Method for preparing triterpenoid compounds

Abstract

A method for preparing a triterpenoid compound represented by formula (I), comprising the step of converting a compound of formula (II) into a compound of formula (I). JPEG2025511059000047.jpg7864 During the ceremony, R1 and R2 are independently hydrogen or a C1-C8 alkyl group, an aryl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, (C6-C 12 )Aryl(C1-C8)alkyl group, tri(C1-C8)alkylsilyl group, di(C1-C8)alkyl(C6-C 12 )arylsilyl group, di(C6-C 12 )aryl(C1-C8)alkylsilyl group, tri(C6-C 12 ) an arylsilyl group, -C(O)R7, and -C(O)OR8, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of a hydroxy group, a cyano group, a halo, a halo(C1-C6)alkyl group, a halo(C1-C6)alkyloxy group, a (C1-C6)alkylthio group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C7 cycloalkyl group, and a C1-C6 alkoxy group; R7 and R8 are independently a C1-C8 alkyl group or a C6-C 12 It is an aryl group.

Description

[Technical Field] 【0001】 This application claims priority based on U.S. Provisional Application 63 / 325,792 filed on 31 March 2022. The entirety of the above patent application is incorporated herein by reference and forms part of this Specification. 【0002】 This disclosure relates to a method for preparing triterpenoid compounds. More specifically, this disclosure relates to a method for preparing quillaic acid for use as a triterpenoid saponin vaccine adjuvant. [Background technology] 【0003】 The name "saponin" originates from the Latin word "sapo," meaning the ability to produce soap-like foam. Its amphiphilic properties stem from its structure, which includes an isoprenoid-derived aglycone (sapogenin) linked to one or more sugar chains by either ether or ester bonds. The structural classification of saponins is primarily based on their sapogenin skeleton and can be divided into two main groups: triterpenoid saponins and steroid saponins. Triterpenoid saponins are widely distributed in dicotyledonous plants and include four main skeletons such as pentacyclic oleanane, ursan, lupin, and tetracyclic dammarane (Figure 1a). Steroid saponins are mainly derived from monocotyledonous plants and include four main skeletons such as tetracyclic cholestane, hexacyclic spirostan, pentacyclic frostan, and lactone-containing cardenolides (Figure 1b). Sugar-containing sapogenins are classified into monodesmosides (one sugar residue), videsmosides (two sugar residues), and polydesmosides (three or more sugar residues) depending on the number of sugar residues. 【0004】 In nature, saponins are found in plants and marine animals and are involved in host defense against pathogens and herbivores. Saponins are present in many medicinal plants and herbal medicines, and their rich biological activity, including antifungal, antibacterial, antiviral, anti-inflammatory, anticancer, antioxidant, and immunomodulatory effects, makes them a good starting point for the development of naturally derived pharmaceuticals. However, the mechanisms and structure-activity relationships (SARs) of saponins remain unclear, and their molecular heterogeneity and deficiencies can make isolating them from plants in appropriate quantities cumbersome and laborious. Therefore, applying organic synthesis methods to produce artificial saponins is a promising way to efficiently expand structural libraries and explore highly active compounds. 【0005】 Oleanane-type saponins are the most studied synthetic saponins due to their promising pharmacological effects and high natural abundance. As shown in Figure 2, oleanane-type skeletons modified by common chemical approaches include oleanolic acid, hederagenin, and chiric acid. These have been isolated as free triterpenoids or saponins from a vast number of plant species, and are particularly abundant in the Oleaceae family. Oleanane-type saponins have been reported to exhibit multiple biological activities, particularly antitumor, antiviral, and immunomodulatory effects. However, toxicity caused by hemolytic and membrane-lytic effects is a major challenge in drug development, and the understanding of the relationship between structure and toxicity is still in its early stages. 【0006】 Saponins with immunomodulatory effects were classified into upregulatory and downregulatory types. Upregulatory immunomodulatory activity was mainly evaluated for chiric acid saponins, and compared to GPI-0100 and QS-21, they have been widely studied for enhancing serum IgG production for vaccine adjuvant development, and various chiric acid-based derivatives have been developed. 【0007】 QS-21 is an FDA-approved vaccine adjuvant widely used in the treatment of infectious diseases and cancer. Despite its versatile uses, its natural sources are limited. Traditional methods of isolating quillaic acid require extraction from roots or bark. To preserve natural sources and make its application more sustainable, chemical synthesis of quillaic acid is necessary. However, the chemical synthesis of quillaic acid, starting from protoescigenin, has been reported to involve 24 steps before obtaining the quillaic acid (Zeng et al., Chemical synthesis of quillaic acid, the aglycone of QS-21. Org. Chem. Front. 2021, 8, 748-753). In addition to chemical synthesis, biosynthesis has become a popular method in recent years. In 2021, Qian et al. identified the biosynthetic pathways of CYP716A262 and CYP72A567, which can provide an alternative source of chiric acid by initiating synthesis from β-amylin metabolites. Transformation of S. cerevisiae strain BY-bAS with the CYP716A567 and CYP72A262 genes can produce 314.01 mg / L of chiric acid. However, this method requires cloning specific RNA sequences of CYP716A567 and CYP72A262 and cannot be scaled up at present. In the pharmaceutical industry, versatile CH activation offers us a new platform. In terpenoid and steroid CH functionalization, the abundance of aliphatic CH in their structures and the low reactivity of aliphatic CH binding make methodology development and strategy design paramount challenges. To date, limited β-C(sp) 3)-H oxidation has been reported to be used for oleanane-type terpenoids. However, C-23 oxidation remains problematic and is not practical for industrial use. For example, the [Ir(cod)(OMe)]2-catalyzed C-23 oxidation reported by Hartwig's group requires operation under a glove box, and the sodium(II) tetrachloropalladate-mediated C-23 oxidation reported by Baldwin's group requires the use of stoichiometric palladium salts (Figure 3A). For these reasons, designing synthetic strategies is a critical issue in terpenoid synthesis. 【0008】 Over the past few decades, CH bond functionalization strategies assisted by directing groups have emerged. Monodentate amides, pyridines, or imines, and bidentate directing groups with Lewis base properties that allow for controllable regioselectivity, are utilized. In most cases, the directing group covalently bonds to the substrate. However, removing such directing groups results in redundant steps and low yields. Therefore, native directing groups, traceless directing groups, transient directing groups, and undirected CH activations are developed to meet the needs of economic efficiency. 【0009】 Among the various directing groups described above, bidentate transient directing groups occupy a niche in CH oxidation. The family of bidentate directing groups is classified by their coordination sites, e.g., N,N-dentate (Figure 4), N,O-dentate, and N,S-dentate auxiliary groups. Over the past few decades, bidentate directing groups have been widely used in transition metal-catalyzed CH bond functionalization reactions because they are more readily coordinated to metals and possess adjustable coordination properties compared to monodentate groups. In 2020, Yu et al. (Site-selective CH hydroxylation of pentacyclic triterpenoids directed by transient chiral pyridine-imino groups. Nat.Commun. 2020, 11, 4371.) successfully established site-selective functionalization of triterpenoids using the chiral directing group (R / S)-(pyridine-2-yl)ethane-1-amine (Figure 3B). By forming a transient imine bond, the bidentate directing group complexes with copper and directly hydroxylates C-22 and C-16 at the D / E ring of the triterpenoid. [Overview of the Initiative] 【0010】 This disclosure utilizes a transient N,N-positioning strategy to access the CH bond hydroxylation of oleanane-type terpenoids. This strategy reduces the number of synthetic steps due to its features of easy removal and high selectivity. By combining two CH activations, this disclosure provides an environmentally friendly and industrially practical method for synthesizing chiric acids, as an alternative to conventional extraction methods. 【0011】 This disclosure provides a method for preparing a triterpenoid compound represented by formula (I), comprising the step of converting a compound of formula (II) to a compound of formula (I). [ka] During the ceremony, R1 and R2 are independently hydrogen, or a protecting group selected from the group consisting of a C1-C8 alkyl group, an allyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a (C6-C 12 ) aryl(C1-C8)alkyl group, a tri(C1-C8)alkylsilyl group, a di(C1-C8)alkyl(C6-C 12 )arylsilyl group, a di(C6-C 12 )aryl(C1-C8)alkylsilyl group, a tri(C6-C 12 )arylsilyl group, -C(O)R7 and -C(O)OR8, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of a hydroxy group, a cyano group, a halo, a halo(C1-C6)alkyl group, a halo(C1-C6)alkyloxy group, a (C1-C6)alkylthio group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C7 cycloalkyl group and a C1-C6 alkoxy group, R7 and R8 are independently a C1-C8 alkyl group or a C6-C 12 aryl group. 【0012】 In one exemplary embodiment of the present disclosure, the method further includes a step of converting a compound of formula (II) to a compound of formula (III) by oxidizing the aldehyde group of formula (II) to a carboxyl group and then forming an oxygen protecting group by bonding a protecting group to one oxygen atom of the carboxyl group. 【Chemical formula】 wherein R3 is a C1-C8 alkyl group, an allyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a (C6-C 12 ) aryl(C1-C8)alkyl group, a C6-C 12 arylacyl group, a tri(C1-C8)alkylsilyl group, a di(C1-C8)alkyl(C6-C 12 )arylsilyl group, a di(C6-C 12 )aryl(C1-C8)alkylsilyl group and a tri(C6-C 12) is a protecting group selected from the group consisting of arylsilyl groups, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of hydroxyl groups, cyano groups, halo, halo(C1-C6)alkyl groups, halo(C1-C6)alkyloxy groups, (C1-C6)alkylthio groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, and C1-C6 alkoxy groups. 【0013】 In one exemplary embodiment of the present disclosure, the method further includes the step of converting a compound of formula (III) to a compound of formula (IV) by sequentially performing epimerization, deprotection, and oxidation. [ka] 【0014】 In one exemplary embodiment of the present disclosure, the method further comprises the steps of: epimerizing a compound of formula (III) at the carbon position to which its hydroxyl group is attached to form a compound of formula (VI); and converting the compound of formula (VI) to a compound of formula (IV) by sequentially deprotection and oxidation. [ka] In the deprotection step, R1 and R2 are removed from the compound of formula (VI). 【0015】 In one exemplary embodiment of the present disclosure, the method further includes a step of converting a compound of formula (IV) to a compound of formula (I) by a deprotection reaction. [ka] In the deprotection process, R3 is removed from the compound of formula (IV). 【0016】 In one exemplary embodiment of the present disclosure, the method further includes the step of converting a compound of formula (VII) to a compound of formula (II) by sequentially introducing an orientation group and activating CH. [ka] 【0017】 In another exemplary embodiment of the present disclosure, the method further includes the steps of converting compound (VII) to compound (VIII) by reacting compound (VII) with compound (a) via the introduction of an oriented group, and converting compound (VIII) to compound (II) by CH activation. [ka] During the ceremony, The R6 is [ka] Representing, W is H or a C1-C8 alkyl group. X and Y are independently hydrogen, hydroxyl group, cyano group, halo, C6-C 12 Aryl group or C5-C 12 Represents a heteroaryl element, Compound (a) is, [ka] It represents. 【0018】 In another exemplary embodiment of the present disclosure, the method further includes the step of converting oleanolic acid to a compound of formula (VII) via sequential halolactone oxime formation, CH activation, protecting group bonding, and reduction. [ka] 【0019】 In another exemplary embodiment of the present disclosure, the compound of formula (VII) is obtained by converting the compound of formula (IX) to the compound of formula (VII) through successive reduction and optional protecting group bonding. [ka] In the formula, Rx is F, Cl, Br, or I. 【0020】 In another exemplary embodiment of the present disclosure, the compound of formula (IX) is obtained by converting the compound of formula (X) to the compound of formula (IX) via sequential CH activation and protecting group bonding. [ka] In the formula, Rx is F, Cl, Br, or I. 【0021】 In another exemplary embodiment of the present disclosure, the compound of formula (X) is obtained by converting oleanolic acid to the compound of formula (X) by halolactone oxime formation. [ka] 【0022】 In another exemplary embodiment of the present disclosure, the method further includes the step of converting hederagenin to a compound of formula (VII) by sequentially performing protecting group bonding, reduction, and oxidation. [ka] 【0023】 In another exemplary embodiment of the present disclosure, the method further includes the step of oxidizing the compound of formula (XI) to the compound of formula (VII). [ka] In the formula, R4 is hydrogen, or a C1-C8 alkyl group, an allyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, (C6-C 12 ) Aryl (C1-C8) alkyl groups, C6-C 12 Arylacyl group, tri(C1-C8)alkylsilyl group, di(C1-C8)alkyl(C6-C 12 ) Arylsilyl group, di(C6-C 12)aryl(C1-C8)alkylsilyl group and tri(C6-C 12 ) is a protecting group selected from the group consisting of arylsilyl groups, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of hydroxyl groups, cyano groups, halo, halo(C1-C6)alkyl groups, halo(C1-C6)alkyloxy groups, (C1-C6)alkylthio groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, and C1-C6 alkoxy groups. 【0024】 In another exemplary embodiment of the present disclosure, the method further includes the step of reducing the compound of formula (XII) to the compound of formula (XI). [ka] In the formula, R5 is hydrogen, or a C1-C8 alkyl group, an allyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, (C6-C 12 ) Aryl (C1-C8) alkyl groups, C6-C 12 Arylacyl group, tri(C1-C8)alkylsilyl group, di(C1-C8)alkyl(C6-C 12 ) Arylsilyl group, di(C6-C 12 )aryl(C1-C8)alkylsilyl group and tri(C6-C 12 The group is selected from the group consisting of arylsilyl groups, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of hydroxyl groups, cyano groups, halo, halo(C1-C6)alkyl groups, halo(C1-C6)alkyloxy groups, (C1-C6)alkylthio groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, and C1-C6 alkoxy groups. 【0025】 In another exemplary embodiment of the present disclosure, the method includes the step of converting hederagenin to a compound of formula (XII) by attaching a protecting group to the hydroxyl group of hederagenin. [ka] [Brief explanation of the drawing] 【0026】 [Figure 1a] The main representative structures of triterpenoid saponins are shown. 【0027】 [Figure 1b] The main representative structures of steroid saponins are shown. 【0028】 [Figure 2] A typical structure of an oleanane-type saponin is shown. 【0029】 [Figure 3A] This document outlines strategies for triterpenoid C-23 oxidation. 【0030】 [Figure 3B] This diagram shows a scheme in which C-22 and C-16 in the triterpenoid D / E ring are directly hydroxylated using bidentate-directing groups. 【0031】 [Figure 4] A scheme is shown to use bidentate-directing groups to improve C-16 oxidation. 【0032】 [Figure 5] This disclosure shows a scheme for synthesizing chiral acid from compound 6 according to one embodiment of this disclosure. 【0033】 [Figure 6] A scheme for synthesizing compound 6 from oleanolic acid according to another embodiment of this disclosure is shown. 【0034】 [Figure 7] This disclosure shows a scheme for synthesizing compound 15 from hederagenin according to one embodiment of this disclosure. [Modes for carrying out the invention] 【0035】 The following disclosure provides many different embodiments or examples for implementing the different features of this disclosure. Hereinafter, for the sake of brevity, specific examples of components and arrangements are described. Naturally, these are merely examples and are not intended to be limiting. Furthermore, this disclosure may repeat reference numbers and / or letters in various examples. This repetition is for the purpose of brevity and clarity and is not in itself intended to limit the relationships between the various embodiments and / or arrangements discussed. 【0036】 As used herein, the term “alkyl group” refers to a linear or branched saturated aliphatic hydrocarbon group. Alkyl groups include groups having 1 to 8 carbon atoms (C1-C8 alkyl groups), groups having 1 to 6 carbon atoms (C1-C6 alkyl groups), and groups having 1 to 4 carbon atoms (C1-C4 alkyl groups), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Unless otherwise specified herein, alkyl groups may be optionally substituted. 【0037】 An "alkenyl group" refers to a linear or branched alkene group having at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-C8 alkenyl groups, C2-C6 alkenyl groups, and C2-C4 alkenyl groups having 2 to 8, 2 to 6, or 2 to 4 carbon atoms. The double bond of the alkenyl group may be unconjugated or conjugated to another unsaturated group. Non-limiting examples of alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, and cyclopenta-1-en-1-yl. In this specification, unless otherwise specified, alkenyl groups may be optionally substituted. 【0038】 The term "alkynyl group" refers to a linear or branched alkyne group having one or more unsaturated carbon-carbon bonds (at least one of which is a triple bond). Alkynyl groups include C2-C8 alkynyl groups, C2-C6 alkynyl groups, and C2-C4 alkynyl groups, each having 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively. The triple bond of the alkynyl group may be unconjugated or conjugated to another unsaturated group. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. In this specification, unless otherwise specified, alkynyl groups may be optionally substituted. 【0039】 A "cycloalkyl group" is a group comprising one or more saturated rings and / or partially saturated rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decahydronaphthalenyl, octahydroindenyl, and other groups where all ring members are carbon, as well as the aforementioned partially saturated variants such as cyclohexenyl. 【0040】 As used herein, "alkoxy group" refers to an alkyl group linked via an oxygen bridge. Alkoxy groups include C1-C8 alkoxy groups and C1-C4 alkoxy groups, each having 1 to 8 or 1 to 4 carbon atoms, respectively. Specific alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. 【0041】 The term "aryl group" refers to a hydrocarbon ring system group comprising at least six carbon atoms or six to twelve carbon atoms and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include condensed or bridged ring systems. Non-limiting examples of aryl groups include aryl groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In this specification, unless otherwise specified, the aryl group may be optionally substituted. 【0042】 The terms “heteroaryl group” or “heteroaromatic” refer to aromatic monocyclic, bicyclic, or polycyclic ring groups that incorporate one or more heteroatoms (e.g., 1 to 4, particularly 1, 2, or 3) selected from nitrogen, oxygen, or sulfur. The term “heteroaryl group” includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10. Heteroaryl groups may be 5- or 6-membered monocyclic rings, or 9- or 10-membered bicyclic rings, and may be, for example, fused 5- and 6-membered rings or bicyclic structures formed from two fused 6-membered rings. Each ring may typically contain up to about 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to 3 heteroatoms, more typically up to 2 heteroatoms, for example, 1 heteroatom. In one embodiment, the heteroaryl ring contains at least one nitrogen atom. The nitrogen atoms in a heteroaryl ring may be basic, as in imidazole or pyridine, or they may be inherently non-basic, as in indole or pyrrole. Generally, the number of basic nitrogen atoms present in a heteroaryl group is less than five, including any amino group substituents on the ring. 【0043】 The term "substituted" means that one, two, or three or more hydrogen atoms are independently substituted by substituents, and such substituents include -F, -Cl, -Br, -I, -OH, and C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkinyl, -C3-C 12 Cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-C1-C 12 Alkyl, -NH-C2-C8 alkenyl, -NH-C2-C8 alkynyl, -NH-C3-C 12 Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 Alkyl, -O-C2-C8 alkenyl, -O-C2-C8 alkynyl, -O-C3-C 12 Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 Alkyl, -C(O)-C2-C8 alkenyl, -C(O)-C2-C8 alkynyl, -C(O)-C3-C 12 Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 Alkyl, -CONH-C2-C8 alkenyl, -CONH-C2-C8 alkynyl, -CONH-C3-C 12 Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 Alkyl, -OCO2-C2-C8 alkenyl, -OCO2-C2-C8 alkynyl, -OCO2-C3-C 12 Cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C 12Cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterosiloalkyl, -OCONH2, -OCONH-C1-C 12 Alkyl, -OCONH-C2-C8 alkenyl, -OCONH-C2-C8 alkynyl, -OCONH-C3-C 12 Cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C1-C 12 Alkyl, -NHC(O)-C2-C8 alkenyl, -NHC(O)-C2-C8 alkynyl, -NHC(O)-C3-C 12 Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1-C 12 Alkyl, -NHCO2-C2-C8 alkenyl, -NHCO2-C2-C8 alkynyl, -NHCO2-C3-C 12 Cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C 12 Alkyl, -NHC(O)NH-C2-C8 alkenyl, -NHC(O)NH-C2-C8 alkynyl, -NHC(O)NH-C3-C 12 Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1-C 12 Alkyl, -NHC(S)NH-C2-C8 alkenyl, -NHC(S)NH-C2-C8 alkynyl, -NHC(S)NH-C3-C 12 Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 Alkyl, -NHC(NH)NH-C2-C8 alkenyl, -NHC(NH)NH-C2-C8 alkynyl, -NHC(NH)NH-C3-C 12Cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C1-C 12 Alkyl, -NHC(NH)-C2-C8 alkenyl, -NHC(NH)-C2-C8 alkynyl, -NHC(NH)-C3-C 12 Cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 Alkyl, -C(NH)NH-C2-C8 alkenyl, -C(NH)NH-C2-C8 alkynyl, -C(NH)NH-C3-C 12 Cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1-C 12 Alkyl, -S(O)-C2-C8 alkenyl, -S(O)-C2-C8 alkynyl, -S(O)-C3-C 12 Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1-C 12 Alkyl, -SO2NH-C2-C8 alkenyl, -SO2NH-C2-C8 alkynyl, -SO2NH-C3-C 12 Cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 Alkyl, -NHSO2-C2-C8 alkenyl, -NHSO2-C2-C8 alkynyl, -NHSO2-C3-C 12 Cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C 12Alkyl, -S-C2-C8 alkenyl, -S-C2-C8 alkynyl, -S-C3-C 12 The substituents include, but are not limited to, cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It is understood that the aforementioned aryl group, heteroaryl group, alkyl group, cycloalkyl group, etc., may be further substituted. In one embodiment of the present disclosure, the substituents may be selected from the group consisting of hydroxyl group, cyano group, halo, halo(C1-C6)alkyl group, halo(C1-C6)alkyloxy group, (C1-C6)alkylthio group, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C7 cycloalkyl group, and C1-C6 alkoxy group. 【0044】 The phrase "substituted with 0 to X substituents" also indicates "arbitrarily substituted," which means either unsubstituted or substituted with one or more suitable groups (which may be the same or different) other than hydrogen at one or more available positions, typically one, two, three, four, five, or six positions, where X is the maximum number of acceptable substituents. Certain arbitrarily substituted groups are substituted with 0 to 2, three, or four independently selected substituents (i.e., unsubstituted or substituted with up to the maximum number of substituents listed). Other arbitrarily substituted groups are substituted with at least one substituent (e.g., substituted with 1 to 2, three, or four independently selected substituents). 【0045】 The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodine. 【0046】 The term “protecting group” means any protecting group for alcohols known in the art. Non-limiting examples include 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), benzyloxymethyl acetal (BOM), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS, TBDMS), or tert-butyldiphenylsilyl ether (TBDPS). 【0047】 The terms "deprotection" and "to deprotect" refer to the removal of a protecting group by any conventional means known to those skilled in the art. It will be readily apparent that the conditions for deprotection depend on the type of protecting group used. 【0048】 The term "CH activation" (also known as CH bond activation, and sometimes used interchangeably with CH functionalization) refers to a series of mechanistic processes in which stable carbon-hydrogen bonds in organic compounds are cleaved. The goal is to enable the functionalization of these molecules, often leading to the synthesis of more complex intermediate or product compounds containing CO, CC, and CN bonds. The ability to cleave CH bonds allows for the transformation of inexpensive source molecules into commercially valuable molecules. Directional CH activation enables selectivity and specificity in the synthesis of important and more complex molecules for pharmaceutical and fine chemical applications. 【0049】 The term "directing group" (DG) refers to a substituent on a molecule or ion that facilitates a reaction by interacting with a reagent. This term is typically applied to the CH activation of hydrocarbons and is defined as "a coordinating moiety (internal ligand) that guides a metal catalyst to a particular CH bond." 【0050】 The term "halolactone" refers to the formation of a lactone with a halogen attached through halolactonization. Haloractonization is an intramolecular variation of the halohydrin synthesis reaction. This reaction was first reported by M. J. Bougalt in 1904 and has since become one of the most effective methods for synthesizing lactones. 【0051】 The term "oxime" refers to compounds of the structure R2C=NOH derived from the condensation of an aldehyde or ketone with a hydroxylamine. Oximes derived from aldehydes may be called aldoximes, and those derived from ketones may be called ketoximes. 【0052】 Preparation of triterpenoid compounds 【0053】 In one embodiment of the present disclosure, the compound of formula (X) can be prepared by halolactone oxime formation according to Scheme 1. Oleanolic acid (OA) is added to a solvent such as dichloromethane (DCM) and pyridine. Then, in halolactone oxime formation, a halogenating agent used for halolactonization (such as N-bromosuccinimide (NBS)), an oxidizing agent used for oxidation of the C-3-OH group (such as trichloroisocyanuric acid (TCCA)), and an oximing agent used for oxime formation (such as hydroxylamine hydrochloride (HONH2·HCl)) are sequentially added at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain the compound of formula (X). In one embodiment of the present disclosure, a halogenating agent is added and the mixture is stirred for 1 to 2 hours (e.g., 1 hour, 1.5 hours, and 2 hours), an oxidizing agent is added and the mixture is stirred for 1.5 to 2.5 hours (e.g., 1.5 hours, 2 hours, and 2.5 hours), and an oximizing agent is added and the mixture is stirred for 0.5 to 1.5 hours (e.g., 0.5 hours, 1 hour, and 1.5 hours). [ka] 【0054】 In one embodiment of the present disclosure, the compound of formula (IX) can be prepared by sequentially performing CH activation and protecting group bonding according to Scheme 2. The compound of formula (X) is dissolved in a cosolvent (e.g., acetic anhydride (Ac2O) / acetic acid (AcOH)), and then a palladium metal catalyst (e.g., PdCl2, Pd(allyl)Cl2, and Pd(OAc)2, but not limited to these) and an oxidizing agent (e.g., phenyliodine(III) diacetate (PIDA)) are sequentially added at 40-50°C (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50°C). The mixture is then to be mixed with a cosolvent (e.g., tetrahydrofuran (THF) / acetone) at 50-60°C (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60°C) in the presence of an acid, e.g., HCl, to obtain the compound of formula (IXa). The compound of formula (IXa) is dissolved in a solvent (e.g., dimethylformamide (DMF), dichloromethane (DCM), or dimethyl sulfoxide (DMSO)) under an N2 atmosphere. Imidazole and a protecting compound (e.g., tert-butyldimethylsilyl chloride (TBSCl)) are added sequentially between -4 and 4°C (e.g., -4, -3, -2, -1, 0, 1, 2, 3, or 4°C), and then stirred at 15 to 30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain the compound of formula (IX). In one embodiment of the present disclosure, a palladium metal catalyst is added and the mixture is stirred for 1 to 2 minutes (e.g., 1 minute, 1.5 minutes, and 2 minutes), an oxidizing agent is added and the mixture is stirred for 7.5 to 8.5 hours (e.g., 7.5 hours, 8 hours, and 8.5 hours), and an acid is added and the mixture is stirred for 7.5 to 8.5 hours (e.g., 7.5 hours, 8 hours, and 8.5 hours). In one embodiment of the present disclosure, an imidazole and a protecting compound are added and the mixture is stirred for 3.5 to 4.5 hours (e.g., 3.5 hours, 4 hours, and 4.5 hours). [ka] 【0055】 In one embodiment of the present disclosure, the compound of formula (VII) can be prepared by reduction and optional protecting group bonding according to Scheme 3. A reducing agent (e.g., lithium tri-tert-butoxyaluminum hydride (LTBA)) dissolved in a solvent (e.g., tetrahydrofuran (THF)) is added to the compound of formula (IX) at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C), and the mixture is then cooled to approximately -82°C--75°C (e.g., -82, -81, -80, -79, -78, -76, or -75°C), and, A reducing agent (e.g., diisobutylaluminum hydride (DIBAL-H)) is added. The catalyst AcOH / Zn is added at 45-55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55°C) and cooled to 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30°C) to obtain compound (VIIa). Compound (VIIa) is dissolved in a solvent (e.g., under an N2 atmosphere) Then, dissolve in dimethylformamide (DMF), dichloromethane (DCM), or dimethyl sulfoxide (DMSO). Add the imidazole and protecting compound (e.g., tert-butyldimethylsilyl chloride (TBSCl)) sequentially between -4 and 4°C (e.g., -4, -3, -2, -1, 0, 1, 2, 3, or 4°C), and then heat to 15 and 30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Stirring at 30°C to obtain the compound of formula (VII). In one embodiment of the present disclosure, a reducing agent is added and the mixture is stirred for 0.5 to 2 hours (e.g., 0.5 hours, 1 hour, 1.5 hours, and 2 hours), and a catalyst is added and the mixture is stirred for 0.5 to 1.5 hours (e.g., 0.5 hours, 1 hour, and 1.5 hours). In one embodiment of the present disclosure, an imidazole and a protecting compound are added and the mixture is stirred for 3.5 to 4.5 hours (e.g., 3.5 hours, 4 hours, and 4.5 hours). [ka] 【0056】 In one embodiment of the present disclosure, the process further includes a step of converting compound (VII) to compound (VIII) by reacting compound (VII) with compound (a) via introduction of an directing group, according to Scheme 4, and a step of converting compound (VIII) to compound (II) by CH activation. Compound (VII) and compound (a) are reacted in the presence of a solvent (e.g., toluene) and heated to 75-85°C (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 and 85°C) to obtain compound (VIII). A copper salt (e.g., Cu(OTf)2 or (CuOTf)2·C6H6) and sodium ascorbate are added to a mixture of compounds of formula (VIII), and then a solvent (e.g., methanol / acetone) is added to the mixture and stirred at 15–30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C). The mixture is then bubbling with an O2 balloon and heated to 45–55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55°C) to obtain compound (II). Compound (a) can be obtained from a commercial source, synthesized from commercially available precursors using established protocols known in the field of synthetic organic chemistry, or modified in a manner understandable to those skilled in the art. In one embodiment of the present disclosure, the compound of formula (a) is added and the mixture is stirred for 1.5 to 2.5 hours (e.g., 1.5 hours, 2 hours, and 2.5 hours). In one embodiment of the present disclosure, the copper salt and sodium ascorbate are added and the mixture is stirred for 1.5 to 2.5 hours (1.5 hours, 2 hours, and 2.5 hours). [ka] 【0057】 Another embodiment of the present disclosure further includes a step of converting compound (VII) to compound (VIII) by reacting compound (VII) with compound (a) via introduction of an directing group, according to scheme 4-1, and a step of converting compound (VIII) to compound (II) by CH activation. A mixture containing compound (VII) and an organic soluble acid catalyst (e.g., p-toluenesulfonic acid monohydrate (TsOH)) is reacted with compound (a) in the presence of a solvent (e.g., toluene) and heated to 75-85°C (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 and 85°C) to obtain compound (VIII). A mixture of a cupric salt (e.g., copper(II) nitrate trihydrate (Cu(NO3)2·3H2O)) and the compound of formula (VIII) is added to a solvent (e.g., THF / methanol / acetone) and stirred at 15–30°C (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C). An oxidizing agent (e.g., hydrogen peroxide (H2O2)) is then added to the reaction mixture to obtain the compound of formula (II). In one embodiment of this disclosure, the mixture is stirred for 0.5 to 1.5 hours (e.g., 0.5 hours, 1 hour, and 1.5 hours) after adding the cupric salt and the compound of formula (VIII), and then stirred for 23 to 25 hours (e.g., 23 hours, 24 hours, and 25 hours) after adding the oxidizing agent. [ka] 【0058】 In one embodiment of the present disclosure, the compound of formula (III) can be prepared by sequentially oxidizing the aldehyde group of formula (II) to a carboxyl group according to Scheme 5, and forming an oxygen protecting group by bonding an oxygen protecting group to one oxygen atom of the carboxyl group. The compound of formula (II), dissolved in a solvent (e.g., DMSO / tert-butanol), is added at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to a solution containing an oxidizing agent (e.g., NaClO2) and a buffer (e.g., NaH2PO4·H2O). The mixture is then acidified with a solution (e.g., aqueous HCl solution) to obtain a crude mixture. The crude mixture is dissolved in a solvent (e.g., THF / H2O), and then a protecting agent (e.g., allyl bromide), a catalyst (tetra-n-butylammonium iodide), and a reaction reagent (e.g., K2CO3) are added sequentially at 60-70°C (e.g., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69-70°C) to obtain the compound of formula (III). In one embodiment of the present disclosure, the oxidizing agent is added and the mixture is stirred for 3.5 to 4.5 hours (e.g., 3.5 hours, 4 hours, and 4.5 hours), and then the protecting agent is added and the mixture is stirred for 3.5 to 4.5 hours (e.g., 3.5 hours, 4 hours, and 4.5 hours). 【0059】 [ka] 【0060】 In one embodiment of the present disclosure, the process further includes the steps of: epimerizing a compound of formula (III) at the carbon position to which its hydroxyl group is attached to form a compound of formula (VI), according to Scheme 6; and sequentially deprotecting and oxidizing the compound of formula (VI) to convert it to a compound of formula (IV). The compound of formula (III) is dissolved in a solvent (dimethylformamide (DMF), dichloromethane (DCM), or dimethyl sulfoxide (DMSO)); and then an oxidizing agent (desmartin periodinane (DMP)) is added at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain the compound. The compound from the previous step is dissolved in a solvent (e.g., ethanol or isopropanol), and then a reducing agent (sodium borohydride (NaBH4)) is added at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain compound (VI). Compound (VI) is dissolved at 45-55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55°C) in a solvent (e.g., THF) containing a deprotection agent (e.g., tetra-n-butylammonium fluoride (TBAF)) to obtain compound (VIa). The compound of formula (VIa) is dissolved in a solvent (e.g., dimethylformamide (DMF), dichloromethane (DCM), or dimethyl sulfoxide (DMSO)), and a catalyst (e.g., 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and potassium bromide (KBr)) is added. Then, a solution containing an oxidizing agent (e.g., sodium hypochlorite (NaOCl)) is added at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain the compound of formula (IV). In one embodiment of the present disclosure, the mixture is stirred for 1.5 to 2.5 hours (e.g., 1.5, 2, and 2.5 hours) after the addition of the oxidizing agent, and then stirred for 3.5 to 4.5 hours (e.g., 3.5, 4, and 4.5 hours) after the addition of the reducing agent. In one embodiment of the present disclosure, a deprotection reagent is added and the mixture is stirred for 3.5 to 4.5 hours (e.g., 3.5 hours, 4 hours, and 4.5 hours).In one embodiment of the present disclosure, the catalyst and oxidizing agent are added and the mixture is stirred for 3.5 to 4.5 hours (e.g., 3.5 hours, 4 hours, and 4.5 hours). [ka] 【0061】 In one embodiment of the present disclosure, the compound of formula (I) can be prepared by a deprotection reaction according to Scheme 7. The compound of formula (IV) is dissolved in a solvent (e.g., 1,4-dioxane) containing a catalyst for the reaction (e.g., Pd(OAc)2 and triphenylphosphine (PPh3)). A protecting group scavenger (e.g., piperidine) is added to the reaction mixture and stirred at 15-30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain the compound of formula (I). In one embodiment of the present disclosure, the protecting group scavenger is added and stirred for 2.5-3.5 hours (e.g., 2.5 hours, 3 hours, and 3.5 hours). [ka] 【0062】 One embodiment of the present disclosure further includes the step of converting hederagenin to a compound of formula (XII) by attaching a protecting group to the hydroxyl group of hederagenin according to Scheme 8. Hederagenin and a protecting group compound (e.g., benzyl bromide (BnBr)) are dissolved in a solvent containing a strong base (e.g., NaH) (e.g., dimethylformamide (DMF), dichloromethane (DCM), or dimethyl sulfoxide (DMSO)) at -4 to 4°C (e.g., -4, -3, -2, 1, 0, 1, 2, 3, or 4°C). The mixture is then stirred at 15 to 30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain a compound of formula (XII). In one embodiment of the present disclosure, the protecting compound is added and the mixture is stirred for 11 to 13 hours (e.g., 11, 12, and 13 hours). [ka] 【0063】 One embodiment of the present disclosure further includes a step of reducing the compound of formula (XII) to the compound of formula (XI) according to Scheme 9. The compound of formula (XII) is dissolved in a solvent (e.g., THF), and then a reducing agent (e.g., lithium aluminum hydride (LiAlH4)) is added at -4 to 4°C (e.g., -4, -3, -2, -1, 0, 1, 2, 3 or 4°C). The mixture is heated to 45 to 55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55°C) to allow it to react completely, and then cooled to -4 to 4°C (e.g., -4, -3, -2, -1, 0, 1, 2, 3 or 4°C), and a strong base (e.g., sodium hydroxide (NaOH)) is added to obtain the compound of formula (XI). One embodiment of the present disclosure adds the strong base and continues stirring for 14 to 16 minutes (e.g., 14 minutes, 15 minutes and 16 minutes). [ka] 【0064】 In one embodiment of the present disclosure, the process further includes the step of oxidizing the compound of formula (XI) to the compound of formula (VII) according to scheme 10. The compound of formula (XI) is dissolved in a solvent (e.g., dimethylformamide (DMF), dichloromethane (DCM), or dimethyl sulfoxide (DMSO)), and then an oxidizing agent (e.g., desmartin periodinane (DMP)) is added at 15 to 30°C (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30°C) to obtain the compound of formula (VII). In one embodiment of the present disclosure, the mixture is stirred for 1.5 to 2.5 hours (e.g., 1.5 hours, 2 hours, and 2.5 hours) after the addition of the oxidizing agent. [ka] [Examples] 【0065】 The following embodiments are provided to illustrate some aspects of the present disclosure. These embodiments should not be considered to limit the scope of the present disclosure. 【0066】 In this embodiment, the preparation processes for Examples 1 to 6 can be referenced from the preparation scheme in Figure 6. The preparation processes for Examples 7 to 12 can be referenced from the preparation scheme in Figure 5. Furthermore, the preparation processes for Examples 13 to 17 can be referenced from the preparation scheme in Figure 7. 【0067】 Example 1: Preparation of Compound 1 【0068】 120 g of oleanolic acid (OA) was added to 1.2 L of DCM and 275 mL of pyridine. The solution was stirred at room temperature and turned into a clear yellow solution. 48 g of NBS was added and the mixture was stirred at room temperature for 1.5 hours. 48.8 g of trichloroisocyanuric acid (TCCA) was added and the mixture was stirred at room temperature for 2 hours (caution against gas generation). After complete conversion, 32 mL of IPA was added to the mixture and the mixture was stirred at room temperature for 1 hour to quench the excess TCCA. 58.2 g of HONH2·HCl was added to the mixture and the mixture was stirred at room temperature for 4 hours. 【0069】 To remove excess reagent after the reaction, the mixture was diluted in 1200 mL of DCM and extracted with 4050 mL of 1 M HCl. Then, water was back-extracted with 1500 mL of DCM. Subsequently, the combined organic layer was washed with 4050 mL of 0.5 M NaOH and 3000 mL of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and excess solvent was removed under reduced pressure to obtain compound 1 as a pale yellow solid (132.1 g, yield 94.3%). 【0070】 Example 2: Preparation of Compound 2 【0071】 Compound 1 (39.4 g), a pale yellow solid from the previous step, was dissolved in 400 mL of Ac2O:AcOH = 1:1 cosolvent. After stirring at 45°C for 90 minutes, 2.5 g of Pd(OAc)2 and 35.7 g of phenyliodo(III) diacetate were added sequentially, and stirring continued at 45°C for 8 hours. The solvent was then removed under reduced pressure, and 600 mL of THF:acetone:1M HCl = 1:1:1 cosolvent was added to the mixture, and the mixture was stirred at 55°C for 8 hours. After acid catalysis, the mixture was diluted with 650 mL of ethyl acetate and extracted three times with water (650 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate:hexane = 1:10) yielded Compound 2 as a white foam (15.3 g, yield 37.7%). 1 H NMR (600 MHz, CDCl3) δ 4.31 (dd, J = 3.1, 2.4 Hz, 1H), 3.68 (d, J = 11.3 Hz, 1H), 3.42 (d, J = 11.3 Hz, 1H), 2.63 (ddd, J = 17.9, 10.7, 7.2 Hz, 1H), 2.44 (ddd, J = 15.1, 11.9, 3.7 Hz, 1H), 2.36 (ddd, J = 16.4, 6.0, 2.8 Hz, 1H), 2.3 (d, J = 9.5 Hz, 1H), 2.17 (td, J = 13.4, 5.6Hz, 1H), 2.01-1.93 (m, 5H), 1.91-1.86 (m, 4H), 1.77 (dd, J = 5.8, 1.9 Hz, 1H), 1.65-1.63 (m, 3H), 1.59-1.50 (m, 2H), 1.45 (s, 3H), 1.44-1.41 (m, 1H), 1.36-1.32 (m, 2H), 1.28 (s, 3H), 1.26-1.24 (m, 1H), 1.08 (s, 3H), 1.00 (s, 6H), 0.9 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ 218.3, 178.8, 91.5, 66.8, 56.0, 52.5, 52.3, 48.6, 45.5, 44.8, 43.5, 42.4, 39.9, 38.6, 36.1, 35.1, 33.9, 33.8, 33.2, 31.9, 30.7, 29.1, 27.5, 23.5, 21.3, 21.0, 19.0, 18.5, 16.7, 16.6 ppm. HRMS(ESI-TOF) C 30 H 45 BrO4[M+H] + The calculated value is 549.2574, and the measured value is 549.2574. 【0072】 Example 3: Preparation of Compound 3 【0073】 Compound 2 (15.3 g), a white foamy substance from the previous step, was dissolved in DMF (60 mL) under an N2 atmosphere. Imidazole (5.7 g) and tert-butyldimethylsilyl chloride (TBSCl, 10.6 g) were added sequentially in an ice bath. The solution was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (750 mL) and quenched by adding NaHCO3 (saturated) (950 mL) dropwise. The aqueous layer was extracted twice with ethyl acetate (750 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate:hexane = 1:20) to obtain compound 3 as a white foamy substance (15.9 g, yield 86.2%). 1H NMR (600 MHz, CDCl3) δ 4.32 (dd, J = 3.7, 2.3 Hz, 1H), 3.68 (d, J = 9.3 Hz, 1H), 3.42 (d, J = 9.3 Hz, 1H), 2.52-2.50 (m, 1H), 2.45-2.34 (m, 2H), 2.36-2.34 (m, 1H), 2.20-2.14 (m, 2H), 2.05-1.93 (m, 5H), 1.91-1.86 (m, 2H), 1.66-1.56 (m, 6H), 1.52-1.47 (m, 1H), 1.46 (s, 3H), 1.37-1.28 (m, 5H), 1.27 (s, 3H), 1.26-1.24 (m, 1H), 0.99 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.89 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 217.1, 178.7, 91.6, 68.6, 56.2, 52.4, 52.9, 45.8, 45.5, 44.2, 43.5, 42.1, 40.0, 37.3, 36.0, 35.6, 33.9, 33.6, 33.2, 31.9, 30.9, 29.1, 27.5, 25.8, 25.8, 25.8, 23.5, 21.3, 20.7, 19.0, 18.7, 18.2, 17.0, 16.5, -5.5, -5.8 ppm. HRMS(ESI-TOF) C 36 H 59 BrO4Si[M+H] + について, calculated value 663.3439, measured value 663.3440. 【0074】 Example 4: Preparation of compound 4 【0075】 To compound 3 (1.76 g) from the previous step, lithium tri-tert-butoxyaluminum hydride (1.72 g) in THF (30 mL) was added under an N2 atmosphere and stirred at room temperature. After 1 hour, the mixture was cooled to -78°C, and diisobutylaluminum hydride (1.72 mL, 20 wt%) was added dropwise, and stirring continued for 90 minutes. Before warming to room temperature, the excess hydride was quenched by the dropwise addition of MeOH (3.5 mL). AcOH (30 mL) and Zn powder (2.7 g) were added sequentially, and the mixture was sonicated for 1 minute. Then, the mixture was stirred at 50°C for 1 hour and cooled to room temperature for 16 hours. The mixture was diluted with 60 mL of ethyl acetate and extracted three times with 50 mL of water. The mixture was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate:hexane = 1:20) to obtain compound 4 as a white foam (1.2 g, 80.3%). 1 H NMR (600 MHz, CDCl3) δ 9.39 (s, 1H), 5.34 (t, J = 3.6 Hz, 1H), 3.7 (d, J = 9.4 Hz, 1H), 3.59 (dd, J = 11.1, 4.4 Hz, 1H), 3.35 (d, J = 9.3 Hz, 1H), 2.62 (dd, J = 13.7, 4.3 Hz, 1H), 1.97 (dt, J = 13.8, 4.1 Hz, 1H), 1.89-1.87 (m, 2H), 1.70-1.60 (m, 5H), 1.58-1.51 (m, 3H), 1.48-1.38 (m, 3H), 1.33-1.22 (m, 6H), 1.20-1.17 (m, 2H), 1.12 (s, 3H), 1.07-1.04 (m, 1H), 1.01-0.95 (m, 2H), 0.94 (s, 3H), 0.913-0.910(m, 6H), 0.90 (s, 6H), 0.86 (s, 3H), 0.85-0.84 (m, 1H), 0.071 (s, 3H), 0.067 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 207.5, 142.8, 123.3, 76.7, 73.2, 49.9, 49.1, 47.6, 45.6, 41.7, 41.6, 40.5, 39.5, 38.1, 36.8, 33.1, 33.1, 32.5, 30.6, 27.7, 26.7, 26.0, 25.8, 25.8, 25.8, 25.5, 23.4, 23.4, 22.1, 18.5, 18.1, 17.1, 15.5, 11.6, -5.7, -5.7 ppm. HRMS(ESI-TOF) C 36 H 62 O3Si [M+H] + The calculated value is 571.4541, and the measured value is 571.4544. 【0076】 Example 5: Preparation of Compound 5 【0077】 Compound 4 (2.2 g) from the previous step was dissolved in DMF (12 mL) and DCM (12 mL) under an N2 atmosphere. Imidazole (0.67 g) and tert-butyldimethylsilyl chloride (TBSCl 1.16 g) were added sequentially in an ice bath. The solution was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (120 mL) and quenched by adding NaHCO3 (saturated) (150 mL) dropwise. The aqueous layer was extracted twice with ethyl acetate (120 mL). The mixture was dried over anhydrous magnesium sulfate, filtered, and the organic layer was concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate:hexane = 1:200) to obtain compound 5 as a white foam (2.5 g, yield = 95.0%). 1H NMR (600 MHz, CDCl3) δ 9.40 (s, 1H), 5.34 (s, 1H), 3.7 (dd, J = 11.5, 4.7 Hz, 1H), 3.35 (d, J = 9.6 Hz, 1H), 3.15 (d, J = 9.6 Hz, 1H), 2.62 (dd, J = 13.6, 4.1 Hz, 1H), 1.96 (dt, J = 13.7, 4.0 Hz, 1H), 1.88-1.86 (m, 2H), 1.71-1.66 (m, 2H), 1.64-1.60 (m, 2H), 1.58-1.52 (m, 4H), 1.51-1.43 (m, 3H), 1.32-1.28 (m, 4H), 1.25-1.17 (m, 5H), 1.11 (s, 3H), 1.07-1.04 (m, 1H), 0.92-0.91(m, 8H), 0.90 (s, 9H), 0.86 (s, 9H), 0.73 (s, 3H), 0.57 (s, 3H), 0.03-0.02 (m, 12H) ppm; 13 C NMR (100 MHz, CDCl3) δ 207.7, 142.8, 123.4, 71.6, 63.9, 49.1, 47.6, 45.9, 45.6, 43.2, 41.8, 40.6, 39.5, 38.1, 36.4, 33.2, 33.0, 32.2, 30.6, 27.7, 27.2, 26.7, 26.0, 26.0, 26.0, 25.9, 25.9, 25.9, 25.3, 23.4, 23.4, 22.1, 18.1, 18.0, 17.9, 17.1, 15.6, 12.7, -3.7, -4.9, -5.3, -5.8 ppm. HRMS(ESI-TOF) C 42 H 76 O3Si2[M+H] + について, calculated value 685.5406, measured value 685.5406. 【0078】 Example 6: Preparation of compound 6 【0079】 Under an N2 atmosphere, compound 5 (2.06 g) was placed in a round bottle. Anhydrous toluene (30 ml) and (S)-1-pyridine-2-ylethylamine (0.73 g) were added sequentially. The reaction mixture was then heated to 80°C and stirred for 2 hours. Excess solvent was removed by vacuum, and compound 6 was obtained without further purification. 【0080】 Example 7: Preparation of Compound 7 【0081】 Cu(OTf)2 (1.4 g) and sodium ascorbate (1.19 g) were added to the mixture of compound 6 from the previous step. Methanol (15 ml) and acetone (15 ml) were also added to the mixture and stirred at room temperature. The mixture was bubbling with an O2 balloon for 30 minutes. The mixture was then heated to 50°C and stirred for 120 minutes. After the reaction, 30 ml of ethyl acetate and saturated aqueous Na4EDTA solution (30 mL) were added and stirred for 1 hour. The layers were separated, and the aqueous layer was extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (ethyl acetate:hexane = 1:40) to obtain compound 7 as a white solid (1.1 g, yield = 51.8%). 1 H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 5.39 (s, 1H), 4.16 (d, J = 11.8 Hz, 1H), 3.68 (d, J = 7.8 Hz, 1H), 3.35 (d, J = 9.6 Hz, 1H), 3.14 (d, J = 9.5 Hz, 1H), 2.70 (d, J = 10.3 Hz, 1H), 1.97-1.94 (m, 1H), 1.86-1.79 (m, 3H), 1.61-1.50 (m, 11H), 1.37-1.27 (m, 6H), 1.17 (s, 3H), 0.95 (s, 3H), 0.91 (s, 6H), 0.89 (s, 9H), 0.85 (s, 9H), 0.76 (s, 3H), 0.57 (s, 3H), 0.02 (s, 12H) ppm; 13 13C NMR (100 MHz, CDCl3) δ 210.0, 141.7, 124.2, 71.6, 65.7, 63.9, 52.5, 46.7, 45.9, 45.3, 43.9, 43.3, 43.2, 39.7, 38.2, 36.7, 36.3, 33.1, 32.4, 32.1, 30.4, 27.2, 26.4, 26.0, 26.0, 26.0, 25.9, 25.9, 25.9, 23.5, 23.5, 21.7, 18.1, 18.0, 17.8, 17.2, 15.6, 12.7, -3.7, -4.9, -5.3, -5.9 ppm. HRMS(ESI-TOF) C 42 H 76 O4Si2 [M+H] + calculated value: 701.5355, measured value: 701.5354. 【0082】 Example 8: Preparation of Compound 8 【0083】 Compound 7 (7.55 g) was dissolved in DMSO (21.6 mL) and tert-butanol (99.2 mL), and an aqueous solution of NaClO2 (6.96 g) and NaH2PO4·H2O (9.24 mg) in water (51.8 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with 10% aqueous NaOH solution (to pH = 9), and the aqueous phase was extracted with hexane. Then, the aqueous phase was acidified with 1N aqueous HCl solution (to pH = 1) and extracted with DCM (200 mL). The combined DCM layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to obtain a crude mixture without further purification. 【0084】 The crude mixture from the previous step was dissolved in THF / H2O=10 / 1 (330 mL), and allyl bromide (1.9 mL, 22.0 mmol), tetra-n-butylammonium iodide (162.5 mg, 0.44 mmol), and K2CO3 (3.0 g, 22.0 mmol) were added sequentially. The reaction mixture was stirred at 65°C for 4 hours. THF was removed by vacuum. The mixture was diluted with ethyl acetate (300 mL), the layers were separated, and the aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (ethyl acetate:hexane=1:40) to obtain compound 8 as a white solid (5.5 g, yield=66.4%, 2 steps). 1 H NMR (400 MHz, CDCl3) δ 5.90 (ddd, J = 15.0, 7.1, 3.7 Hz, 1H), 5.38-5.25 (m, 3H), 4.56 (ddd, J = 19.2, 8.9, 3.8, Hz, 2H), 4.17 (dd, J = 5.3, 2.8 Hz, 1H), 3.70 (dd, J = 7.5, 3.1 Hz, 1H), 3.37 (d, J = 6.5 Hz, 1H), 3.16 (d, J = 6.4 Hz, 1H), 3.04 (dd, J = 9.2, 2.2 Hz, 1H), 2.27 (d, J = 8.5 Hz, 1H), 1.88 (dd, J = 5.8, 2.1 Hz, 2H), 1.71-1.62 (m, 5H), 1.56-1.50 (m, 7H), 1.30-1.27 (m, 6H), 1.19 (s, 3H), 0.97 (s, 3H), 0.93 (s, 6H), 0.92 (s, 9H), 0.88 (s, 9H), 0.74 (s, 3H), 0.59 (s, 3H), 0.04 (s, 12H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.9, 142.3, 131.8, 123.1, 118.4, 71.6, 65.1, 64.8, 63.9, 50.6, 46.8, 46.0, 45.5, 44.0, 43.3, 43.2, 39.4, 38.1, 37.4, 36.4, 33.3, 33.0, 32.1, 30.5, 27.2, 26.7, 26.7, 26.0, 26.0, 26.0, 25.9, 25.9, 25.9, 23.9, 23.5, 18.1, 18.0, 17.9, 17.0, 15.6, 12.7, -3.7, -4.9, -5.3, -5.9 ppm. HRMS(ESI-TOF) C 45 H 80 O5Si2[M+H] + The calculated value is 757.5617, and the measured value is 757.5621. 【0085】 Example 9: Preparation of Compound 9 【0086】 Compound 8 (5.5 g) was dissolved in DCM (73.0 mL), and desmartin periodinane (12.4 g) and NaHCO3 (1.84 g) were added. After stirring at 25°C for 2 hours, the excess reagent was quenched with saturated aqueous solution of Na2SO3 (100 mL), and the resulting mixture was extracted three times with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to obtain a white foam compound without further purification. 【0087】 The white foamy compound from the previous step was dissolved in ethanol (73 mL), and sodium borohydride (2.8 g) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with H2O (100 mL), and then ethanol was removed under vacuum. The mixture was diluted with DCM (100 mL), and the layers were separated. The aqueous layer was extracted three times with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:40) to afford Compound 9 as a white foam (3.4 g, yield = 60.4%, over two steps). 1 H NMR (600 MHz, CDCl3) δ 5.90 - 5.83 (m, 1H, all internal alkenyl CH), 5.40 (t, J = 3.6 Hz, 1H), 5.30 (ddd, J = 17.0, 4.5 Hz, 1H), 5.21 (ddd, J = 10.6, 3.8 Hz, 1H), 4.54 - 4.46 (m, 3H), 3.70 (dd, J = 11.4, 4.8 Hz, 1H), 3.35 (d, J = 9.7 Hz, 1H), 3.15 (d, J = 9.6 Hz, 1H), 3.07 (dd, J = 14.4, 4.4 Hz, 1H), 2.18 - 2.13 (m, 1H), 1.90 - 1.87 (m, 3H), 1.85 - 1.81 (m, 1H), 1.79 - 1.72 (m, 2H), 1.62 - 1.61 (m, 1H), 1.59 - 1.57 (m, 3H), 1.53 - 1.51 (m, 2H), 1.37 (dd, J = 15.1, 3.8 Hz, 1H), 1.32 (s, 3H), 1.29 - 1.28 (m, 1H), 1.26 - 1.25 (m, 3H), 1.21 - 1.11 (m, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 0.90 (s, 12H), 0.86 (s, 9H), 0.73 (s, 3H), 0.57 (s, 3H), 0.03 - 0.02 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3) δ 176.5, 142.5, 132.2, 123.2, 118.0, 75.1, 71.6, 65.1, 63.9, 48.9, 46.8, 46.4, 46.0, 43.2, 41.5, 40.8, 39.6, 38.1, 36.5, 35.5, 35.5, 32.8, 32.4, 30.6, 30.4, 27.2, 26.9, 26.0, 26.0, 26.0, 25.9, 25.9, 25.9, 24.6, 23.4, 18.1, 18.0, 17.9, 17.2, 15.8, 12.6, -3.7, -4.9, -5.3, -5.8 ppm. HRMS(ESI-TOF) C 45 H 80 O5Si2[M+H] + The calculated value is 757.5617, and the measured value is 757.5621. 【0088】 Example 10: Preparation of Compound 10 【0089】 Compound 9 (2.3g) was dissolved in THF (60mL), and TBAF (7.8g, 1M solution in THF) was added. The reaction mixture was stirred at 50°C for 4 hours. THF was removed by vacuum. The mixture was diluted with DCM (80mL), the layers were separated, and the aqueous layer was extracted three times with DCM (80mL). The combined organic layers were washed with brine (80mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography 9 (ethyl acetate:hexane = 1:4) to obtain compound 10 as a white foam (1.32g, yield = 83.3%). 1¹H NMR (600 MHz, CDCl₃) δ 5.90–5.84 (m, 1H, CH₃), 5.39 (t, J = 3.5 Hz, 1H), 5.30 (ddd, J = 17.1, 4.4 Hz, 1H), 5.21 (ddd, J = 10.6, 3.8 Hz, 1H), 4.54–4.46 (m, 3H), 3.73 (d, J = 10.3 Hz, 1H), 3.64 (dd, J = 9.1, 7.0 Hz, 1H), 3.44 (d, J = 10.3 Hz, 1H), 3.07 (dd, J = 14.5, 4.4 Hz, 1H). 2.17-2.13 (m, 1H), 1.90-1.88 (m, 3H), 1.83-1.81 (m, 3H), 1.79-1.75 (m, 6H), 1.65-1.60 (m, 4H), 1.50-1.46 (m, 1H), 1.37-1.35 (m, 4H), 1.27-1.25 (m, 4H), 1.14-1.11 (m, 1H), 0.97 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.73 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 176.4, 142.7, 132.2, 122.8, 118.1, 74.9, 72.1, 65.2, 49.9, 48.8, 46.7, 46.3, 41.8, 41.2, 40.6, 39.5, 38.2, 36.9, 35.5, 32.8, 32.7, 30.6, 30.4, 29.7, 29.7, 27.0, 26.8, 24.7, 23.3, 18.4, 17.1, 15.8, 11.4 ppm. HRMS(ESI-TOF) C 33 H 52 O5[M+H] + について, calculated value 529.3888, measured value 529.3887. 【0090】 Example 11: Preparation of agaric acid 【0091】 Compound 10 (1.0 g) was dissolved in DCM (20 mL), and TEMPO (1.48 g) and KBr (22.3 mg) were added. Then, a 5% NaHCO3 aqueous solution (0.035 M) of NaOCl (848.6 mg) was added. The reaction mixture was vigorously stirred at room temperature for 4 hours. The mixture was diluted with DCM (30 mL). The organic layer was washed with H2O (30 mL) and brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:4) to obtain allyl chiric acid as a white foam (831.7 mg, yield = 83.1%). 1 H NMR (600 MHz, CDCl3) δ 9.41 (s, 1H, H-23), 5.90-5.83 (m, 1H, all internal alkenyl CH), 5.36 (d, J = 3.5, 1H, H-12), 5.27 (dd, J = 17.2, 1.2 Hz, 1H, all terminal alkenyl CH a ), 5.21 (d, J = 10.4 Hz, 1H, all terminal alkenyl CH b ), 4.55-4.46 (m, 3H, H-16, allylic CH2), 3.77 (dd, J = 11.2, 4.6 Hz, 1H, H-3), 3.08 (dd, J = 14.4, 4.3 Hz, 1H, H-18), 2.17 (t, J = 13.7 Hz, 1H, H-19), 1.93-1.89 (m, 3H), 1.83-1.65 (m, 8H), 1.54-1.48 (m, 6H), 1.38 (s, 3H), 1.36-1.27 (m, 4H), 1.22-1.20 (m, 1H), 1.13 (dd, J = 12.9, 4.1, 1H), 1.07 (s, 3H), 1.05-0.99 (m, 3H), 0.98 (s, 6H), 0.91 (s, 3H), 0.74 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 207.0 (C-23), 176.3 (C-28), 142.8, 132.1, 122.5, 118.1, 74.9, 71.8, 65.2, 55.2, 48.7, 48.2, 46.6, 46.4, 41.4, 40.6, 39.9, 38.1, 36.0, 35.5, 35.4, 32.8, 32.3, 30.7, 30.4, 27.0, 26.1, 24.6, 23.3, 20.7, 17.0, 15.7, 8.9 ppm. HRMS(ESI-TOF) C 33 H 51 O5[M+H] + The calculated value is 527.3731, and the measured value is 527.3733. 【0092】 Example 12: Preparation of chiral acid 【0093】 Allyl chiric acid (800 mg) was dissolved in 1,4-dioxane (20 mL). The allyl chiric acid solution was added to a mixture of Pd(OAc)2 (34 mg) and triphenylphosphine (0.2 g) dissolved in 1,4-dioxane (13 mL) and carried out the reaction. Piperidine (260 mg) was added to the reaction mixture and stirred at room temperature for 3 hours. The mixture was concentrated under vacuum until dry. The residue was purified by column chromatography (ethyl acetate:hexane = 1:15) to obtain chiric acid as a white foam (502.7 mg, yield = 68%). 1 ¹H NMR (600 MHz, methanol-d4) δ 9.30 (s, 1H, H-23), 5.30 (1H, alkenyl CH), 4.46 (1H, -OH), 3.77 (1H, H-3), 3.00 (1H), 2.30 (t, 1H), 1.98-1.67 (m, 11H), 1.61-1.47 (m, 2H), 1.40 (s, 3H), 1.32-1.35 (m, 2H), 1.28-1.25 (m, 1H), 1.16-1.12 (m, 2H), 1.02-0.97 (m, 11H), 0.91-0.88 (m, 4H), 0.80 (s, 3H); 13¹³C NMR (150 MHz, methanol-d4) δ 208.7 (C-23), 181.2 (C-28), 145.3, 123.3, 75.4, 72.9, 56.9, 49.7, 48.9, 48.2, 47.8, 42.9, 42.2, 41.1, 39.6, 37.1, 36.7, 36.3, 33.7, 33.6, 32.9, 31.6, 27.4, 27.1, 25.0, 24.6, 21.9, 17.9, 16.3, 9.5 ppm. 【0094】 Example 13: Preparation of Compound 11 【0095】 To a stirred solution of hederagenin (6.00 g, 12.6 mmol) and BnBr (14.8 mL, 124.7 mmol) in anhydrous DMF (20.0 mL), NaH (60 wt%, dispersed in mineral oil, 2.3 g, 94.5 mmol) was gradually added at 0°C. After the addition was complete, stirring was continued for a further 12 hours at room temperature under an N2 atmosphere, and then the reaction mixture was diluted with ethyl acetate (20.0 mL). The resulting mixture was thoroughly washed with water (2 × 20 mL) and brine (20 mL), and the organic layer was then dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (siRNA / hexane = 1:100) to obtain compound 11 as a white foam (6.9 g, yield 73.8%). 【0096】 Example 14: Preparation of Compound 12 【0097】 A solution of compound 11 (6.0 g, 8.0 mmol) in anhydrous THF (10 mL) was slowly added at 0°C to a solution of lithium aluminum hydride (0.929 g, 24.0 mmol) in anhydrous THF (10 mL). The solution was heated to 50°C. After the reaction was complete, the mixture was cooled to 0°C and excess LiAlH4 was inactivated by adding water (10 mL). 1N sodium hydroxide aqueous solution (10 mL) was added, and the mixture was stirred for 15 minutes. The solid was filtered off and washed with ethyl acetate (2 × 20 mL), and the organic phase was washed with water (2 × 20 mL) and brine (20 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure. After column chromatography (hexane / siRNA = 20:1), compound 12 was obtained as a white foam (3.28 g, yield 64.2%). 【0098】 Example 15: Preparation of Compound 13 【0099】 To a stirred solution of compound 12 (2.0 g, 3.1 mmol) in CH2Cl2 (4.0 mL), desmartin periodinane (2.63 g, 6.2 mmol) was added. After stirring at 25°C for 2 hours, the excess reagent was quenched with saturated aqueous solution of Na2SO3 (5.0 mL), and the resulting mixture was extracted with HCl (3 × 5.0 mL). The combined organic phase was washed with brine (4.0 mL), dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (HCl / hexane = 1:50) to obtain compound 13 as a white foam (1.3 g, yield 63%). 1H NMR (600 MHz, CDCl3) δ 9.39 (s, 1H, H-28), 7.30-7.20 (10H, Ar-H) 5.33(t, 1H, alkenylCH), 4.60-4.29 (4H, -CH2) 3.50 (dd, 1H), 3.37 (1H), 3.08 (1H), 2.62 (dd, 1H), 1.89-1.85 (m, 2H), 1.70-1.50 (9H), 1.47-1.36 (3H), 1.30-1.20 (8H), 1.14 (s, 3H, CH3), 0.92 (s, 3H, CH3), 0.91(s, 3H, CH3), 0.90(s, 3H, CH3), 0.71 (s, 3H, CH3), 0.68 (s, 3H, CH3). 【0100】 Example 16: Preparation of Compound 14 【0101】 In a flame-dried flask, amine(S)-1-pyridine-2-yl-ethylamine (28.8 μL, 0.48 mmol) was added to a solution of compound 13 (100 mg, 0.16 mmol) and p-toluenesulfonic acid monohydrate (2.8 mg, 0.016 mmol) in toluene (2 mL). The mixture was heated to 80°C until the formation of the imine could be monitored by TLC. The mixture was cooled to 25°C and concentrated under vacuum to obtain compound 14. 【0102】 Example 17: Preparation of Compound 15 【0103】 Copper(II) nitrate trihydrate (77.2 mg, 0.32 mmol) and the resulting crude imine compound 14 were added to a reaction flask, followed by the addition of THF, acetone, and MeOH (3 mL, 1:1:1) at room temperature. The mixture was vigorously stirred for 1 hour. Hydrogen peroxide (18.8 μL, 35 wt% in H2O, 0.8 mmol) was then added dropwise to the reaction mixture, resulting in the disappearance of the precipitate and the acquisition of a blue-green solution. The reaction mixture was then stirred at room temperature for 24 hours. Saturated aqueous Na4EDTA solution (3.0 mL) was added, and the mixture was stirred for 1 hour. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous MgSO4, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (RINKAN / hexane = 1:20) to obtain compound 15 as a white foam (32 mg, 30% yield). 1 H NMR (600 MHz, CDCl3) δ 9.50 (1H, H-28), 7.34-7.28 (10H, Ar-H) 5.43(t, 1H, alkenylCH), 4.65-4.33 (4H, -CH2), 4.21 (m, 1H,-CH-OH) 3.54 (dd, 1H), 3.41 (d, 1H), 3.13 (d, 1H), 2.74 (dd, 1H), 2.02-1.81 (6H), 1.68-1.54 (8H), 1.46-1.40 (3H), 1.36-1.32 (4H), 1.25 (s, 3H, CH3), 0.99 (s, 3H, CH3), 0.98(s, 3H, CH3), 0.97 (s, 3H, CH3), 0.79 (s, 3H, CH3), 0.72 (s, 3H, CH3). 【0104】 While this disclosure has been described in considerable detail with reference to several embodiments, other embodiments are also possible. Therefore, the claims are not limited to the descriptions contained herein. 【0105】 It will be apparent to those skilled in the art that various modifications and changes can be made to the structure of this disclosure, as long as they do not deviate from the scope of this disclosure. In view of the foregoing, this disclosure is intended to encompass modifications and changes to the disclosure insofar as they fall within the scope of the claims. The various aspects and embodiments that may be included in the present invention are summarized below. [1] A method for preparing a triterpenoid compound represented by formula (I), comprising the step of converting a compound of formula (II) to a compound of formula (I). [C1] JPEG0007873511000029.jpg7864 In the formula, R 1 and R 2 These are, independently, hydrogen, or C 1 -C 8 Alkyl group, allyl group, C 2 -C 8 Alkenyl group, C 2 -C 8 Alkynyl group, (C 6 -C 12 )aryl(C 1 -C 8 ) Alkyl(C) 1 -C 8 ) Alkylsilyl group, di(C 1 -C 8 ) Alkyl(C 6 -C 12 ) Arylsilyl group, di(C 6 -C 12 )aryl(C 1 -C 8 ) Alkylsilyl group, tri(C 6 -C 12 ) Arylsilyl group, -C(O)R 7 and -C(O)OR 8 This represents a protecting group selected from the group consisting of hydroxyl, cyano, halo, and halo(C). 1 -C 6 ) Alkyl, halo(C 1 -C 6 ) alkyloxy group, (C 1 -C 6 ) Alkylthio group, C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 7 Cycloalkyl groups and C 1 -C 6 It is substituted with 0 to 4 substituents independently selected from the group consisting of alkoxy groups. R 7 and R 8 Independently, C 1 -C 8 Alkyl or C6 -C 12 It is an aryl group. [2] The method according to item 1, further comprising the step of converting a compound of formula (II) to a compound of formula (III) by oxidizing the aldehyde group of formula (II) to a carboxyl group, and then forming an oxygen protecting group by bonding a protecting group to one oxygen atom of the carboxyl group. [Case 2] JPEG0007873511000030.jpg8375 In the formula, R 3 C 1 -C 8 Alkyl group, allyl group, C 2 -C 8 Alkenyl group, C 2 -C 8 Alkynyl group, (C 6 -C 12 )aryl(C 1 -C 8 ) Alkyl alkyl group, C 6 -C 12 Arylacyl group, tri(C) 1 -C 8 ) Alkylsilyl group, di(C 1 -C 8 ) Alkyl(C 6 -C 12 ) Arylsilyl group, di(C 6 -C 12 )aryl(C 1 -C 8 ) Alkylsilyl group and tri(C 6 -C 12 )A protecting group selected from the group consisting of arylsilyl groups, each of which is a hydroxyl group, a cyano group, a halo, a halo(C) 1 -C 6 ) Alkyl, halo(C 1 -C 6 ) alkyloxy group, (C 1 -C 6 ) Alkylthio group, C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 7 Cycloalkyl groups and C 1 -C 6 It is substituted with 0 to 4 substituents independently selected from the group consisting of alkoxy compounds. [3] The method according to item 2 above, further comprising the step of converting a compound of formula (III) to a compound of formula (IV) by sequential epimerization, deprotection, and oxidation. [C3] JPEG0007873511000031.jpg8174 [4] The method according to item 2 above, further comprising the steps of: epimerizing a compound of formula (III) at the carbon position to which its hydroxyl group is attached to form a compound of formula (VI); and converting the compound of formula (VI) to a compound of formula (IV) by sequentially deprotecting and oxidizing it. [C4] JPEG0007873511000032.jpg12372 [5] The method according to item 1, further comprising the step of converting a compound of formula (IV) to a compound of formula (I) by a deprotection reaction. [5] JPEG0007873511000033.jpg7768 [6] The method according to item 1 above, further comprising the step of converting a compound of formula (VII) to a compound of formula (II) by sequentially introducing an orientation group and activating CH. [6] JPEG0007873511000034.jpg7465 [7] The method according to item 6 above, further comprising the steps of converting compound (VII) to compound (VIII) by reacting compound (VII) and compound (a) after introducing an oriented group, and converting compound (VIII) to compound (II) by CH activation. [7] JPEG0007873511000035.jpg11075 In the formula, R 6 teeth, [8] JPEG0007873511000036.jpg1926 Representing, W is H or C 1 -C 8 It is an alkyl group, X and Y are independently hydrogen, hydroxyl group, cyano group, halo, C 6 -C 12 Aryl group or C 5 -C 12 Represents a heteroaryl element, Compound (a) is, [9] JPEG0007873511000037.jpg1826 It represents. [8] The method according to item 6, further comprising the step of converting oleanolic acid to a compound of formula (VII) via sequential halolactone oxime formation, CH activation, protecting group bonding, and reduction. [C10] JPEG0007873511000038.jpg3969 [9] The method described in item 7 above, wherein the compound of formula (VII) is obtained by converting the compound of formula (IX) to the compound of formula (VII) through sequential reduction and optional protecting group bonding. [C11] JPEG0007873511000039.jpg8168 In the formula, Rx is F, Cl, Br, or I.

[10] The compound of formula (IX) is obtained by converting the compound of formula (X) to the compound of formula (IX) through sequential CH activation and protecting group bonding, as described in item 9 above. [C12] JPEG0007873511000040.jpg7660 In the formula, Rx is F, Cl, Br, or I.

[11] The compound of formula (X) is obtained by converting oleanolic acid to the compound of formula (X) by halolactone oxime formation, as described in item 10 above. [C13] JPEG0007873511000041.jpg3352

[12] The method according to item 6, further comprising the step of converting hederagenin to a compound of formula (VII) by sequentially performing protecting group bonding, reduction, and oxidation. [C14] JPEG0007873511000042.jpg3969

[13] The method according to item 6 above, further comprising the step of oxidizing a compound of formula (XI) to a compound of formula (VII). [C15] JPEG0007873511000043.jpg7867 In the formula, R 4 is hydrogen, or C 1 -C 8 Alkyl group, allyl group, C 2 -C 8 Alkenyl group, C 2 -C 8 Alkynyl group, (C 6 -C 12 )aryl(C 1 -C 8 ) Alkyl alkyl group, C 6 -C 12 Arylacyl group, tri(C) 1 -C 8 ) Alkylsilyl group, di(C 1 -C 8 ) Alkyl(C 6 -C 12 ) Arylsilyl group, di(C 6 -C 12 )aryl(C 1 -C 8 ) Alkylsilyl group and tri(C 6 -C12 )A protecting group selected from the group consisting of arylsilyl groups, each of which is a hydroxyl group, a cyano group, a halo, a halo(C) 1 -C 6 ) Alkyl, halo(C 1 -C 6 ) alkyloxy group, (C 1 -C 6 ) Alkylthio group, C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 7 Cycloalkyl groups and C 1 -C 6 It is substituted with 0 to 4 substituents independently selected from the group consisting of alkoxy compounds.

[14] The method according to item 13 above, further comprising the step of reducing the compound of formula (XII) to the compound of formula (XI). [C16] JPEG0007873511000044.jpg8173 In the formula, R 5 is hydrogen, or C 1 -C 8 Alkyl group, allyl group, C 2 -C 8 Alkenyl group, C 2 -C 8 Alkynyl group, (C 6 -C 12 )aryl(C 1 -C 8 ) Alkyl alkyl group, C 6 -C 12 Arylacyl group, tri(C) 1 -C 8 ) Alkylsilyl group, di(C 1 -C 8 ) Alkyl(C 6 -C 12 ) Arylsilyl group, di(C 6 -C 12 )aryl(C 1 -C 8 ) Alkylsilyl group and tri(C 6 -C 12 )A group selected from the group consisting of arylsilyl groups, each of which is a hydroxyl group, a cyano group, a halo, a halo(C) 1 -C 6 ) Alkyl, halo(C 1 -C 6 ) alkyloxy group, (C 1 -C 6 ) Alkylthio group, C 1 -C 6 Alkyl alkyl group, C 2 -C 6 Alkenyl group, C 2 -C 6 Alkynyl group, C 3 -C 7 Cycloalkyl groups and C1 -C 6 It is substituted with 0 to 4 substituents independently selected from the group consisting of alkoxy groups.

[15] The method according to item 14, comprising the step of converting hederagenin into a compound of formula (XII) by attaching a protecting group to the hydroxyl group of hederagenin. [C17] JPEG0007873511000045.jpg3973

Claims

[Claim 1] A step of converting a compound of formula (II) to a compound of formula (III) by oxidizing the aldehyde group of formula (II) to a carboxyl group, and then forming an oxygen protecting group by bonding a protecting group to one oxygen atom of the carboxyl group, A step of converting a compound of formula (III) to a compound of formula (IV) by sequentially performing epimerization, deprotection, and oxidation, A step of converting compound (IV) to compound (I) by a deprotection reaction, and A method for preparing a triterpenoid compound represented by formula (I), which includes [the specified compound]. 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 In the formula, R １ and R ２ each independently represents hydrogen or a protecting group selected from the group consisting of a C １ -C ８ alkyl group, an allyl group, a C ２ -C ８ alkenyl group, a C ２ -C ８ alkynyl group, a (C ６ -C １２ aryl)(C １ -C ８ alkyl group, a tri(C １ -C ８ alkylsilyl group, a di(C １ -C ８ alkyl)(C ６ -C １２ aryl)silyl group, a di(C ６ -C １２ aryl)(C １ -C ８ alkyl)silyl group, a tri(C ６ -C １２ arylsilyl group, -C(O)R ７ and -C(O)OR ８ and each of them is substituted with 0 to 4 substituents independently selected from the group consisting of a hydroxy group, a cyano group, a halo, a halo(C １ -C ６ alkyl group, a halo(C １ -C ６ alkyloxy group, a (C １ -C ６ alkylthio group, a C １ -C ６ alkyl group, a C ２ -C ６ alkenyl group, a C ２ -C ６ alkynyl group, a C ３ -C ７ cycloalkyl group and a C １ -C ６ alkoxy group. R ７ and R ８ Independently, C １ -C ８ Alkyl or C ６ -C １２ It is an aryl group, R3 is a protecting group selected from the group consisting of C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, (C6-C12)aryl(C1-C8) alkyl groups, C6-C12 arylacyl groups, tri(C1-C8)alkylsilyl groups, di(C1-C8)alkyl(C6-C12)arylsilyl groups, di(C6-C12)aryl(C1-C8)alkylsilyl groups, and tri(C6-C12)arylsilyl groups, each of which is a protecting group selected from the group consisting of a hydroxyl group, a cyano group, a halo, a halo(C1-C6) alkyl group, a halo(C1-C6) alkyloxy group, and a (C1-C6 ) It is substituted with 0 to 4 substituents independently selected from the group consisting of alkylthio groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, and C1-C6 alkoxy groups. [Claim 2] The method according to claim 1, further comprising the steps of: epimerizing a compound of formula (III) at the carbon position to which its hydroxyl group is attached to form a compound of formula (VI); and converting the compound of formula (VI) to a compound of formula (IV) by sequentially deprotecting and oxidizing it. 【Chemistry 4】 [Claim 3] The method according to claim 1, further comprising the step of converting a compound of formula (VII) to a compound of formula (II) by sequentially introducing an orienting group and performing C-H activation. 【Transformation 5】 [Claim 4] The method according to claim 3, further comprising the steps of: converting a compound of formula (VII) to a compound of formula (VIII) by reacting a compound of formula (VII) with a compound of formula (a) after introducing an oriented group; and converting a compound of formula (VIII) to a compound of formula (II) by C-H activation. 【Transformation 6】 In the formula, R ６ teeth, 【Transformation 7】 Representing, W is H or C １ -C ８ It is an alkyl group, X and Y are independently hydrogen, hydroxyl group, cyano group, halo, C ６ -C １２ Aryl group or C ５ -C １２ Represents a heteroaryl element, Compound (a) is, 【Transformation 8】 It represents. [Claim 5] The method according to claim 3, further comprising the step of converting oleanolic acid to a compound of formula (VII) via sequential halolactone oxime formation, C-H activation, protecting group bonding, and reduction. 【Chemistry 9】 [Claim 6] The method according to claim 4, wherein the compound of formula (VII) is obtained by converting the compound of formula (IX) to the compound of formula (VII) through sequential reduction and optional protecting group bonding. 【Chemistry 10】 In the formula, Rx is F, Cl, Br, or I. [Claim 7] The method according to claim 6, wherein the compound of formula (IX) is obtained by converting the compound of formula (X) to the compound of formula (IX) through sequential C-H activation and protecting group bonding. 【Chemistry 11】 In the formula, Rx is F, Cl, Br, or I. [Claim 8] The method according to claim 7, wherein the compound of formula (X) is obtained by converting oleanolic acid to the compound of formula (X) by halolactone oxime formation. 【Chemistry 12】 [Claim 9] The method according to claim 3, further comprising the step of converting hederagenin to a compound of formula (VII) by sequentially performing protecting group bonding, reduction, and oxidation. 【Chemistry 13】 [Claim 10] The method according to claim 3, further comprising the step of oxidizing a compound of formula (XI) to a compound of formula (VII). 【Chemistry 14】 In the formula, R ４ is hydrogen or a C １ -C ８ alkyl group, a C ２ -C ８ alkenyl group, a C ２ -C ８ alkynyl group, a (C ６ -C １２ aryl)(C １ -C ８ alkyl group, a C ６ -C １２ aryl acyl group, a tri(C １ -C ８ alkyl silyl group, a di(C １ -C ８ alkyl)(C ６ -C １２ aryl silyl group, a di(C ６ -C １２ aryl)(C １ -C ８ alkyl silyl group, and a tri(C ６ -C １２ aryl silyl group selected from the group consisting of, each of which is a hydroxy group, a cyano group, a halo, a halo(C １ -C ６ alkyl group, a halo(C １ -C ６ alkyloxy group, a (C １ -C ６ alkylthio group, a C １ -C ６ alkyl group, a C ２ -C ６ alkenyl group, a C ２ -C ６ alkynyl group, a C ３ -C ７ cycloalkyl group, and a C １ -C ６ alkoxy group, and is independently substituted with 0 to 4 substituents selected from the group consisting of. [Claim 11] The method according to claim 10, further comprising the step of reducing the compound of formula (XII) to the compound of formula (XI). 【Chemistry 15】 wherein, R ５ is hydrogen, or C １ -C ８ alkyl group, C ２ -C ８ alkenyl group, C ２ -C ８ alkynyl group, (C ６ -C １２ aryl (C １ -C ８ alkyl group, C ６ -C １２ aryl acyl group, tri(C １ -C ８ alkyl silyl group, di(C １ -C ８ alkyl (C ６ -C １２ aryl silyl group, di(C ６ -C １２ aryl (C １ -C ８ alkyl silyl group, and tri(C ６ -C １２ aryl silyl group, and is a group selected from the group consisting of, each of which is a hydroxy group, a cyano group, a halo, halo(C １ -C ６ alkyl group, halo(C １ -C ６ alkyloxy group, (C １ -C ６ alkylthio group, C １ -C ６ alkyl group, C ２ -C ６ alkenyl group, C ２ -C ６ alkynyl group, C ３ -C ７ cycloalkyl group, and C １ -C ６ alkoxy group, and is independently selected from the group consisting of 0 to 4 substituents. [Claim 12] The method according to claim 11, comprising the step of converting hederagenin into a compound of formula (XII) by attaching a protecting group to the hydroxyl group of hederagenin. 【Chemistry 16】

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