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KR-20260066126-A - Comprehensive synthesis of the pantomolin family through the total synthesis of the sesquiterpene lactone molephantine

KR20260066126AKR 20260066126 AKR20260066126 AKR 20260066126AKR-20260066126-A

Abstract

A process for generating an intermediate in the total synthesis of (+)-molephantine or its derivatives, and the total synthesis of (+)-molephantine or its derivatives are disclosed herein. Additionally, a method for forming a compound of Formula XIV and a method for forming a compound of Formula XV are disclosed herein, wherein the compound of Formula XIV and the compound of Formula XV are as defined in the description of the invention.

Inventors

  • 치바 šœ수케
  • 파투어레트 레미 헨리 루이스

Assignees

  • 난양 바이오로직스 피티이 리미티드

Dates

Publication Date
20260512
Application Date
20240905
Priority Date
20230906

Claims (20)

  1. As a process for generating an intermediate in the total synthesis of (+)-molephantine or its derivatives, The above process is (a) Step of providing the compound of Formula I: Here, Prot 1 represents an acid-instability protecting group; X represents Cl, or more specifically Br; and (b) a step of reacting the compound of Formula I with the compound of Formula II for a predetermined period of time under reaction conditions involving a stoichiometric excess of one or both of a metal salt and a metal for the compound of Formula I at a temperature of 0 to 25°C, and a solvent to provide the compound of Formula III; comprising a process: Here, Prot 2 is selected from a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, or a tert-butyldiphenylsilyl group, or more specifically, a trimethylsilyl group; Here, Prot 1 is as defined above.
  2. In claim 1, The above acid-unstable protecting group is methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl A process selected from the group consisting of ethers and benzyloxymethyl acetals, wherein the acid-unstable protecting group is optionally methoxymethyl ether.
  3. In claim 1 or claim 2, Process applying one or more of the following: (ai) The metal and/or metal salt is selected from one or more of zinc metal, indium metal, chromium (III) salt with manganese metal, samarium (II) iodide, tin (II) chloride, and chromium (II) salt, optionally the metal and/or metal salt is chromium (II) bromide, or more specifically chromium (II) chloride; (bi) The solvent is selected from one or more of the group consisting of tetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethyl sulfoxide, and dimethylacetamide, and more specifically, dimethylformamide; (ci) The above temperature is about 10℃.
  4. As a process for generating an intermediate in the total synthesis of (+)-molephantine or its derivatives, The above process is (aii) Step providing the compound of Formula IV: Here, Prot 1 represents an acid-instability protecting group; and (bii) A step comprising reacting the compound of Formula IV for a predetermined period at a temperature of 5 to 60°C under reaction conditions involving one or both of a catalytic amount of nickel (II) salt or palladium (II) salt in a solvent, a stoichiometric excess of a metal and a metal salt for the compound of Formula IV, to provide the compound of Formula V; Here, R is Prot 1 , and Prot 1 is as defined above.
  5. In claim 4, The above acid-unstable protecting group is methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, 1,3-benzodithiolan-2-yl A process selected from the group consisting of ethers and benzyloxymethyl acetals, wherein the acid-unstable protecting group is optionally methoxymethyl ether.
  6. In claim 4 or claim 5, Process applying one or more of the following: (aiii) The metal and/or metal salt is selected from one or more of the chromium (III) salt with manganese metal, samarium (II) iodide, and chromium (II) salt, and optionally the metal and/or metal salt is chromium (II) bromide, or more specifically chromium (II) chloride; (biii) The solvent is selected from one or more of the group consisting of tetrahydrofuran, 2-methyl-tetrahydrofuran, 3-methyl-tetrahydrofuran, 1,2-dimethoxyethane, 1,1-dimethoxyethane, dimethylformamide, and dimethylacetamide, more specifically, dimethyl sulfoxide; (ciii) The above temperature is about 25℃; and (diii) The catalytic nickel(II) salt or palladium(II) salt is selected from one or more of the group consisting of nickel(II) chloride, nickel(II) bromide, nickel(II) iodide, nickel(II) chloride ethylene glycol dimethyl ether complex, 1,2-bis(diphenylphosphino)ethane nickel(II) chloride, bis(1,5-cyclooctadiene)nickel(II), 1,3-bis(diphenylphosphino)propane]dichloronickel(II), tetrakis(triphenylphosphine)nickel, palladium(II) chloride, palladium(II) acetate, and nickel(II) bis(acetylacetonate), optionally the catalytic nickel(II) salt or palladium(II) salt is nickel(II) bis(acetylacetonate).
  7. As a total synthesis of (+)-molefanthine or its derivatives, The process comprises a synthesis process according to any one of claims 1 to 3 and a synthesis process according to any one of claims 4 to 6, total synthesis.
  8. In claim 7, The compound of Formula IV is Here, Prot 1 represents an acid-instability protecting group; (aiv) Step of providing the compound of Formula III: Here, Prot 1 is as defined above; and (biv) a step of oxidizing a compound of Formula III to provide a compound of Formula IV, wherein the oxidation conditions optionally comprise a stoichiometric excess of manganese dioxide in a solvent (e.g., methylene chloride) at a temperature of 5 to 35°C (e.g., about 25°C); and Optionally, the acid-unstable protecting group is methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, A process selected from the group consisting of 1,3-benzodithiolan-2-yl ether and benzyloxymethyl acetal, wherein the acid-unstable protecting group is optionally methoxymethyl ether.
  9. In claim 7 or claim 8, The compound of Formula I is Here, Prot 1 represents an acid-instability protecting group; (av) Step of providing a compound of formula Ia: ; and (bv) prepared by the step of protecting the free hydroxyl group of the compound of formula Ia with an acid-unstable protecting group using conditions suitable for the selected protecting group, and Optionally, the acid-unstable protecting group is methoxymethyl ether, methoxyethoxymethyl ether, (phenyldimethylsilyl)methoxymethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, guaiacolmethyl ether, 2-(trimethylsilyl)ethoxymethyl ether, tetrahydropyranyl ether, 1,4-dioxane-2-yl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ester, 1-methyl-1-phenoxyethyl ether, t-butyl ether, allyl ether, p-methoxybenzyl ether, triphenylmethyl ether, A process selected from the group consisting of 1,3-benzodithiolan-2-yl ether and benzyloxymethyl acetal, wherein the acid-unstable protecting group is optionally methoxymethyl ether.
  10. In claim 9, The protecting group is methoxymethyl ether, and the reaction conditions involve a process involving 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., triflic acid).
  11. In claim 9 or claim 10, A process in which a compound of Formula Ia is provided by reacting a compound of Formula VI with a stoichiometric excess of hydrobromide in a solvent (e.g., ethyl acetate) at a suitable temperature (e.g., about 25°C): .
  12. In claim 11, A process in which the compound of Formula VI is provided by reacting the compound of Formula VII 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): .
  13. In claim 12, A process in which the compound of Formula VII is provided by reacting the compound of Formula VIII 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): .
  14. In claim 13, A process in which a compound of Formula VIII is provided by reacting a compound of Formula IX with (iodomethyl)triphenylphosphonium iodide in a suitable solvent (e.g., tetrahydrofuran) and a suitable base (e.g., sodium hexamethyldisilazide) at a suitable temperature (e.g., about -78°C): .
  15. In claim 14, A process in which the compound of Formula IX is provided by reacting the compound of Formula X with methyl lithium in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about -78°C): .
  16. In any one of claims 7 to 15, A process comprising: oxidizing a compound of Formula V to yield a compound of Formula XI, wherein the oxidation reaction optionally involves a stoichiometric excess of manganese dioxide and a solvent (e.g., methylene chloride) at a suitable temperature (e.g., 25°C): Here, R is Prot 1 , and Prot 1 is as defined in Claim 8; Here, R is as defined above.
  17. In claim 16, A process in which a compound of Formula XI reacts with methacrylic anhydride or (2E)-2-methyl-2-butenoic anhydride, a base (e.g., triethylamine), or a catalytic base (e.g., dimethylaminopyridine) in a suitable solvent (e.g., tetrahydrofuran) at a suitable temperature (e.g., 25°C) to provide a compound of Formula XII: Here, R is Prot 1 , Prot 1 is as defined in claim 8, and R' is H or CH 3 .
  18. In claim 17, A process in which a compound of Formula XII reacts with an acid (e.g., trifluoroacetic acid) in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., 25°C) to provide a compound of Formula XIII: Here, R' is H or CH3 .
  19. A method for forming a compound of Formula XIV by a cyclization reaction of a compound of Formula XIII through the application of ultraviolet light to a compound of Formula XIII in a suitable solvent (e.g., methylene chloride) at a suitable temperature (e.g., about 25°C), Here, R' is H or CH3 and; Herein, R' is as defined above, and optionally, the ultraviolet light is provided at a wavelength of 200 to 400 nm (e.g., about 370 nm) at a suitable power (e.g., 10 to 100 watts, e.g., about 40 watts) using a light source at a suitable distance (e.g., 1 to 10 cm, e.g., about 4 cm) from a reaction vessel containing the compound of Formula XIII.
  20. A method of forming a compound of formula XV from a compound of formula XIV by reacting a compound of formula XIV with an alcohol of formula XVI in the presence of an acid catalyst (e.g., the catalyst is para-toluenesulfonic acid): Here, R" is selected from C1 to C10 alkyl or C2 to C10 alkenyl; Here, R' is H or CH3 : .

Description

Comprehensive synthesis of the pantomolin family through the total synthesis of the sesquiterpene lactone molephantine The present invention generally relates to the synthesis of the phantomolin family, and more specifically, to a process and method for the collective synthesis of the phantomolin family through the total synthesis of sesquiterpene lactone molephantin. Listing or discussing prior art documents within this specification should not be construed as an acknowledgment that such documents are part of the state of the art or are ordinary, general art. Various families of sesquiterpene lactones (germacranolides), which are secondary metabolites of plants, have received significant attention in the fields of natural product chemistry, medicinal chemistry, and synthetic chemistry over the years. Molepanthin (1), a highly oxygenated germanocranolide, was first isolated from the medicinal herb Elephantopus mollis by Lee in 1973 (K.-H. Lee et al. , J. Chem. Soc. Chem. Commun. 1973 , 476-477), and was subsequently discovered from Elephantopus tomentosus by Liu and Dai in 2012 (W.-L. Mei et al. , Phytochem. Lett. 2012 , 5 , 800-803) (Fig. 1a). Molephantine ( 1 ) is known to exhibit strong in vivo antitumor activity in Ehrlich and Walker 256 carcinosarcoma tumors (IH Hall et al. , J. Pharm. Sci. 1978 , 67 , 1235-1239), as well as anti-inflammatory and leishmanicidal 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 molephantine ( 1 ) consists of a 10-membered macrocyclic core having an (E,Z)-dienon moiety (C10-1-4) fused with α-methylene-γ-butyrolactone and decorated with four consecutive stereogenic centers (C5-8). Tomenphantopin F ( 2 ), isolated from *Elephantopus tomentosus* by Liu and Dai in 2012, is structurally similar to molephantine ( 1 ) (B. Wang et al. , Chin. J. Chem. 2012 , 30 , 1320-1322). The structure is based on the same 10-membered macrocyclic core having an α-(S)-methyl-γ-butyrolactone moiety and a free hydroxyl group at the C8 position. Other topologically related components found in Elephantopus mollis and Elephantopus tomentosus are furanogermacranolides, such as EM-2 (2-deethoxy-2β-methoxypantomolin) ( 3 ) (S. Banerjee et al., Planta Med. 1986, 52, 29-32), phantomolin ( 4 ) (K.-H. Lee et al. , J. Pharma. Sci. 1980 , 68 , 1050-1056), 2-O-demethyltomenphantopin C ( 5 ) (Z.-N. Wu et al. , Phytochemistry 2017 , 137 , 81-86), and tomenphantopin C ( 6 ) (W.-L. Mei et al. This includes al. , Phytochem. Lett. 2012 , 5 , 800-803; and M. Bai et al. , J. Nat. Prod. 2022 , 85 , 2433-2444). Notably, EM-2( 3 ) was observed to make breast cancer cells more sensitive to epirubicin when co-administered with epirubicin by primarily inhibiting the protective autophagy pathway of breast cancer cells (J. Li et al. , Phytomedicine 2023 , 116 , 154878). Their 10-membered macrocyclic core contains a (Z,Z)-skipped diene centered on a C2 (hemi)ketal carbon. Although the biosynthetic pathway of these highly oxygenated (furano)germacranolides remains unclear, the inventors hypothesized that molephantine ( 1 ) could be a biosynthetic precursor of EM-2 ( 3 ) and other furanogermacranolides. This hypothesis is based on their interesting topological similarities and suggests a potential synthetic pathway in which the C1-C10 double bond of molephantine ( 1 ) is E/Z-isomerized to the (Z,Z)-dienon congener A , followed by successive (hemi)ketalization with the C5-hydroxyl group. Despite groundbreaking research in the synthesis of highly oxygenated germane cranolides isolated from different plant species, such as eremantholide ( J. Am. Chem. Soc.1991 , 113 , 9682-9684) and goyazensolide ( ACS Cent. Sci. 2021 , 7 , 954-962), to the extent of the inventors' knowledge, the total synthesis of (furano)germa cranolides derived from Elephantopus species has not been reported (Fig. 1b). An exception to this gap is the synthesis of nordeoxyelephantopin, a non-natural analogue of deoxyelephantopin derived from Elephantopus scaber (R. Lagoutte et al. , Nat. Commun. 2016 , 7 , 12470; and R. Lagoutte et al. , J. Antibiot. 2018 , 71 , 248-256). Therefore, there is a need for a new synthetic pathway that enables access to sesquiterpene lactones. Aspects and embodiments of the present invention are provided in the following numbered items. 1. A process for generating an intermediate in the total synthesis of (+)-molephantine or its derivative, wherein the process is (a) A step of providing a compound of Formula I; Here, Prot 1 represents an acid-instability protecting group; X represents Cl, or more specifically Br; and (b) a step of reacting the compound of Formula I with the compound of Formula II for a predetermined period of time under reaction conditions involving a stoichiometric excess of one or both of a metal salt and a metal for the compound of Formula I at a temperature of 0 to 25°C, and a solvent to provide the compound of Form