201] n-BuLi (1.5 M in hexane, 183 mL, 275 mmol) was added dropwise to trimethyl phosphonoacetate 7 (50.0 g, 275 mmol) in THF (600 mL) at -20°C (dry ice-acetone bath), and the mixture was stirred at the same temperature for 30 minutes. 4,4-dimethoxy-2-butanone (8) (40 mL, 39.8 g, 301 mmol) was added dropwise to the mixture, and the reaction mixture was heated to 4°C (ice bath) and stirred for 4 hours. Then, the mixture was removed from the bath and stirred for a further 16 hours at 25°C. The mixture was cooled back to 4°C and rapidly cooled with saturated NH4Cl aqueous solution (500 mL). The organic material was extracted twice with Et2O (500 mL x 2), and the combined organic phase was dried over MgSO4 and concentrated under vacuum. The obtained crude residue was purified by flash chromatography (silica gel, hexane / ethyl acetate (SiO) = 100:0 to 80:20), and 7 (41.5 g, 221 mmol) was obtained in 80% yield at a ratio of 71:29. 1 It was obtained as an E / Z mixture (based on 1H NMR analysis). For analysis, E-10 and Z-10 could be partially separated by flash column chromatography (silica gel, hexane / ԅ = 95:5~90:10).

[0202] About E-10 Appearance: Pale yellow oil. TLC:R f = 0.60 (20% siRNA / hexane). FTIR (undiluted, cm -1 )2949[ν(C=C)], 1714[ν(C=O)], 1651[ν(C=C)], 1225[ν(CO)], 1082[ν(CO)], 813[ν(C=C)]. 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 ). 13 C NMR (100 MHz, CDCl3) δ 167.1, 155.1, 117.9, 102.9, 53.2, 51.0, 44.1, 19.4. HRMS (ESI) C9H 17 O5 + [M+H] + The calculated value is 189.1127; the measured value is 189.1126. Z-10について Appearance: Pale yellow oily substance. TLC:R f =0.62(20%EtOAc / ヘキサン). FTIR (Unknown, cm) -1 )2949[ν(C=C)], 1714[ν(C=O)], 1643[ν(C=C)], 1269[ν(CO)], 1082[ν(CO)], 735[ν(C=C)]. 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 ). 13 C NMR (100 MHz, CDCl3) δ 166.7, 156.3, 117.4, 104.5, 53.8, 51.0, 37.2, 26.6. HRMS (ESI) C9H 17 O5 + [M+H] + The calculated value is 189.1127; the measured value is 189.1113.

[0203] Example 2 Synthesis of 11

[0204] [ka]

[0205] Diisobutylaluminum hydride (DIBAL, 1M in cyclohexane, 463 mL, 463 mmol) was added dropwise to a solution of 10 (71:29 E / Z mixture, 39.5 g, 210 mmol) in CH2Cl2 (800 mL) at -50°C (dry ice-acetone bath), and the reaction was stirred for 30 minutes. The mixture was heated to -20°C, quenched with siRNA (30 mL), and diluted with a saturated aqueous solution of Rochelle salt (500 mL). The mixture was heated to 25°C and stirred for 3 hours. From the separated aqueous phase, the organic material was extracted once with CH2Cl2 (400 mL), the combined organic phase was washed with brine (500 mL), dried over MgSO4, and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 80:20~50:50) to obtain the following four fractions containing 11. Fraction 1: m = 3.98 g, E / Z = 22: 88 Fraction 2: m = 7.70 g, E / Z = 49:51 Fraction 3: m = 4.9g, E / Z = 90:10 Fraction 4: m = 11.9 g, E / Z = 100:0

[0206] The yield for E-11 was 62% based on the calculated mass (m=20.7g), while the yield for Z-11 was 24% (m=7.92g). About the E-11: Appearance: Colorless oil. TLC:R f = 0.25 (40% SiO / hexane). FTIR (undiluted, cm -1 )3410[ν(OH)], 2920[ν(C=C)], 1666[ν(C=C)], 1122[ν(CO)], 1065[ν(CO)]. 1H 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 ). 13 C NMR (100 MHz, CDCl3) δ 134.9, 126.7, 103.4, 59.3, 52.9, 42.6, 16.9. HRMS (ESI) C8H 17 O3 + [M+H] + The calculated value is 161.1178; the measured value is 161.1180. Z-11(E-11とのmixtureとして)について: Appearance: Colorless oily substance. TLC:R f =0.30(40%EtOAc / ヘキサン). FTIR (Unknown, cm) -1 )3388[ν(OH)], 2934[ν(C=C)], 1668[ν(C=C)], 1126[ν(CO)], 1045[ν(CO)]. 1 H 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 ). 13 C NMR (100 MHz, CDCl3) δ 135.8, 127.4, 103.0, 58.2, 53.8, 36.0, 24.4. HRMS C8H 17 O3 + [M+H] + Calculated value: 161.1178; Measured value: 161.1156.

[0207] Example 3 Synthesis of 12

[0208] [ka]

[0209] Trimethylsilyltrifluoromethanesulfonate (TMSOTf, 41.6 mL, 228 mmol) was added dropwise to a solution of E-11 (9.15 g, 57.1 mmol) and 2,6-lutidine (39.8 mL, 343 mmol) in CH2Cl2 (550 mL) at -5°C (ice-NaCl-water bath), and the reaction mixture was stirred for 15 minutes. Then, water (250 mL) was slowly added to rapidly cool the mixture, and the organic phase was washed four times with aqueous CuSO4 solution (1 M, 4 × 300 mL) to completely remove 2,6-lutidine (insufficient washing at this stage would result in contamination of aldehyde 12 with 2,6-lutidine, which would hinder the subsequent Barbier-type allylation), dried over MgSO4, and concentrated under vacuum. The obtained crude residue (m=9.45g) contains aldehyde 12 as its main component (Figure 2). 1 (See 1H NMR spectrum), which was used for coupling with 17 in Example 9 without further purification due to the instability of 12.

[0210] For analysis, a portion of the crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 95:5 to 70:30). Appearance: Pale yellow oil. TLC:R f = 0.5 (5% τ / hexane). FTIR (undiluted, cm -1 )2924[ν(C=C)], 1720[ν(C=O)], 1439[ν(C=O)], 1045[ν(OTMS)]. 11H 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 Me 3). 13 13C NMR (100 MHz, CDCl3) δ 200.0, 130.2, 128.9, 59.3, 54.2, 17.3, -0.3. HRMS (ESI) C9H 19 O2Si + [M+H] + calcd. 187.1154; found 187.1159.

[0211] Example 4 Synthesis of (Z)-iodoalkene 14

[0212]

Chemical Structure

[0213] Methyllithium (MeLi, 3.1 M in diethoxymethane, 75 mL, 232 mmol) was added dropwise to a solution of 9 (38.0 g, 174 mmol) in CH2Cl2 (380 mL) at -78°C (dry ice-acetone bath. After the reaction mixture was stirred for 2 hours, it was quenched with saturated aqueous NH4Cl solution (150 mL) while maintaining the internal temperature below -65°C. The solution was allowed to warm to 25°C, diluted with water (400 mL), and stirred for an additional 5 minutes. The organic material 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 in vacuo. The crude material (m = 25.5 g) containing methyl ketone 13 as the main component obtained was used in the next step without further purification 11H NMR analysis revealed that, as shown in Figure 3, 13, 9, and the diketone are contained in a molar ratio of 1:0.08:0.07).

[0214] Sodium hexamethyldisilazide (2 M in THF, 76 mL, 152 mmol) was added dropwise at 4°C (ice-water bath) to a solution of (iodomethyl)triphenylphosphonium iodide [prepared from triphenylphosphine and diiodomethane (Seyferth, D. et al., J. Organomet. Chem. 1966, 5, 267-274), 80.0 g, 151 mmol] in THF (700 mL) in the dark (by covering the flask with aluminum foil). The solution was stirred for 30 minutes, then cooled to -78°C (dry ice-acetone bath). A solution of crude 13 (25.5 g) in THF (75 mL) was added dropwise to the mixture. After stirring the mixture at the same temperature for 30 minutes, it was warmed to 0°C (ice-water bath). The reaction was quenched with saturated aqueous NH4Cl (100 mL), and filtered through a celite pad to remove solids. The filtrate was diluted with water (600 mL) and Et2O (600 mL), and the aqueous phase was separated. The organic material was extracted once with Et2O (400 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel, hexane / EtOAc = 100:0 to 90:10) to give (Z)-iodoalkene 14 (25.8 g, 79.1 mmol, 45% yield over 2 steps). Of the purified product 1 1H NMR analysis revealed that the purity of 14 was around 98% (Figure 4). Appearance: pale yellow oil. TLC: R f = 0.5 (5% EtOAc / Hex). [α] 20 D +69.9° (C = 1, CHCl3). FTIR (neat, cm -1 ) 2989 [ν(C=C)], 1759 [ν(C=O)], 1207 [ν(C-O)], 1103 [ν(C-O)], 509 [ν(C-I)].[ 1H 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 アセタール ), 1.52 (s, 3H, Me アセタール ). 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. HRMS (ESI) C 10 H 16 IO4 + [M+H] + Calculated value: 327.0094; Measured value: 327.0090.

[0215] Example 5: Synthesis of 15

[0216] [ka]

[0217] Diisobutylaluminum hydride (DIBAL, 1 M in cyclohexane, 91 mL, 91 mmol) was added to a solution of 14 (25.8 g, 79.1 mmol) in CH2Cl2 (260 mL) at -78°C (dry ice-acetone bath), and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was then rapidly cooled with ethyl acetate (siRNA, 30 mL) at -78°C and diluted with a saturated aqueous solution of Rochelle salt (500 mL). The mixture was heated to 25°C and stirred for 3 hours. The organic material was extracted once with CH2Cl2 (400 mL), the combined organic phase was 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 in the next step without further purification.

[0218] 1,4-Diazabicyclo[2.2.2]octane (DABCO, 22.2 g, 198 mmol) was added to the solution of the crude aldehyde obtained above in methyl acrylate (540 mL, 5.96 mol). The reaction mixture was stirred at 25°C for 40 hours in the dark (with aluminum foil around the flask). The reaction mixture was rapidly cooled with saturated NH4Cl aqueous solution (500 mL) and diluted with CH2Cl2 (600 mL). The organic material was extracted twice with CH2Cl2 (300 mL), and the combined organic extract was dried over MgSO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 90:10~80:20) to obtain 15 (22.6 g, 59.1 mmol, 75% yield in 2 steps) as a mixture of diastereoisomers (51:49).

[0219] For analysis, the two diastereomers were partially separated by flash column chromatography. Their stereochemistry at C7 was not determined. Main diastereoisomer 15-main Appearance: Pale yellow oil. TLC:R f = 0.3 (20% siRNA / hexane). [α] 20 D +5.2° (C=1, CHCl3). FTIR (undiluted, 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)]. 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 アセタール ), 1.46 (s, 3H, Me アセタール ). 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. HRMS (ESI) C 13 H 20 IO5 + [M+H] + The calculated value is 383.0355; the measured value is 383.0355. MANASA's heterosexual body 15-MANASA Appearance: Pale yellow oily substance. TLC:R f =0.3(20%EtOAc / ヘキサン). [α] 20 D +24.6° (C=1, CHCl3). FTIR (Unknown, 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)]. 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 アセタール ). 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. HRMS (ESI) C 13 H 20 IO5 + [M+H] + Calculated value: 383.0355; Measured value: 383.0356.

[0220] Example 6 Synthesis of 16

[0221] [ka]

[0222] 15 (14.0 g, 36.6 mmol) was dissolved in hydrobromic acid (HBr 48% in water, Sigma Aldrich-268003, 125 mL) and toluene (125 mL), and the reaction mixture was stirred at 25°C for 16 hours. After diluting the solution with water (500 mL) and toluene (500 mL), the separated organic phase was washed with H2O and brine and dried over MgSO4. The solvent was removed under reduced pressure to obtain a crude mixture, which was purified by flash chromatography (silica gel, hexane / toluene = 90:10~70:30) to obtain an inseparable mixture of 16 and 16' (8.80 g). 1Based on 1H NMR analysis, 16' was obtained in an 85:15 molar ratio (16: 55% yield, 16': 10% yield). By treating the mixture of 16 and 16' with diisopropyl ether (i-Pr2O), 16 could be precipitated, allowing for the isolation of 16 (6.10 g, 16.4 mmol). The structure of 16' was confirmed by its conversion to MOM ether 17' using the mixture of 16 and 16' obtained from the filtrate (see Example 8). Appearance: Solid white. Melting point: 112°C. TLC:R f = 0.2 (30% siRNA / hexane). [α] 20 D +77.0° (C=1, CHCl3). FTIR (undiluted, cm -1 )3437[ν(OH)], 2985[ν(C=C)], 1764[ν(C=O)], 1745[ν(C=C)], 1265[ν(C-Br)], 1076[ν(CO)], 632[ν(C-Br)]. 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 ). 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. HRMS (ESI) C9H 11 BrIO3 + [M+H] + Calculated value: 372.8936; Measured value: 372.8944.

[0223] Example 7: Synthesis of 17

[0224] [ka]

[0225] Trifluoromethanesulfonic acid (TfOH, TCI-T0751, 740 μL, 8.40 mmol) was added dropwise at 25°C to a solution of 16 (15.7 g, 42.1 mmol) in dimethoxymethane (700 mL). The mixture was stirred for 2 hours and then diluted with water (700 mL) and Et2O (500 mL). After separation of the aqueous phase, the organic material was extracted twice with Et2O (500 mL x 2). The combined extracts were dried over MgSO4 and the solvent was removed under vacuum. The resulting crude material was purified by flash chromatography (silica gel, hexane / siRNA = 100:0 to 80:20) to obtain 17 (14.0 g, 33.6 mmol, 80% yield). Single crystals were produced by recrystallization of 17 from diisopropyl ether (i-Pr2O) and diethyl ether (Et2O), and their structure and stereochemistry were confirmed by X-ray crystallography (CCDC-2312148, Figure 5).

[0226] [Table 1]

[0227] Appearance: Pale yellow solid / becomes colorless crystal when recrystallized. Melting point: 114°C. TLC:R f = 0.4 (30% SiO / hexane). [α] 20 D +92.2° (C=1, CHCl3). FTIR (undiluted, 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)]. 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 = 6.0 Hz, 1H, H5), 4.59 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.55 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.12 (dd, J = 1.2. 1.2 Hz, 2H, H 13 ), 3.39 (s, 3H, OCH2O CH 3), 1.95 (d, J = 1.2 Hz, 3H, H 14 ). 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. HRMS (ESI) C 11 H 15 BrIO4 + [M+H] + The calculated value is 416.9198; the measured value is 416.9196.

[0228] Example 8 Synthesis of 17'

[0229]

change

[0230] The filtrate containing 16 and 16' (1.50 g, approximately 1:1 molar ratio) obtained in Example 6 was treated with TfOH (125 mL) in dimethoxymethane (50 mL) at 25°C to yield a mixture of MOM ethers 17 and 17'. These were separated by flash column chromatography (silica gel, hexane / siRNA = 95:5~70:30) (the yield could not be determined by this method). Single crystals of 17' were obtained by recrystallization from diisopropyl ether (i-Pr2O), and their structure and stereochemistry were confirmed by X-ray crystallography (CCDC-2312149, Figure 6).

[0231] [Table 2]

[0232] Appearance: White solid / becomes colorless crystal when recrystallized. Melting point: 92°C. TLC:R f = 0.45 (30% Ether / Hexane). [α] 20 D +160.1° (C=1, CHCl3). FTIR (undiluted, 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)]. 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 CH 2OCH3), 4.61 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.46 (dd, J = 6.0, 3.2 Hz, 1H, H6), 4.28 (dd, J = 11.6, 1.2 Hz, 2H, H13a ), 4.16 (dd, J = 11.6, 1.2 Hz, 2H, H 13b ), 3.33 (s, 3H, OCH2O CH 3), 2.10 (d, J = 1.6 Hz, 3H, H 14 ). 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. HRMS C 11 H 15 BrIO4 + [M+H] + Calculated value: 416.9198; Measured value: 416.9203.

[0233] Example 9 Synthesis of 18

[0234] [ka]

[0235] Crude aldehyde 12 (from Example 3, 9.45 g, approximately 50.7 mmol, approximately 1.95 equivalents) was added at 10°C (ice bath) to a solution of aldehyde 17 (10.8 g, 26.0 mmol) in DMF (180 mL), followed by a solution of chromium chloride (CrCl2, Sigma Aldrich-450782, 8.95 g, 72.8 mmol) in DMF (110 mL). The reaction mixture was heated to 25°C and stirred for 3 hours. The mixture was diluted with saturated aqueous NH4Cl (600 mL) and p-toluenesulfonic acid (494 mg, 2.60 mmol). The mixture was then monitored for the complete disappearance of the TMS ether intermediate (by TLC: R of the silyl ether intermediate). fThe mixture was stirred for 30 minutes until the concentration reached 0.35 (30% HCl / hexane). The organic material was extracted three times with HCl (400 mL x 3), and the combined organic phase was washed with saturated NH4Cl aqueous solution (400 mL) and brine (400 mL), dried over MgSO4, and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / HCl = 50:50 to 20:100) to obtain 18 (9.22 g, 20.4 mmol) in 79% yield (diastereomer ratio = >99:1). Appearance: Pale yellow oil. TLC:R f = 0.25 (70% alkyl / hexane). [α] 20 D +61.5° (C=1, CHCl3). FTIR (undiluted, cm -1 )3402[ν(OH)], 2928[ν(C=C)], 1759[ν(C=O)], 1662[ν(C=C)], 1276[ν(CO)], 1018[ν(CO)]. 1 H 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 CH 2OCH3), 4.53 (d, J = 4.8 Hz, 1H, H5), 4.50 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.18 (d, J = 6.8 Hz, 1H, H2), 3.91 - 3.81 (m, 1H, H8), 3.39 (s, 3H, OCH2O CH 3), 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 14 ), 1.70 (s, 3H, H 15 ). 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. HRMS (ESI) C 17 H 26 IO6 + [M+H] + Calculated value: 453.0774; Measured value: 453.0775. (Figure 7)

[0236] Example 10 Synthesis of 19

[0237] [ka]

[0238] Manganese oxide (MnO2, 21.1 g, 243 mmol) was added to a solution of 18 (11.0 g, 24.3 mmol) in CH2Cl2 (380 mL), and the suspension was stirred at 25°C for 3 hours. The solution was filtered through a Celite pad to remove solids, and the filtrate was concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 70:30~30:70) to obtain 19 (9.32 g, 20.7 mmol) in 85% yield. Appearance: Pale yellow oil. TLC:R f = 0.25 (50% τ / hexane). [α] 20 D +130.6° (C=1, CHCl3). FTIR (undiluted, cm -1)3441[ν(O-H)]、2947[ν(C=C)]、1766[ν(C=O)]、1666[ν(C=O)]、1273[ν(C-O)]、1122[ν(C-O)]。 1 H 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 CH 2OCH3), 4.53 (d, J = 4.4 Hz, 1H, H5), 4.49 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.00 - 3.92 (m, 1H, H8), 3.38 (s, 3H, OCH2O CH 3), 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 ). 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. HRMS (ESI) C 17 H 24 IO6 +[M+H] + Calculated value: 451.0618; Measured value: 451.0617.

[0239] Example 11 Synthesis of 20

[0240] [ka]

[0241] Anhydrous chromium chloride (CrCl2, 2.46 g, 20.0 mmol) was slowly dissolved in anhydrous DMSO (950 mL, degassed by blowing Ar gas for 30 minutes before use) at 4°C (ice bath) to avoid strong exothermic reaction. A solution of 19 (2.25 g, 5.00 mmol) in degassed anhydrous DMSO (40 mL) was added, followed by the addition of a solution of nickel(II) acetylacetonate (Ni(acac)2, 25.7 mg, 0.04 mmol) in degassed anhydrous DMSO (10 mL). The mixture was stirred at 25°C for 16 hours (the reaction progress was monitored by LC-MS; see Note 3, Figure 8 and Table 3). The reaction mixture was diluted with saturated NH4Cl aqueous solution (1 L) and brine (1 L), and the mixture was stirred at 25°C for 30 minutes. The organic material was extracted seven times from the separated aqueous phase with SiO (500 mL × 7), and the combined organic phase was washed with brine (1 L). The residual organic material in the brine phase was extracted once with SiO (500 mL × 1), and the combined organic phase was dried with MgSO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, CH2Cl2 / SiO = 50:50~0:100) to obtain 20 (820 mg, 2.55 mmol) in 51% yield (diastereomer ratio = >99:1). Single crystals of 20 were obtained by recrystallization from diethyl ether (Et2O) and dichloromethane (CH2Cl2), and these single crystals were analyzed by X-ray crystallography (CCDC-2312151, Figure 9).

[0242] Note 1: Several anhydrous CrCl2 from different suppliers (Sigma Aldrich-450782, TCI-C3788, and Fluorochem-101514) were tested, and no significant differences in reactivity were observed (see Table 4 for optimization of reaction conditions).

[0243] Note 2: Adding brine to the aqueous phase facilitated the extraction of 20.

[0244] Note 3: Monitoring of the reaction progress by LC-MS showed the formation of organochromium species, which are protonated after passing through the LC column and analyzed by mass spectrometry as [M+Na] + It was possible to form the reduced alkene intermediate 19-H, which was detected as =347.1 (Figure 8). 19-H was gradually converted to the cyclization product 20 along with the formation of a byproduct. Mass spectrometry ([M+Na] + Based on (671.3), the inventors speculated that the byproduct could be a dimer (19-dimer) derived from an intermolecular NHK reaction.

[0245] [Table 3]

[0246] [Table 4]

[0247] [Table 5]

[0248] Appearance: White solid / becomes colorless crystal when recrystallized. Melting point: 124°C. TLC:R f = 0.25 (70% Â / CH2Cl2). [α] 20 D +132.6° (C=1, CHCl3). FTIR (undiluted, 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)]。 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 CH 2OCH3), 3.93 (d, J = 2.8 Hz, 1H, H6), 3.77 (dddd, J = 10.8, 10.0, 5.2, 4.0 Hz, 1H, H8), 3.30 (s, 3H, OCH2O CH 3), 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 ). 13 C 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. HRMS (ESI) C 17 H 25 O6+ [M+H] + Calculated value: 325.1651; Measured value: 325.1644.

[0249] Origin of diastereoselectivity: Alkenylchromium species 19-Cr is as shown in Figure 10. 7~8 Bond rotation allows for two conformations: 19-Cr major and 19-Cr minor. The 19-Cr major has a C8 tether facing the opposite side of the α-ethylene-γ-butyrolactone moiety, and an alkenylchromium species nucleophilically attacks from the top of the C2 carbonyl group to produce 20. On the other hand, the 19-Cr minor, which could lead to another stereoisomer of 20, is energetically unfavorable due to a serious steric collision between the C8 tether and the α-ethylene-γ-butyrolactone moiety.

[0250] Example 12: Synthesis of 21

[0251] [ka]

[0252] Manganese oxide (MnO2, 3.36 g, 38.7 mmol) at 25°C was added to a solution of 20 (1.25 g, 3.87 mmol) in CH2Cl2 (40 mL), and the suspension was stirred for 3 hours. The solution was filtered through a Celite pad to remove solids, and the filtrate was concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, CH2Cl2 / siRNA = 80:20~50:50) to obtain 21 (1.01 g, 3.14 mmol) in 81% yield. Appearance: Pale yellow oil. TLC:R f = 0.3 (50% Â / CH2Cl2). [α] 20 D +136.5° (C=1, CHCl3). FTIR (undiluted, 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)]。 1 H NMR (400 MHz, CDCl3) δ 6.45 (d, J = 2.8 Hz, 1H, H 13a ), 6.20 (s, 1H, H1), 6.06 (s, 1H, H3), 5.98 (d, J = 2.8 Hz, 1H, H 13b ), 5.39 (s, 1H, H5), 4.53 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.48 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.16 (d, J = 2.8 Hz, 1H, H6), 3.93 (dddd, J = 10.8, 10.8, 4.2, 3.8 Hz, 1H, H8), 3.31 (s, 3H, OCH2O CH 3), 3.02 (dddd, J = 10.8, 2.8, 2.8, 2.8 Hz, 1H, H7), 2.79 (dd, J = 12.4, 3.8 Hz, 1H, H 9b ), 2.47 (dd, J = 12.4, 10.8 Hz, 1H, H 9a ), 2.29 (d, J = 4.2 Hz, 1H, O H ), 1.99 (d, J = 1.6 Hz, 3H, H 14 ), 1.73 (s, 3H, H 15 ). 13 C 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. HRMS (ESI) C 17 H 22 O6Na + [M+Na] +Calculated value: 345.1314; Measured value: 345.1310.

[0253] Example 13 Synthesis of 22

[0254] [ka]

[0255] Methacrylic anhydride (560 μL, 3.74 mmol) was added to a solution of 21 (1.00 g, 3.11 mmol), triethylamine (Et3N, 1.3 mL, 9.3 mmol), and 4-dimethylaminopyridine (DMAP, 75.9 mg, 0.62 mmol) in THF (30 mL), and the reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with CH2Cl2 (80 mL) and aqueous HCl (0.1 M, 80 mL). The organic material was extracted twice from the separated aqueous phase with CH2Cl2 (40 mL x 2), and the combined organic phase was dried over MgSO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 70:30~50:50) to obtain 22 (1.02 g, 2.62 mmol) in 84% yield. Appearance: Pale yellow oil. TLC:R f = 0.3 (50% τ / hexane). [α] 20 D +162.9° (C=1, CHCl3). FTIR (undiluted, cm -1 )2954[ν(C=C)], 1769[ν(C=O)], 1717[ν(C=O)], 1643[ν(C=C)], 1269[ν(CO)], 1155[ν(CO)]. 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 CH 2OCH3), 4.49 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.25 (d, J = 3.2 Hz, 1H, H6), 3.32 (s, 3H, OCH2O CH 3), 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, H 15 ). 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. HRMS (ESI) C 21 H 27 O7 + [M+H] + The calculated value is 391.1757; the measured value is 391.1759.

[0256] Example 14 Synthesis of モレファンチン(1)

[0257] [ka]

[0258] 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 product was slowly quenched with saturated NaHCO3 aqueous solution (150 mL), and the organic material was extracted three times from the separated aqueous phase with CH2Cl2 (50 mL x 3). The combined organic phase was dried over MgSO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 80:20~40:60) to obtain morephanthin 1 (690 mg, 1.99 mmol) in 76% yield. Appearance: Solid white. Melting point: 217°C. TLC:R f = 0.2 (50% SiO / hexane). [α] 20 D +158.2° (C=1, CHCl3). FTIR (undiluted, cm -1 )3437[ν(OH)], 2924[ν(C=C)], 1759[ν(C=O)], 1730[ν(C=O)], 1697[ν(C=O)], 1639[ν(C=C)], 1263[ν(CO)]. 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, 4.0 Hz, 1H, H8), 4.25 (d, J = 4.0 Hz, 1H, H6), 3.40 (dddd, J = 10.8, 4.0, 2.4, 2.0 Hz, 1H, H7), 2.78 (dd, J = 12.0, 4.0 Hz, 1H, H 9a ), 2.51 (dd, J = 12.0, 10.8 Hz, 1H, H 9b ), 2.39 (d, J = 12.0 Hz, 1H, O H ), 2.02 (s, 3H, H 14 ), 1.96 (s, 3H, H 19 ), 1.80 (s, 3H, H 15 ). 13 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). HRMS C 19 H 23 O6 + [M+H] + calculated value: 347.1495; found: 347.1490. (Figure 11)

[0259] Example 15 Synthesis of 23

[0260] [Chemical Formula]

[0261] Sodium borohydride (NaBH4, 585 μL, 0.155 mmol, 10 mg / mL solution in MeOH) was added at 0°C (ice bath) to a solution of 20 (50 mg, 0.154 mmol) in MeOH (2 mL), and the reaction mixture was stirred at the same temperature for 0.5 hours. The mixture was rapidly cooled with saturated NH4Cl aqueous solution (2 mL) and diluted with brine (20 mL). The organic material was extracted from the aqueous phase three times with  (20 mL × 3). The combined organic phase was dried over MgSO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, CH2Cl2 /  = 50:50~0:100) to obtain 23 (37 mg, 0.113 mmol) in 73% yield. A colorless single crystal was produced by the spontaneous crystallization of 23 from deuterated chloroform (CDCl3), and this single crystal was analyzed by X-ray crystallography (CCDC-2312152, Figure 12).

[0262] [Table 6]

[0263] Appearance: White solid / becomes colorless crystal when recrystallized. Melting point: 158°C. TLC:R f = 0.25 (70% Â / CH2Cl2). [α] 20 D +38.5° (C=1, CHCl3). FTIR (undiluted, cm -1 )3439[ν(OH)], 2918[ν(C=C)], 1755[ν(C=O)], 1643[ν(C=C)], 1273[ν(CO)], 1018[ν(CO)]. 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 CH2OCH3), 4.56 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 3.91 - 3.82 (m, 1H, H8), 3.84 (d, J = 5.2 Hz, 1H, H6), 3.44 (s, 3H, OCH2O CH 3), 2.72 (qd, J = 7.2, 7.2 Hz, 1H, H 11 ), 2.62 (dd, J = 12.0, 3.2 Hz, 1H, H 9b ), 2.37 (dd, J = 12.0, 12.0 Hz, 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 ). 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. HRMS C 17 H 26 O6Na + [M+Na] + The calculated value is 349.1627; the measured value is 349.1630.

[0264] Synthesis of Example 16 24

[0265]

change

[0266] MnO2 (80 mg, 0.92 mmol) was added at 25°C to a solution of 23 (30 mg, 0.092 mmol) in CH2Cl2 (2 mL), and the reaction suspension was stirred for 3 hours. Solid matter was removed by filtration through a Celite pad, and the filtrate was concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, CH2Cl2 / siRNA = 80:20~50:50) to obtain 24 (23 mg, 0.071 mmol) in 77% yield. Appearance: Colorless oil. TLC R f = 0.3 (50% Â / CH2Cl2). [α] 20 D +84.6° (C=1, CHCl3). FTIR (undiluted, cm -1 )3458[ν(OH)], 2938[ν(C=C)], 1768[ν(C=O)], 1643[ν(C=O)], 1633[ν(C=C)], 1238[ν(CO)], 1192[ν(CO)], 1018[ν(CO)]. 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 CH 2OCH3), 4.52 (d, J = 6.8 Hz, 1H, O CH 2OCH3), 4.04 (d, J = 5.6 Hz, 1H, H6), 4.05 - 3.96 (m, 1H, H8), 3.45 (s, 3H, OCH2O CH 3), 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, H14 ), 1.71 (s, 3H, H 15 ), 1.43 (d, J = 7.6 Hz, 3H, H 13 ). 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. HRMS C 17 H 24 O6Na + [M+H] + Calculated value: 347.1471; Measured value: 347.1472.

[0267] Example 17 Synthesis of tomenphanthopine F(2)

[0268] [ka]

[0269] 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 product was rapidly cooled with saturated NaHCO3 aqueous solution (50 mL), and the organic material was extracted three times from the separated aqueous phase with siRNA (20 mL x 3). The combined organic phase was dried over MgSO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, CH2Cl2 / siRNA = 70:30~10:90) to obtain tomenphantopine F(2) (13 mg, 0.046 mmol) in 74% yield. Appearance: Solid white. Melting point: 184°C. TLC:R f = 0.3 (70% Â / CH2Cl2). [α] 20 D +34.8° (C=1, MeOH). FTIR (undiluted, cm -1) 3388 [ν(O-H)], 2949 [ν(C=C)], 1753 [ν(C=O)], 1631 [ν(C=O)], 1203 [ν(C-O)], 1018 [ν(C-O)]. 1 1H NMR (400 MHz, methanol-d4) 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 ). 13 13C NMR (100 MHz, methanol-d4) δ 198.4 (C2), 182.3 (C12), 165.1 (C4), 139.0 (C10), 133.7 (C1), 129.3 (C3), 84.6 (C6), 74.0 (C5 and C8 overlapping), 57.7 (C7), 49.8 (C9), 40.6 (C11), 21.0 (C14), 18.6 (C15), 18.4 (C13). HRMS C 15 H 20 O5Na + [M+H] + calculated value 303.1208; found 303.1205. (Figure 13)

[0270] Example 18 Synthesis of 25 - Photoinduced cyclization isomerization of morephantin (1)

[0271] [ka]

[0272] Molefantine (1) (50 mg, 0.144 mmol) was dissolved in degassed CH2Cl2 (5 mL, degassed by blowing Ar gas over 30 minutes), and the solution was irradiated with 370 nm light (40 W x 2) at ambient temperature of 29°C (with fan cooling) for 100 minutes (see Figure 14). The solvent was removed under vacuum to obtain 25 (50 mg, over 99% yield). 25 was pure enough for analysis and was used in the next step.

[0273] Note 1: Compound 25 is unstable on silica gel.

[0274] Note 2: In CDCl3 1 Monitoring of the photochemical reaction by 1H NMR spectroscopy revealed the rapid formation of multiple intermediates with different alkene peaks, which were gradually converted to compound 25 (Figure 16). Appearance: Pale yellow oil. TLC:R f = 0.4 (50% alkyl / hexane). [α] 20 D +42.2° (C=1, CHCl3). FTIR (undiluted, 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)]. 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, 0.8 Hz, 3H, H 19 ), 1.78 (s, 3H, H 15 ), 1.72 (qd, J = 0.8, 0.8 Hz, 3H, H 14 ). 13 13C 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). HRMS C 19 H 23 O6 + [M+H] + calcd. 347.1495; found 347.1490. (Figure 17)

[0275] Example 19 Synthesis of EM-2(3)

[0276] [ka]

[0277] p-toluenesulfonic acid (TsOH·H2O, 160 μL, 8.4 μmol, 10 mg / mL solution in MeOH) was added to a solution of 25 (30 mg, 0.087 mmol) in MeOH (1 mL), and the reaction mixture was stirred at 25°C for 10 minutes. The solvent was removed under vacuum, and the resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 95:5~70:30) to obtain EM-2(3) (29 mg, 0.081 mmol) in 93% yield. Single crystals of 3 were produced by recrystallization from diisopropyl ether (i-Pr2O), and their structure and stereochemistry were confirmed by X-ray crystallography (CCDC-2324191, Figure 18).

[0278] [Table 7]

[0279] Appearance: White solid / becomes colorless crystal when recrystallized. Melting point: 102°C. TLC:R f = 0.4 (20% SiO / hexane). [α] 20 D +48.6° (C=1, CHCl3). FTIR (undiluted, cm -1 )2928[ν(C=C)], 1767[ν(C=O)], 1713[ν(C=O)], 1659[ν(C=C)], 1635[ν(C=C)], 1273[ν(CO)], 1153[ν(CO)], 1092[ν(CO)], 1045[ν(CO)]. 1 H NMR (400 MHz, CDCl3) δ 6.32 (d, J = 3.2 Hz, 1H, H 13a ), 6.16 (qd, J = 1.2, 1.2 Hz 1H, H 18a ), 5.79 (d, J = 2.8 Hz, 1H, H13b ), 5.71 (qd, J = 1.2, 1.2 Hz, 1H, H 18b ), 5.63 (qd, 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 = 6.4, 4.0 Hz, 1H, H6), 3.73 (qd, J = 1.2, 14.4 Hz, 1H, H 9b ), 3.22 (s, 3H, O CH 3), 3.15 (dddd, J = 11.2, 6.4, 3.2, 2.8 Hz, 1H, H7), 2.23 (dd, J = 14.4, 4.4 Hz, 1H, H 9a ), 1.99 (dd, J = 1.2, 1.2 Hz, 3H, H 19 ), 1.78 (d, J = 1.2 Hz, 3H, H 15 ), 1.74 (dd, 3H, J = 1.6, 0.8 Hz, H 14 ). 13 13C 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). HRMS C 20 H 25 O6 + [M+H] + calculated: 361.1651; found: 361.1651. (Figure 19)

[0280] Example 20 Synthesis of fantomoline (4)

[0281] [ka]

[0282] Molefantine (1) (50 mg, 0.144 mmol) was dissolved in degassed CH2Cl2 (0.5 mL) and irradiated with 370 nm light (40 W × 2, 4 cm) at 29 °C for 100 minutes. The solvent was removed by vacuum, and the resulting 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 solution in EtOH). After stirring at 25 °C for 10 minutes, the solvent was removed by vacuum to obtain the crude material, which was purified by flash chromatography (silica gel, hexane / siRNA = 95:5~70:30) to obtain phantomolin (4) (46 mg, 0.123 mmol) in 85% yield. Appearance: Colorless oil. TLC:R f = 0.4 (20% SiO / hexane). [α] 20 D +55.2° (C=1, CHCl3). FTIR (undiluted, cm -1 )2924[ν(C=C)], 1771[ν(C=O)], 1717[ν(C=O)], 1659[ν(C=C)], 1635[ν(C=C)], 1273[ν(CO)], 1153[ν(CO)], 1092[ν(CO)], 1045[ν(CO)]. 1 H 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 CH 2CH3), 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 CH 3). 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 CH 2CH3), 39.1 (C7), 32.8 (C9), 28.8 (C15), 18.6 (C19), 15.6 (OCH2 CH 3), 13.3 (C14). (Figure 20)

[0283] Example 21 Synthesis of 2-O-demethyltomenthopin C(5)

[0284] [[Chemical formula]]

[0285] Sodium methoxide (MeONa, 50 μL, 9.3 μmol, 10 mg / mL solution in MeOH: freshly prepared from NaOMe powder, NaOMe, and MeOH) was added to a solution of 25 (30 mg, 0.087 mmol) in MeOH (1 mL), and the reaction mixture was stirred at 25°C for 3 hours. The mixture was then diluted with siRNA (20 mL) and H2O (20 mL). The separated organic phase was washed with brine (10 mL), dried over MgSO4, and concentrated under vacuum. The resulting crude residue was purified by flash chromatography (silica gel, hexane / siRNA = 90:10~70:30) to obtain 2-O-demethyltomenphantopine C(5) (26 mg, 0.069 mmol) in 79% yield. Appearance: Solid white. Melting point: 272°C (decomposition). TLC:R f = 0.4 (50% alkyl / hexane). [α] 20 D -15.1° (C=1, CHCl3). FTIR (undiluted, cm -1 )3444[ν(OH)], 2924[ν(C=C)], 1782[ν(C=O)], 1713[ν(C=O)], 1666[ν(C=C)], 1635[ν(C=C)], 1296[ν(CO)], 1165[ν(CO)], 1034[ν(CO)]. 1 H 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 CH 3), 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, H 11 ), 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 ). 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. 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 CH 3), 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 ). 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). HRMS C 20 H 27 O7 + [M+H] + calculated: 379.1757; found: 379.1773. (Figure 21)

[0286] Example 22 Synthesis of Tomenfantopin C(6)

[0287]

Chemical Formula

[0288] Sodium methoxide (MeONa, 50 μL, 9.3 mmol, 10 mg / mL solution in MeOH) was added to a solution of 25 (30 mg, 0.087 mmol) in MeOH (1 mL), and the mixture was stirred at 25°C for 3 hours. p-toluenesulfonic acid (TsOH·H2O, 32 μL, 16.8 mmol, 10 mg / mL solution in MeOH) was added, and the mixture was stirred at 25°C for 10 minutes. The solvent was then removed under vacuum, and the resulting crude residue was purified by flash chromatography (silica gel, hexane / Â=95:5~80:20) to obtain tomenphantopine C(6) (26 mg, 0.066 mmol) in a 76% concentration. Single crystals of 6 were obtained by recrystallization from diisopropyl ether (i-Pr2O), and their structure was analyzed by X-ray crystallography (CCDC-2312153, Figure 22).

[0289] [Table 8]

[0290] Appearance: White solid / becomes colorless crystal when recrystallized. Melting point: 272°C (decomposition). TLC:R f = 0.4 (30% SiO / hexane). [α] 20 D -27.0° (C=1, CHCl3). FTIR (undiluted, cm -1 )2924[ν(C=C)], 1778[ν(C=O)], 1712[ν(C=O)], 1664[ν(C=C)], 1634[ν(C=C)], 1265[ν(CO)], 1161[ν(CO)], 1037[ν(CO)]. 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 CH 3), 3.21 (s, 3H, C2O CH 3), 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 ). 13 C12 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 and C8), 79.56 (C6 and 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). HRMS C 21 H 29 O7 + [M+H] + The calculated value is 393.1913; the measured value is 393.1906. (Figure 23)

[0291] Comparative Example 1

[0292] [Table 9]

[0293] Comparative Example 2

[0294] [Table 10]

[0295] Comparative Example 3

[0296] [Table 11]

[0297] Comparative Example 4

[0298] [Table 12]

[0299] Comparative Example 5

[0300] [Table 13]

[0301] Comparative Example 6

[0302] [Table 14]

[0303] Comparative Example 7

[0304] [Table 15]

[0305] Example 23 Retrosynthetic approach to molephanthin (1) A retrosynthetic approach to molephantin (1) involves highly strained C(sp) 2 The process began with the construction of a Ricci 10-membered ring skeleton. This involved the construction of a C2-C3 bond by macrocyclization of E-enal I, which is linked to a Z-iodoalkene (Nozaki, Hiyama, Kishi (NHK) (A. Gil et al., Chem. Rev. 2017, 117, 8420~8446), followed by oxidation of the resulting secondary alcohol (Figure 24). The stereoselective construction of the α-methylene-γ-butyrolactone moiety of I is thought to be achieved by the construction of a C7-C8 bond by Barbier-type allylation of β,γ-unsaturated aldehyde II with optically active 3-bromomethyl-5H-furan-2-one III (DMHodgson et al., Org. Lett. 2011, 13, 2594~2597). While the inventors assumed that the preparation of aldehyde II could start from commercially available trimethyl phosphonoacetate (7) and 4,4-dimethoxy-2-butanone (8), 3-bromomethyl-5H-furan-2-one III was expected to be synthesized from dimethyl 2,3-O-isopropylidene-L-tartrate (9), derived from L-tartaric acid as an inexpensive chiral source of C5 and C6, thus ensuring the potential for expansion of the developed synthetic route.

[0306] The inventors have commenced research using the synthesis of aldehyde II containing the C8-10-1-2 fragment (Figure 25A). This was achieved through the following three steps: (i) a Horner-Wadsworth-Emons reaction of ketone 8 and phosphonoacetic acid 7 to prepare a trisubstituted alkene 10 as an E / Z mixture (71:29); (ii) DIBAL reduction of the ester moiety of 10 to obtain allyl alcohol 11, where the desired E-11 can be separated from Z-11 by silica gel column chromatography; (iii) treatment of E-11 with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in the presence of 2,6-lutidine (H. Fujioka et al., J. Am. Chem. Soc. 2004, 126, 11800~11801) to produce a β,γ-unsaturated aldehyde 12 supporting the trimethylsilyl ether moiety. Due to the instability of 12, it was used in the next step without purification (Figure 25C). In parallel, optically active 3-bromomethyl-5H-furan-2-one III was synthesized from 2,3-O-isopropylidene-L-dimethyl tartrate (9) in five steps (Figure 25B). Nucleophilic acyl substitution with MeLi at one of the methoxycarbonyl groups of 9 enabled the construction of methyl ketone 13, and subsequent whittihyiodoalkenylation proceeded stereoselectively to produce the desired (Z)-iodoalkene 14 (purity over 98%) (G. Stork and K. Zhao, Tetrahedron Lett. 1989, 30, 2173-2174). This two-step sequence was scalable to tens of grams. When the ester portion of 14 was reduced to a monohydride 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 obtain α-methylene-β-hydroxyester 15 as a mixture of less important diastereoisomers (D. Basavaiah et al., Chem. Rev. 2010, 110, 5447~5674).Following the protocol developed by Winssinger (R. Lagoutte et al., Tetrahedron 2018, 74, 6012-6021), treatment of 15 with an aqueous HBr solution enabled the construction of 3-bromomethyl-5,6-dihydro-2H-pyran-2-one 16' as a trace component, along with the optically active 3-bromomethyl-5H-furan-2-one 16 as the main product. After isolation of pure 16 by reprecipitation from diisopropyl ether, its free hydroxyl group was protected with methoxymethyl ether to obtain 17.

[0307] Two main fragment moieties, β,γ-unsaturated aldehyde 12 and 3-bromomethyl-5H-furan-2-one 117, were obtained. A mixture of 12 (approximately 2 equivalents) and 17 was treated with chromium(II) chloride (CrCl2) in dimethylformamide (DMF) to perform a coupling reaction of 12 and 17 via intermolecular Barbier-type allylation, yielding α-methylene-γ-butyrolactone 18 with excellent selectivity and the desired stereochemical configuration at C7 and C8 (diastereomer ratio >99:1, no other diastereomers detected on a 400 MHz 1H NMR spectroscopic scale) (Figure 25C). Workup with an acidic aqueous solution resulted in simultaneous deprotection of the trimethylsilyl ether at the C2 position. This stereocontrol can be rationalized by a Zimmermann-Traxler pseudo-Iss transition state B between aldehydes 12 and 17 and the allylchromium species, where aldehyde 12 is sp on the opposite side of the C5-C6 bond. 2The reaction was primarily initiated from the top surface of the hybridized C7 (HEZimmerman and MDTraxler, J.Am.Chem.Soc. 1957, 79, 1920-1923). Subsequently, the C2-allyl alcohol moiety of 18 was chemoselectively oxidized with manganese dioxide (MnO2) to obtain α,β-unsaturated aldehyde 19. Extensive screening of reaction conditions for NHK macrocyclization of 19 (see example above) revealed that treatment of 19 at 25°C with CrCl2 (4 equivalents) and Ni(acac)2 (2 mol%) in DMSO (5 mM) yielded the desired 10-membered macroring 20 as a single diastereomer (diastereomer ratio >99:1) in 51% yield. The structure of 20 was clearly confirmed by single X-ray crystallography (see Example 11). Dienone 21 was obtained by MnO2 oxidation of the bis-allyl alcohol moiety of 20, and subsequent acylation of the remaining C8 hydroxyl group with methacrylic anhydride yielded 22. Finally, the methoxymethyl ether at C5 was deprotected with trifluoroacetic acid (TFA) to obtain morephanthine (1), the spectral data of which were in agreement with reported values ​​(B. Wang et al., Chin. J. Chem. 2012, 30, 1320-1322).

[0308] Furthermore, the inventors utilized the advantages of a 10-membered macrocyclic intermediate 20 in the synthesis of tomenphantopine F(2) (Figure 25D). Treatment of 20 with sodium borohydride (NaBH4) in MeOH enabled diastereoselective reduction of the exomethylene moiety, yielding α-(S)-methyl-γ-butyrolactone 23 as a single stereoisomer. The stereochemical configuration of 23 was verified by X-ray diffraction analysis (see Example 15). Subsequent MnO2 oxidation of 23 facilitated the construction of dienone 24, and subsequent MOM deprotection with TFA yielded tomenphantopine F(2).

[0309] Example 24: Method for converting morephantin (1) to furanogelmacranolide The inventors' next objective was to find a method for converting morephantin (1) to furanogermacranolide. By hypothetical skeletal transposition of 1 to (Z,Z)-dienone [(Z,Z)-1] via isomerization of the (E,Z)-dienone moiety and subsequent hemiketalization with a C5-hydroxyl group, 2-deethoxy-2β-hydroxyphantomorine (25) could be obtained, and 25 was also isolated from Elephantopus mollis (PP-H. But et al., Planta Med. 1996, 62, 474-476).

[0310] The inventors studied the similar photochemical dienone isomerization of morephantin (1). In fact, the inventors found that the ultraviolet-visible (UV / Vis) spectrum of morephantin (1) in CH2Cl2 (0.5 mM) showed λ max A weak absorption band at 348 nm was observed, which is the n-π of the carbonyl group in the dienone moiety. * Characterized as a transition (see example above) (VNGutrov et al., J. Photochem. Photobiol. A 2022, 425, 113678). The inventors used ultraviolet A light (λ) on a solution of 1 in degassed CH2Cl2. max By irradiation at 370nm, 1 As confirmed by 1H NMR analysis, multiple alkene isomers can be generated within minutes, suggesting that the dienone isomers (E,E)-1, (Z,E)-1, and (Z,Z)-1 can be formed under photoequilibrium. The inventors observed that these dienone congeners can ultimately be converted to a quantitative yield of 25 via hemiketalization of (Z,Z)-1.

[0311] Hemiketal 25 served as a primary scaffold for the synthesis of other furanogelmacranolides, such as EM-2 (3) and phantomorine (4), through ketalization by simple treatment of 25 with the corresponding alcohol in the presence of a catalytic amount of p-toluenesulfonic acid (TsOH) (Figure 26). Treatment of 25 with sodium methoxide in methanol (NaOMe) allowed for the chemical and diastereoselective addition of methanol to the exomethylene-γ-butyrolactone moiety to obtain 2-O demethyltomenphantopine C (5). Subsequently, after the addition of methanol to 25 under basic reaction conditions, continuous C2 ketalization was induced by acidification of the solution to obtain tomenphantopine C (6).

[0312] Example 25 Stereoselective synthesis route Figure 27 describes the synthetic route using MOM as the alcohol protecting group.

[0313] Example 26 Bromolactone synthone (Figure 28)

[0314] [ka]

[0315] H3BO3 (8.22 g, 133 mmol) was added to a solution of L-tartaric acid 1 (200 g, 1.33 mol) in MeOH (2.5 L). The mixture was stirred for 36 hours, and the solvent was removed to obtain 234 g (yield = 99%) of (+)-L-dimethyl tartrate. The crude product was used without further purification. TLC:R f = 0.2 (40% Â / Hex). [α] 20 D +1.0° (C=1, CHCl3). FTIR (undiluted, cm -1 )3458, 1748, 1439, 1277, 1240, 1128, 1090, 908, 735, 650. 1H NMR (396 MHz, CDCl3) δ 4.59 (s, 2H), 3.86 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 172.06, 72.21, 53.24. HRMS C6H 11 O6 + [M+H] + Calculated value: 179.0556; Measured value: 179.0557.

[0316] [ka]

[0317] 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 saturated with NaHCO3 (NaHCO3). 3sat The solution was washed with ) and dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â1 95 / 5~60 / 40) to obtain 19.3 g (yield = 79%) of (-)-2,3-O-isopropylidene-L-dimethyl tartrate 9. TLC:R f = 0.3 (20% Â / Hex). [α] 20 D -46° (C=1, CHCl3). FTIR (undiluted, cm -1 )2994, 2957, 1759, 1375, 1254, 1211, 1161, 1113, 1014, 858, 748. 1 H NMR (396 MHz, CDCl3) δ 4.81 (s, 2H), 3.83 (s, 6H), 1.50 (s, 6H). 13 ¹³C NMR (100 MHz, CDCl₃) δ. 170.21, 114.00, 77.11, 52.94, 26.41. HRMS C9H 15 O6 + [M+H] + Calculated value: 219.0869; Measured value: 219.0863.

[0318] [ka]

[0319] Methyllithium (60 mL, 180 mmol, 3 M in DME) was added dropwise to dimethyl-9 isopropylidena tartrate (24 g, 720 mmol) in CH2Cl2 (250 mL) at -78°C. The mixture was stirred for 2 hours to obtain saturated NH4Cl(NH4Cl sat. The mixture was rapidly cooled using ) and heated to room temperature, then stirred for 5 minutes. The aqueous phase was extracted with CH2Cl2, combined with the organic phase, washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â1 95 / 5~60 / 40) to obtain 16.1 g (yield = 72%) of methyl ketone 13. The presence of an inseparable diketone was confirmed. TLC:R f = 0.3 (20% Â / Hex). [α] 20 D -3.5° (C=1, CHCl3). FTIR (undiluted, cm -1 )2993, 2954, 1759, 1724, 1439, 1377, 1358, 1254, 1211, 1157, 1107, 1022, 860, 806, 737, 579, 513. 1 H NMR (396 MHz, CDCl3) δ 4.74 (d, J = 5.6 Hz, 1H), 4.64 (d, J = 5.5 Hz, 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).

[0320] [ka]

[0321] NaHMDS (111 mL, 111 mmol, 1 M in THF) was added dropwise to (iodomethyl)triphenylphosphonium iodide (58.8 g, 111 mmol) in THF (500 mL) at 0°C and stirred for 30 minutes. The mixture was cooled to -78°C and 13 (18.7 g, 92.5 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes and then warmed to 0°C. The mixture was then mixed with NH4Cl sat. The mixture was rapidly cooled and diluted in Et2O. The aqueous phase was extracted with Et2O, the organic phase was combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / siRNA 100 / 0~60 / 40) to obtain 15.8 g (yield = 52%) of trisubstituted alkene 14. Based on the diketone present in the starting material, the yield is estimated to be 70%. TLC:R f = 0.6 (5% Et2O / Hex). [α] 20 D 69.9° (C=1, CHCl3). FTIR (undiluted, cm -1 )3059, 2990, 2920, 2851, 1759, 1620, 1439, 1377, 1292, 1258, 1207, 1165, 1103, 1057, 1026, 984, 887, 856, 806, 756, 694, 509. 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 = 1.5 Hz, 3H), 1.53 (dd, J = 6.1, 0.7 Hz, 6H). HRMS C 10 H 16 IO4 + [M+H] +Calculated value: 327.0094; Measured value: 327.0090.

[0322] [ka]

[0323] DIBAl-H (63 mL, 63 mmol, 1 M in cyclohexane) was added to a solution of 14 (15.8 g, 48.5 mmol) in CH2Cl2 (200 mL) at -78°C. The mixture was stirred at -78°C for 1 hour and then rapidly cooled with siRNA, followed by tartaric acid solution. The mixture was warmed to room temperature, stirred for 2 hours, and then filtered through Celite. The aqueous phase was extracted with siRNA, combined with the organic phase, washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum to obtain 15.7 g of aldehyde. The crude product was used without further purification.

[0324] The sample was partially decomposed on silica. TLC:R f = 0.3 (20% Â / Hex). [α] 20 D 61.2° (C=1, CHCl3). FTIR (undiluted, cm -1 )441, 3055, 2985, 2920, 1735, 1618, 1438, 1377, 1285, 1242, 1219, 1150, 1072, 1026, 887, 810, 783, 737, 702, 509. 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). 13C NMR (100 MHz, CDCl3) δ 141.43, 133.40, 132.61, 132.60, 79.93, 63.54, 21.26. HRMS C9H 14 IO4 + [M+H] + Calculated value: 296.9988; Measured value: 296.9986.

[0325] [ka]

[0326] 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 then mixed with CH2Cl2 and NH4Cl sat. The solution was diluted with CH2Cl2. The aqueous phase was extracted with CH2Cl2, the organic phase was combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â10 90 / 10~70 / 30) to obtain 10.7 g (yield = 58% in 2 steps) of compound 15, characterized by a mixture of diastereoisomers. Diastereoisomer 1 TLC:R f = 0.3(30%Â / Hex) C 13 H 20 IO5 + HRMS calculated value [M+H] + 383.0355; Measured value 383.0355. Diastereoisomer 2 TLC:R f = 0.3 (30% Â / Hex). C 13 H 20 IO5 + HRMS calculated value [M+H] + 383.355; Measured value 383.0356.

[0327] [ka]

[0328] 15 (10.7 g, 28 mmol) was dissolved in HBr / siRNA 1 / 1 (50 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with siRNA 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 flash chromatography (Hex / siRNA 90 / 10~70 / 30). The resulting yellow powder was tritured in diisopropyl ether to obtain 5.2 g (yield = 50%) of 16. TLC:R f =0.2(25%Â / Hex) [α] 20 D 70.0° (C=1, CHCl3). FTIR (undiluted, cm -1 )3437, 3082, 2916, 2357, 1748, 1643, 1431, 1350, 1277, 1242, 1222, 1130, 1061, 1015, 957, 779, 676. 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). 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.

[0329] [ka]

[0330] TfOH (330 μL, 3.75 mmol) was added dropwise to a solution of 16 (4 g, 10.7 mmol) in dimethoxymethane (150 mL) at room temperature, and the mixture was stirred for 2 hours. The mixture was diluted with Et2O and brine. The aqueous phase was extracted with Et2O, the organic phase was combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / siRNA 100 / 0~80 / 20) to obtain 3.46 g (yield = 77%) of 17. TLC:R f = 0.4 (25% Â / Hex). [α] 20 D +92.2° (C=1, CHCl3). FTIR (undiluted, cm -1 )3441, 3082, 2924, 2820, 1755, 1638, 1616, 1427, 1354, 1281, 1211, 1150, 1096, 1065, 1015, 984, 922, 864, 779, 737, 679, 621. 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). 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. HRMS C 11 H 15 BrIO4 + [M+H] + Calculated value: 416.9198; Measured value: 416.9196.

[0331] Example 27: Aldehyde Synthone (Figure 29)

[0332] [ka]

[0333] n-BuLi (183 mL, 275 mmol, 1.5 M in hexane) was added dropwise to trimethyl phosphonoacetate 7 (50 g, 275 mmol) in THF (600 mL) at -20°C. After 30 minutes, 1,1-dimethoxypropan-2-one 8 (40 g, 302 mmol) was added. The mixture was heated to 4°C and stirred for 4 hours. The mixture was heated to room temperature and stirred for 16 hours. The mixture was cooled to 4°C and NH4Cl sat. The mixture was rapidly cooled. The aqueous phase was extracted twice with diethyl ether, the organic phase was combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / SiO 100 / 0~80 / 20) to obtain 41.5 g (yield = 80%) of 10 as a mixture of diastereoisomers (ratio (E) / (Z) 2.4 / 1), and this (E) isomer can be more easily separated in the next step. (E) Analysis of purified isomer samples TLC:R f = 0.4 (10% Â / Hex). FTIR (undiluted, cm -1 )2951, 2831, 1717, 1647, 1435, 1354, 1223, 1153, 1119, 1080, 1065, 968, 918, 868, 814, 598. 1 H NMR (396 MHz, CDCl3) δ 5.74 (q, J = 1.2 Hz, 1H), 4.54 (t, J = 5.7 Hz, 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). 13C NMR (100 MHz, CDCl3) δ 167.08, 155.11, 117.95, 102.95, 53.19, 50.98, 44.08, 19.38. HRMS C9H 14 O5 + [M+H] + Calculated value: 189.1127; Measured value: 189.1126.

[0334] [ka]

[0335] DIBAl-H (530 mL, 530 mmol, 1 M in cyclohexane) was added dropwise to a solution of 10 (41.5 g, 220 mmol) in CH2Cl2 (800 mL) at 4°C, and the mixture was stirred for 0.5 hours. The mixture was then mixed with siRNA + NH4Cl sat. The mixture was then carefully quenched with tartaric acid solution. The mixture was warmed to room temperature and stirred for 2 hours. The aqueous phase was extracted with ethyl acetate, the organic phase was combined, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / ethyl acetate 80 / 20~50 / 50) to obtain 17.4 g (yield = 49%) of pure E-11 with (E) configuration. TLC:R f = 0.3 (50% Â / Hex). FTIR (undiluted, cm -1 )3410, 2920, 2835, 1666, 1447, 1366, 1296, 1234, 1188, 1123, 1065, 1003, 964, 808, 567. 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). 13C NMR (100 MHz, CDCl3) δ 126.71, 103.42, 59.29, 52.86, 42.63, 16.86. HRMS C8H 17 O3 + [M+H] + Calculated value: 161.1178; Measured value: 161.1180.

[0336] [ka]

[0337] 2,6-Lutidine (5 mL, 42.72 mmol) was added dropwise to E-11 (1.14 g, 7.12 mmol) at 4°C, followed by TMSOTf (5.2 mL, 28.46 mmol). The mixture was stirred at 4°C for 30 minutes, 33 mL of water was added, and the mixture was stirred again at 4°C for another 30 minutes. The mixture was then mixed with CH2Cl2 and NH4Cl sat. The solution was diluted with water. 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 flash chromatography (Hex / Â 95 / 5~70 / 30) to obtain 695 mg (yield = 52%) of ¹². TLC:R f = 0.5 (5% τ / Hex). FTIR (undiluted, cm -1 )2924, 2837, 1720, 1663, 1439, 1385, 1096, 1045, 1007, 880, 841, 779, 605. 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). 13C NMR (100 MHz, CDCl3) δ 198.51, 128.66, 127.34, 57.76, 52.67, -1.81. HRMS C9H 19 O2Si + [M+H] + Calculated value: 187.1154; Measured value: 187.1159.

[0338] Example 28: Late-stage sequence (Figure 30)

[0339] [ka]

[0340] A solution of CrCl2 (2.65 g, 21.6 mmol) in DMF (30 mL) was added at 10°C to solutions of 17 (3.00 g, 7.19 mmol) and 12 (2.6 g, 14.0 mmol) in DMF (50 mL). The mixture was warmed to room temperature and stirred for 1 hour. The mixture was then mixed with NH4Cl sat. Diluted and stirred at room temperature for 30 minutes. The aqueous phase was extracted three times with HCl, and the organic phase was combined with NH4Cl. sat. The solution was washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (CH2Cl2 / Â10 70 / 30~20 / 80) to obtain 2.76 g (yield = 85%) of compound 18. TLC:R f =0.3(70% Â / Hex) [α] 20 D +51.3° (C=1, CHCl3). FTIR (undiluted, cm -1 )3402, 2928, 2893, 2361, 1759, 1662, 1639, 1439, 1411, 1277, 1238, 1153, 1099, 1061, 1018, 922, 818, 787, 733, 679. 1H 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). 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. HRMS C 17 H 26 IO6 + [M+H] + Calculated value: 453.0774; Measured value: 453.0775.

[0341] [ka]

[0342] MnO2 (2.88 g, 33.2 mmol) was added to a solution of 18 (1 g, 2.21 mmol) in CH2Cl2 (30 mL), and the mixture was stirred at room temperature for 4 hours. The mixture was filtered through Celite to remove the solvent. The crude product was purified by flash chromatography (Hex / siRNA 80 / 20~50 / 50) to obtain 650 mg (yield = 71%) of 19. TLC:R f = 0.3 (50% Â / Hex). [α] 20 D +130° (C=1, CHCl3). FTIR (Unknown, cm) -1 )3441, 2947, 2924, 1767, 1666, 1439, 1408, 1273, 123, 1068, 1018, 922, 818, 733, 698. 1 H NMR (396 MHz CDCl3) δ 9.98 (d, J = 7.8 Hz, 1H), 6.41 (d, J = 2.0 Hz, 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 = 3.6 Hz, 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). 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. HRMS C 17 H 24 IO6 + [M+H] + The calculated value is 451.0618; the measured value is 451.0617.

[0343]

change

[0344] A solution of 19 (700 mg, 1.55 mmol) in DMSO (5 mL) was added to a solution of CrCl2 (1.15 g, 9.33 mmol) in DMSO (240 mL), followed by the first addition of Ni(acac)2 (12 mg, 0.016 mmol). The mixture was stirred at room temperature for 1 hour, and Ni(acac)2 (12 mg, 0.016 mmol) was added. The mixture was stirred for 5 hours, and siRNA / NH4Cl was added. sat. The solution was diluted and stirred at room temperature for 1 hour. The aqueous phase was extracted three times with HCl, and the organic phase was combined with NH4Cl. sat. The solution was washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (CH2Cl2 / Â 50 / 50~10 / 90) to obtain 245 mg (yield = 49%) of 20. TLC:R f = 0.25 (70% Â / CH2Cl2). [α] 20 D +132° (C=1, CHCl3). FTIR (undiluted, cm -1 )3381, 2939, 2914, 2848, 2351, 1728, 1714, 1651, 1556, 1267, 1153, 1099, 1064, 1020, 995, 918, 871, 815, 797, 732, 702, 615. 1H 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 = 3.9 Hz, 1H), 3.30 (d, J = 1.6 Hz, 3H), 2.96 - 2.86 (m, 1H), 2.67 (dd, J = 12.5, 3.9 Hz, 1H), 2.50 - 2.35 (m, 1H+OH), 1.79 (d, J = 1.8 Hz, 3H), 1.63 (s, 3H). 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. HRMS C 17 H 25 O6 + [M+H] + Calculated value: 325.1651; Measured value: 325.1644.

[0345] [ka]

[0346] MnO2 (964 mg, 11.1 mmol) was added to a solution of 20 (240 mg, 0.74 mmol) in CH2Cl2 (25 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was filtered through Celite to remove the solvent. The crude product was purified by flash chromatography (CH2Cl2 / siRNA 80 / 20~50 / 50) to obtain 190 mg (yield = 80%) of 21. TLC:R f= 0.3 (50% EtOAc / CH₂Cl₂). [α] 20 D +136° (C = 1, CHCl₃). FTIR (neat, cm -1 ) 3518, 2945, 2922, 1755, 1633, 1608, 1435, 1381, 1269, 1246, 1151, 1130, 1103, 1070, 1018, 933, 918, 815, 732, 704. 1 ¹H 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). 13 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. HRMS C 17 H 22 O₆Na+ [M+Na] + Calculated value: 345.1314; Measured value: 345.1310.

[0347] [ka]

[0348] Methacrylic anhydride (103 μL, 0.689 mmol) was added to a solution of 21 (185 mg, 0.574 mmol), Et3N (242 μL, 1.72 mmol), and DMAP (14 mg, 0.115 mmol) in THF (5 mL). The mixture was stirred at room temperature for 3 hours, and the solvent was removed. The crude product was treated with HCl and NH4Cl sat. The solution was diluted with [a specific solution]. The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â 70 / 30~50 / 50) to obtain 170 mg (yield = 76%) of 22. TLC:R f = 0.3 (50% Â / Hex). [α] 20 D +163° (C=1, CHCl3). FTIR (undiluted, cm -1 )2954, 2852, 1769, 1717, 1643, 1611, 1439, 1317, 1269, 1155, 1111, 1076, 1020, 918, 814, 734, 702. 1H 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). 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. HRMS C 21 H 27 O7 + [M+H] + Calculated value: 391.1757; Measured value: 391.1759.

[0349] [ka]

[0350] Dissolve 22 (157 mg, 0.402 mmol) in a CH2Cl2 / TFA solution (1 / 1, 5 mL) and stir the mixture at room temperature for 3 hours. 3satThe mixture was rapidly cooled, 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 flash chromatography (Hex / siRNA 80 / 20~40 / 60) to obtain 101 mg of (+)-molefantin 1 (yield = 73%).

[0351] [ka]

[0352] TLC:R f = 0.2(50% Â / Hex). [α] 20 D +158.0° (C=1, CHCl3). FTIR (undiluted, cm -1 )2955, 2924, 2851, 1759, 1730, 1697, 1639, 1462, 1377, 1263, 1161, 1082, 1047, 743, 706. 1¹H 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 = 6.2 Hz, 1H, H5), 5.30 - 5.18 (m, 1H, H8), 4.25 (d, J = 3.7 Hz, 1H, H6), 3.40 (dd, J = 10.8, 3.7 Hz, 1H, H7), 2.77 (dd, J = 12.1, 4.1 Hz, 2H, H9a+OH), 2.52 (dd, J = 12.2, 10.9 Hz, 1H, H9b), 2.02 (d, J = 1.4 Hz, 3H, H14), 1.96 (d, J = 0.6 Hz, 3H, H18), 1.80 (d, J = 1.0 Hz, 3H, H15). 13 ¹³C 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).

[0353]

Table 16

[0354] 1 H- 1 H COSY correlation: (H9a,b / H8), (H19 / H20), (H8 / H7), (H18 / H19 a,b ), (H7 / H6), (H3 / H14), (H1 / H15). 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 ) NOESY related: (H5 / H1), (H6 / H15), (H5 / H7), (H6-H8). C 19 H 23 O6 + のHRMS calculation value [M+H] + 347.1495; measured value 347.1490. Analysis of モレファンチニン100の

[0355]

change

[0356] TLC:R f =0.2(50%EtOAc / Hex). [α] 20 D +184.5 o (C=1, CHCl3). FTIR (Unknown, cm) -1 )3427, 3053, 2986, 2940, 1759, 1692, 1639, 1601, 1441, 1265, 1238, 1138, 1084, 1047, 1022, 947, 914, 806, 737, 704. 1¹H 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). 13 ¹³C 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).

[0357] Table 17 1 H- 1 H COSY correlation: (H13 a,b / 7), (H19 / H20), (H8 / H7), (H8 / H9 a,b ), (H7 / H6), (H3 / H14), (H1 / H15). HMBC correlation: (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 ). NOESY correlation: (H5 / H1), (H6 / H15), (H9 / H15). C 20 H 25 O6 + HRMS calculated value [M+H] + 361.1652; measured value 361.1649.

[0358] Example 29: Phantomorine family

[0359] [ka]

[0360] Molefantine 1 (10 mg, 0.029 mmol) was dissolved in CH2Cl2 (0.5 mL) and irradiated with 370 nM light (40 watts, 4 cm) for 1 hour and 45 minutes. The solvent was removed under vacuum, and the resulting 25 crude products (10 mg, yield = 100%) were used in the next step without further purification. Analysis of purified samples

[0361] [ka]

[0362] TLC:R f = 0.4 (50% Â / Hex). [α] 20 D +42.2° (C=1, CHCl3). 1¹H 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 = 6.1, 3.9 Hz, 1H, H6), 3.60 (d, J = 14.0 Hz, 1H, H9 a ), 2.98 (d, J = 5.0 Hz, 1H, H7), 2.53 (s, 1H, OH), 2.12 (dd, J = 14.3, 4.4 Hz, 1H H9 b ), 1.77 (s, 3H, H18), 1.62 (d, J = 1.1 Hz, 3H, H15), 1.36 (s, 3H, H14). 13 ¹³C NMR (101 MHz, C₆D₆) δ 168.16 (C-12), 165.25 (C-16), 137.34 (C-4), 136.38 (C-17), 136.01 (C-11), 132.06 (C-10), 131.02 (C-3), 128.28 (C-1), 125.68 (C-13), 125.64 (C-19), 110.33 (C-2), 85.10 (C-5), 78.71 (C-6), 76.94 (C-8), 38.88 (C-7), 32.32 (C-9), 28.38 (C-15), 18.18 (C-18), 12.74 (C-14).

[0363] Table 18

[0364] 1 H- 1H COSY correlation: (H13 a,b / 7), (H19 a (H18), (H8, H7), (H8, H9 b ), (H5 / H6). HMBC correlation: (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). NOESY correlation: (H5 / H6), (H5 / H14), (H6 / H8), (H6 / H9 a ), (H1 / H15). C 19 H 23 O6 + HRMS calculated value [M+H] + 347.1495; Measured value 347.1490.

[0365] [ka]

[0366] Morephantinin 100 (10 mg, 0.029 mmol) was dissolved in CH2Cl2 (0.5 mL) and irradiated with 370 nM light (40 watts, 4 cm) for 1 hour and 45 minutes. The solvent was removed under vacuum, and the resulting crude product 101 (10 mg, yield = 100%) was used in the next step without further purification.

[0367] [ka]

[0368] TLC:R f =0.4(50% Â / Hex) 11H 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, H20). 13 13C NMR (100 MHz, C6D6) δ 168.41 (C-12), 165.94 (C-16), 137.94 (C-19), 133.66 (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).

[0369] Table 19

[0370] 1 H- 1 H COSY correlation: (H13 a,b / H7), (H19 / H18), (H19 / H20), (H8, H7), (H8, H9 b ), (H5 / H6), (H6 / H7), (H3 / H14), (H1 / H15). HMBC correlation: (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). NOESY correlation: (H5 / H6), (H1 / H8), (H6 / H9) a ). C 20 H 25 O6 + HRMS calculated value [M+H] + 361.1651; Measured value 361.1651.

[0371] [ka]

[0372] PTSA (50 mg, 0.29 mmol) was added to 25 (200 mg, 0.5 mmol) in 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 flash chromatography (Hex / siRNA 100 / 0~80 / 0) to obtain 143 mg (yield = 66%) of phantomorin 4. TLC:R f = 0.4 (30% Â / Hex). [α] 20 D+55.2° (C=1, CHCl3). FTIR (Unknown, 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. 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). 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. HRMS C 21 H 27 O6 + [M+H] + The calculated value is 375.1808; the measured value is 375.1794.

[0373] [ka]

[0374] PTSA (25 mg, 0.15 mmol) was added to 25 (100 mg, 0.25 mmol) in 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 flash chromatography (Hex / Â 100 / 0~80 / 0) to obtain 68 mg (yield = 64%) of 2-deethoxy-2β-methoxyphantomolin 3. TLC:R f = 0.4 (30% Â / Hex). [α] 20 D +48.6° (C=1, CHCl3). FTIR (undiluted, cm -1 )2974, 2928, 2886, 1767, 1713, 1659, 1636, 1443, 1404, 1381, 1273, 1153, 1092, 1045, 1011, 964, 841, 818, 737, 683, 664, 610. 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). 13C 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. HRMS C 20 H 25 O6 + [M+H] + Calculated value: 361.1651; Measured value: 361.1651.

[0375] [ka]

[0376] MeONa (19 mg, 0.35 mmol) was added to 25 (100 mg, 0.29 mmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 1 hour. The solvents were CH2Cl2 and NH4Cl. sat. The solution was diluted in water. The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â 100 / 0~80 / 0) followed by GPC to obtain 54 mg (yield = 51%) of compound 5. TLC:R f = 0.4 (50% Â / Hex). 1H 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). 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.

[0377] [ka]

[0378] MeONa (0.8 mg, 0.015 mmol) was added to 24 (55 mg, 0.15 mmol) in MeOH (3 mL), and the mixture was stirred at room temperature for 16 hours. The solvents were CH2Cl2 and NH4Cl. sat The mixture was diluted in water. The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â100 / 0~80 / 0) to obtain 43 mg (yield = 72%) of compound 26.

[0379] Example 30: Racemic synthesis route (Figure 31)

[0380] [ka]

[0381] Methylmagnesium 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) at -10°C. The mixture was warmed to room temperature and stirred for 4 hours. The mixture was cooled to -5°C, and iodine (91 g, 360 mmol) from THF (400 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was then cooled to NH4Cl at 4°C. sat. The mixture was rapidly cooled and filtered through Celite. The aqueous phase was extracted with diethyl ether, combined with the organic phase, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â1 95 / 5~60 / 40) to obtain 44.8 g (yield = 63%) of trisubstituted alkene 50. 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). 13 C NMR (100 MHz, CDCl3) δ 146.20, 74.99, 68.24, 21.77.

[0382] [ka]

[0383] MnO2 (225 g, 2.59 mol) was added in fractions to 51.2 g, 259 mmol of 50 in 1.2 L of CH2Cl2, and the mixture was stirred at room temperature until the starting material was completely gone (TLC monitoring, approximately 36 hours). The mixture was filtered through Celite and cooled to 4°C. Phosphophosphate (86.5 g, 259 mmol) in 500 mL of CH2Cl2 was added dropwise, and the mixture was stirred at 4°C for 30 minutes. The mixture was filtered through a silica pad, and the solvent was removed under vacuum to obtain 60.09 g (crude yield = 92%) of 51. The crude product was used without further purification. 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). 13 C NMR (100 MHz, CDCl3) δ 167.35, 145.14, 140.99, 122.36, 88.41, 51.98, 21.10.

[0384] [ka]

[0385] DibaAl-H (454 mL, 454 mmol, 1 M in THF) was added at -78°C to a solution of 51 (52 g, 206 mmol) in CH2Cl2 (500 mL). The mixture was warmed to 4°C and stirred for 15 minutes. The mixture was cooled to -10°C and quenched with tartaric acid solution. The mixture was warmed to room temperature and subsequently diluted with  and tartaric acid solution. The aqueous phase was extracted with Â, the organic phase was combined, washed with brine, dried over magnesium sulfate, and the solvent was removed under vacuum to obtain 47 g (crude yield 88%) of 52. The crude product was used without further purification. 1H 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). 13 C NMR (100 MHz, CDCl3) δ 141.43, 133.40, 132.61, 132.60, 79.93, 63.54, 21.26.

[0386] [ka]

[0387] A solution of TBSCl (31.5 g, 209 mmol) in CH2Cl2 (300 mL) was added dropwise at 4°C to a solution of 52 (47 g, 209 mmol) and imidazole (21.4 g, 315 mmol) in CH2Cl2 (500 mL). The mixture was warmed at room temperature and stirred for 1 hour. The mixture was diluted with 0.1 M HCl, the organic phase was washed with 0.1 M HCl and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was dissolved in the minimum amount of CH2Cl2 and filtered through a silica pad. After removing the solvent, 51.3 g (crude yield 72%) of 53 was obtained. The crude product was used without further purification. 1 H NMR (396 MHz, CDCl3) δ 6.74 - 6.61 (m, 1H), 6.09 (tq, J = 1.4, 0.7 Hz, 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). 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.

[0388] [ka]

[0389] 53 (24g, 70.94 mmol) is mixed with K2OsO2(OH)4 (1g, 2.71 mmol) and NMO.H2O (9.14g, 78.03 mmol, 50% in water) in tBuOH / H2O 1 / 1 (500mL). wt The mixture was added dropwise to a solution of ). The mixture was stirred at room temperature for 24 hours. The mixture was rapidly cooled over sodium sulfite, stirred for 20 minutes, filtered through Celite, 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 flash chromatography (Hex / siRNA 95 / 5~70 / 30) to obtain 18.1 g (yield = 68%) of 54. 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). 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.

[0390] [ka]

[0391] Acetone (100 mL) was added to 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 pressure, the crude product was dissolved in CH2Cl2, filtered through Celite, and the solvent was removed under pressure. The crude product was purified by flash chromatography (Hex / siRNA 95 / 5~70 / 30) to obtain 1.08 g (yield = 63%) of 55. 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). 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.

[0392] [ka]

[0393] 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) at -78°C. After stirring for 15 minutes, 5.27 g (17.68 mmol) of 55 was added dropwise, and the mixture was stirred for 15 minutes, followed by the dropwise addition of Et3N (12.4 mL, 88.4 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. A hexane / Et2O 1 / 1 solution was added, and the mixture was filtered through a silica pad. The solvent was removed to obtain 5.25 g (crude yield over 100%) of 56. The crude product was used without further purification.

[0394] [ka]

[0395] DABCO (2.18 g, 19.45 mmol) was added to a solution of 56 (5.23 g, 17.67 mmol) in methyl acrylate (60 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was then mixed with CH2Cl2 and NH4Cl sat The solution was diluted with CH2Cl2. The aqueous phase was extracted with CH2Cl2, the organic phase was combined, dried with magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (Hex / Â10 90 / 10~70 / 30) to obtain 3.86 g (yield = 57% in 2 steps) of 57, characterized by a mixture of diastereoisomers.

[0396] [ka]

[0397] 57 (4.1 g, 0.060 mmol) was dissolved in HBr / Â1 / 1 (30 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with Â1 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 flash chromatography (Hex / Â1 90 / 10~70 / 30) to obtain 2.03 g (yield = 51%) of 58. 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). 13C NMR (100 MHz, CDCl3) δ 170.56, 149.35, 144.08, 132.52, 83.22, 78.39, 77.21, 20.71, 20.21.

[0398] [ka]

[0399] Pyridinium p-toluenesulfonate (PPTS, 67 mg, 0.268 mmol) was added at 4°C to a solution of 58 (1 g, 2.68 mmol) and 3,4-dehydro-2H-pyran (367 μL, 4.02 mmol) in CH2Cl2 (10 mL), and the mixture was stirred for 2 hours and 30 minutes. 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 flash chromatography (Hex / siRNA 100 / 0~70 / 30) to obtain 1.11 g (yield = 90%) of 59 as a mixture of diastereoisomers. 1¹H 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). 13 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.

[0400] [[Chemical]]

[0401] Solutions of 59 (449 mg, 0.982 mmol) and 12 (311 mg, 1.67 mmol) in DMF (5 mL) were added at 4°C to a solution of CrCl2 (338 mg, 2.75 mmol) in DMF (5 mL), and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with  and seric acid solutions and stirred at room temperature for 30 minutes. The aqueous phase was extracted twice with Â, 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 flash chromatography (Hex /  70 / 30~20 / 80) to obtain 299 mg (yield = 62%) of 60 as a mixture of diastereoisomers. 1 H NMR (396 MHz, CDCl3) δ 6.34 (d, J = 2.0 Hz, 2H), 6.26 (d, J = 1.6 Hz, 1H), 6.14 (d, J = 1.8 Hz, 1H), 5.73 (t, J = 1.6 Hz, 2H), 5.56 - 5.47 (m, 2H), 4.73 (d, J = 1.4 Hz, 1H), 4.67 - 4.59 (m, 3H), 4.47 (d, J = 5.7 Hz, 1H), 4.40 (s, 1H), 4.20 - 4.12 (m, 4H), 3.84 (d, J = 8.5 Hz, 3H), 3.67 (d, J = 3.3 Hz, 1H), 3.59 - 3.44 (m, 2H), 3.19 (d, J = 3.5 Hz, 1H), 3.02 (dd, J = 5.3, 2.3 Hz, 1H), 2.53 (d, J = 3.9 Hz, 2H), 2.31 - 2.17 (m, 3H), 2.17 - 2.09 (m, 2H), 2.01 (t, J = 1.1 Hz, 3H), 1.90 (d, J = 1.4 Hz, 3H), 1.79 - 1.62 (m, 11H), 1.51 (s, 8H). 13C 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.

[0402] [ka]

[0403] MnO2 (702 mg, 8.08 mmol) was added to a solution of 60 (398 mg, 0.808 mmol) in CH2Cl2 (15 mL) and stirred at room temperature for 16 hours. The mixture was filtered through Celite to remove the solvent. The crude product was purified by flash chromatography (Hex / Â10 / 10~50 / 50) to obtain 321 mg (yield = 81%) of 61 as a mixture of diastereoisomers. 1H 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).

[0404] [ka]

[0405] A solution of 61 (110 mg, 0.224 mmol) in DMSO (2 mL) was added to a solution of CrCl2 (149 mg, 1.212 mmol) and NiCl2 (2.9 mg, 0.0224 mmol) in DMSO (38 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with siRNA and seric acid solution and stirred at room temperature for 30 minutes. The aqueous phase was extracted twice with siRNA, and the organic phases were combined and dissolved in NH4Cl sat.The product was washed with water and brine, dried over magnesium sulfate, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (CH2Cl2 / Â1 80 / 20~30 / 70) to obtain 23 mg (yield = 28%) of 62 as a mixture of diastereoisomers. 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 = 1.5 Hz, 3H), 1.62 (s, 11H).

[0406] [ka]

[0407] MnO2 (79 mg, 0.906 mmol) was added to a solution of 62 (33 mg, 0.091 mmol) in CH2Cl2 (5 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite to remove the solvent. The crude product was purified by flash chromatography (Hex / Â1 90 / 10~50 / 50) to obtain 27 mg (yield = 82%) of 63 as a mixture of diastereoisomers. 1H 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, 3.9 Hz, 1H), 2.45 (t, J = 3.6 Hz, 2H), 2.04 - 1.90 (m, 3H), 1.84 - 1.37 (m, 11H). 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.

[0408] [ka]

[0409] Methacrylic anhydride (13 μL, 0.0894 mmol) was added to a solution of 63 (27 mg, 0.0745 mmol), Et3N (31 μL, 0.223 mmol), and dimethylaminopyridine (DMAP, 1.8 mg, 0.0149 mmol) in THF (2 mL). The mixture was stirred at room temperature for 16 hours, and the solvent was removed. The crude product was treated with HCl and NH4Cl sat.The solution was diluted with [amount]. The organic phase was dried over magnesium sulfate, and the solvent was removed under vacuum to obtain 29 mg (yield = 91% crude) of 64. The crude was used without further purification.

[0410] [ka]

[0411] PTSA (5.8 mg, 0.034 mmol) was added to 64 (29 mg, 0.067 mmol) in 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 flash chromatography (Hex / siRNA 80 / 20~40 / 60) to obtain 15 mg of (+ / -)-molefantin 65 (yield = 60% in 2 steps). The sample was purified by GPC for bioassay. 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).

[0412] conclusion In this study, the inventors successfully completed the collective synthesis of (furanohermacranolides) derived from Elephantopus mollis and Elephantopus tomentosus for the first time. The key to the stereoselective assembly of the highly oxygenated, strained 10-membered macrocyclic cores of morephantin (1) and tomenphantopine F (2) was the use of diastereoselective intermolecular Barbier-type allylation coupled by the Nozaki, Hiyama, and Kishi (NHK) macrocyclization. In addition, photo-induced isomerization of the (E,Z)-dienone moiety of morephantin (1) to the (Z,Z)-dienone moiety, followed by hemiketalization, allows for concise access to four furanogermacranolides: EM-2 (3), phantomolin (4), 2-O-demethyltomenphantopine C (5), and tomen-phantopine C (6), suggesting that morephantin (1) is a likely biosynthetic precursor of furanogermacranolides discovered in Elephantopus mollis and Elephantopus tomentosus.

Claims

1. A method for producing an intermediate in the total synthesis of (+)-molefantine or its derivatives, (a) Compounds of formula I: 【Chemistry 1】 [In the formula, Prot １ [where represents an acid-unstable protecting group, and X represents Cl or especially Br] The process of obtaining, (b) Compound I, compound II: 【Chemistry 2】 [In the formula, Prot ２ [This group is selected from triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, or in particular trimethylsilyl group] Then, the compound of formula I is reacted with a stoichiometrically excess metal salt and / or metal, along with a solvent, under reaction conditions and at a temperature of 0-25°C for a certain period of time to obtain the compound of formula III: 【Transformation 3】 [In the formula, Prot １ This is as defined above. The process of obtaining Methods that include...

2. The method according to claim 1, wherein the acid instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally the acid instability protecting group is methoxymethyl ether.

3. One or more of the following apply: (a) The metal and / or metal salt is selected from one or more of zinc metal, indium metal, manganese metal-added chromium(III) salt, samarium(II) iodide, tin(II) chloride, and chromium(II) salt, and optionally the metal and / or metal salt is chromium(II) bromide or, in particular, 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, and dimethylacetamide, and is particularly dimethylformamide, and (ci) The temperature is approximately 10°C. The method according to claim 1 or claim 2.

4. A method for producing an intermediate in the total synthesis of (+)-molefantine or its derivatives, Compounds of formula IV (aii): 【Chemistry 4】 [In the formula, Prot １ [This represents an acid-unstable protecting group.] The process of obtaining, (biii) The compound of formula IV is subjected to reaction conditions in a solvent at a temperature of 5 to 60°C for a certain period of time, with a catalytic amount of nickel(II) salt or palladium(II) salt, and one or both of the metal and metal salt in a stoichiometric excess relative to the compound of formula IV, to obtain the compound of formula V: 【Transformation 5】 [In the formula, R is Prot １ And Prot １ This is as defined above. The process of obtaining Methods that include...

5. The method according to claim 4, wherein the acid instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally the acid instability protecting group is methoxymethyl ether.

6. One or more of the following apply: (aiii) The metal and / or metal salt is selected from one or more of the following: chromium(III) salt with added manganese metal, samarium(II) iodide, and chromium(II) salt, and optionally the metal and / or metal salt is chromium(II) bromide or, in particular, 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, and dimethylacetamide, and is particularly dimethyl sulfoxide. (Ciii) The temperature is approximately 25°C, and (diiii) The nickel(II) salt catalyst or palladium(II) salt catalyst 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(diphenylphosphino)ethanenickel(II) chloride, bis(1,5-cyclooctadiene)nickel(0), 1,3-bis(diphenylphosphino)propane]dichloronickel(II), tetrakis(triphenylphosphine)nickel, palladium(II) chloride, palladium(II) acetate, and nickel(II)bis(acetylacetonate), and optionally the nickel(II) salt catalyst or palladium(II) salt catalyst is nickel(II)bis(acetylacetonate). The method according to claim 4 or claim 5.

7. Total synthesis of (+)-molefantine or a derivative thereof, comprising the synthesis method described in any one of claims 1 to 3 and the synthesis method described in any one of claims 4 to 6.

8. Compounds of formula IV: 【Transformation 6】 [In the formula, Prot １ [This represents an acid-unstable protecting group.] but, Compounds of formula III (aiv): 【Transformation 7】 [In the formula, Prot １ This is as defined above. By obtaining, and (biv) is prepared by subjecting the compound of formula III to an oxidation reaction to obtain the compound of formula IV. Optionally, the oxidation conditions include a stoichiometrically excess manganese dioxide in a solvent (e.g., methylene chloride) 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally, the acid-unstable protecting group is methoxymethyl ether. The method according to claim 7.

9. Compound of formula I: 【Transformation 8】 [In the formula, Prot １ represents an acid-labile protecting group] but, Compounds of formula Ia (av): 【Chemistry 9】 To obtain, and (bv) Protecting the free hydroxyl of the compound of formula Ia with an acid-unstable protecting group using appropriate conditions for the selected protecting group. Obtained by, Optionally, the acid-instability 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-dioxan-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl ether, and benzyloxymethyl acetal, and optionally, the acid-instability protecting group is methoxymethyl ether. The method according to claim 7 or claim 8.

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 catalytic amount of a suitable acidic catalyst (e.g., trifluic acid).

11. Compound Ia, compound VI: 【Chemistry 10】 The method according to claim 9 or 10, obtained by reacting a stoichiometrically excess hydrobromic acid with a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25°C).

12. Compound of formula VI, compound of formula VII: 【Chemistry 11】 The method according to claim 11, obtained by reacting methyl acrylate with a suitable base (e.g., 1,4-diazabicyclo[2.2.2]octane) at a suitable temperature (e.g., about 25°C).

13. Compound of formula VII, compound of formula VIII: 【Chemistry 12】 The method according to claim 12, obtained by a reaction of a reducing agent (e.g., diisobutylaluminum hydride) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C).

14. Compounds of formula VIII and compounds of formula IX: 【Chemistry 13】 The method according to claim 13, obtained by reacting (iodomethyl)triphenylphosphonium iodide and a suitable base (e.g., sodium hexamethyldisilazide) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., about -78°C).

15. Compounds of formula IX, compounds of formula X: 【Chemistry 14】 The method according to claim 14, obtained by reacting with methyllithium in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C).

16. Compound of formula V: 【Chemistry 15】 [In the formula, R is Prot １ And Prot １ This is as defined in claim 8. When subjected to an oxidation reaction, the compound of formula XI is obtained: 【Chemistry 16】 [In the formula, R is as defined above.] Prepare the following, and optionally, the oxidation reaction will be carried out at an appropriate temperature (e.g., 25°C) with a stoichiometrically excess of manganese dioxide and a solvent (e.g., methylene chloride). The method according to any one of claims 7 to 15.

17. The compound of formula XI is reacted with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g., triethylamine), a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., 25°C) to obtain the compound of formula XII: 【Chemistry 17】 [In the formula, R is Prot １ And Prot １ R' is as defined in claim 8, where R' is H or CH ３ [is] The method according to claim 16, which obtains the result.

18. The compound of formula XII is reacted with an acid (e.g., trifluoroacetic acid) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., 25°C) to obtain the compound of formula XIII: [Chemistry 18] [In the formula, R' is H or CH] ３ [is] The method according to claim 17, which obtains the result.

19. Compound of formula XIV 【Chemistry 19】 [In the formula, R' is H or CH] ３ [is] of, Compounds of formula XIII: 【Chemistry 20】 [In the formula, R' is as defined above.] A method for forming the compound of formula XIII by a cyclization reaction in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about 25°C) by applying ultraviolet light to the compound of formula XIII, Optionally, the ultraviolet light is provided with a wavelength of 200 to 400 nm (e.g., about 370 nm) and at an appropriate power (e.g., 10 to 100 watts, for example, about 40 watts) using a light source at an appropriate distance (e.g., 1 to 10 cm, for example, about 4 cm) from the reaction vessel containing the compound of formula XIII. A method for forming the compound of formula XIV.

20. Compounds of formula XV: 【Chemistry 21】 [In the formula, R'' is C １ ~C １０ Alkyl or C ２ ~C １０ [Selected from Alkenil] Compound of formula XIV 【Chemistry 22】 [In the formula, R' is H or CH] ３ [is] From this, the compound of formula XIV is given by formula XVI: R"-OH XVI A method of forming by reacting an alcohol with an acid catalyst (for example, the catalyst being p-toluenesulfonic acid).

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