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 to U.S. Provisional Application No. 63 / 325,792, filed March 31, 2022. The entirety of the above-referenced patent application is incorporated herein by reference and made a part of this specification.

[0002] The present disclosure relates to methods for preparing triterpenoid compounds, more specifically, the present disclosure relates to methods for preparing quillaic acid for use in triterpenoid saponin-based vaccine adjuvants. [Background technology]

[0003] The name "saponin" comes from the Latin "sapo", meaning its ability to produce soap-like foam, and its amphiphilic properties come from a structure containing an isoprenoid-derived aglycone (sapogenin) linked to one or more glycans by either ether or ester bonds. The structural classification of saponins is mainly based on their sapogenin skeleton and can be divided into two major groups: triterpenoid saponins and steroidal saponins. Triterpenoid saponins are widely distributed in dicotyledonous plants and contain four main skeletons, such as pentacyclic oleananes, ursane, and lupane, and tetracyclic dammaranes (Figure 1a). Steroidal saponins are mainly derived from monocotyledonous plants and contain four main skeletons, such as tetracyclic cholestanes, hexacyclic spirostanes, pentacyclic furostanes, and lactone-containing cardenolides (Figure 1b). Glycosyl sapogenins are classified according to the number of sugar residues into monodesmosides (one sugar residue), bidesmosides (two sugar residues) and polydesmosides (three or more 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 found in many medicinal plants and herbal medicines and exhibit abundant biological activities, including antifungal, antibacterial, antiviral, anti-inflammatory, anticancer, antioxidant, and immunomodulatory effects, and therefore can serve as a good starting point for the development of medicines derived from natural products. However, saponins are still poorly understood in terms of their mechanism and structure-activity relationship (SAR), and due to the microheterogeneity and scarcity of the molecules, their isolation from plants can be cumbersome and laborious to obtain suitable amounts. As a result, applying organic synthesis methods to generate artificial saponins is a promising way to efficiently expand the structural library and explore highly active compounds.

[0005] Oleanane-type saponins have become the most studied synthetic saponins due to their promising pharmacological effects and high natural abundance. As shown in Figure 2, the oleanane-type scaffolds modified by common chemical approaches are oleanolic acid, hederagenin and quillic acid. They 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, especially antitumor, antiviral and immunomodulatory effects. However, toxicity caused by hemolytic and membranolytic activities is a major challenge in drug development, and our understanding of the structure-toxicity relationship is still in its infancy.

[0006] Saponins with immunomodulatory effects were classified into up-regulation and down-regulation. Immune up-regulation activity was mainly evaluated for quillaric acid saponins, which have been extensively studied in enhancing serum IgG production for the development of vaccine adjuvants, compared with GPI-0100 and QS-21, and various derivatives based on quillaric acid have been developed.

[0007] QS-21 is an FDA-approved vaccine adjuvant and is widely used to treat infectious diseases and cancer. Contrary to the versatile use of QS-21, its natural sources are limited. Traditional methods for isolating quillaic acid require extraction from the root or bark. In order to preserve the natural source and make its application more sustainable, chemical synthesis of quillaic acid is necessary. However, it was reported that the chemical synthesis of quillaic acid, starting from protoessigenin, involves a 24-step process to obtain quillaic acid (Zeng et al., Chemical synthetic 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 pathway of CYP716A262 and CYP72A567, which can provide an alternative source of quilacic acid by initiating the synthesis from the metabolites of β-amyrin. By transforming S. cerevisiae strain BY-bAS with CYP716A567 and CYP72A262 genes, 314.01 mg / L of quilacic acid can be produced. However, this method requires cloning the specific RNA sequences of CYP716A567 and CYP72A262, and cannot be scaled up at present. In the pharmaceutical industry, versatile CH activation bestows us with a new platform. In terpenoid and steroid CH functionalization, the abundance of aliphatic CH in their structures and the low reactivity of aliphatic CH bonds make the development of methodology and design of strategies the most important challenge. To date, the limited β-C(sp 3)-H oxidation has been reported for oleanane-type terpenoids. C-23 oxidation remains problematic, making it impractical for industrial use. For example, the [Ir(cod)(OMe)]2-catalyzed C-23 oxidation reported by Hartwig's group needs to be operated under a glove box, and the sodium tetrachloropalladate(II)-mediated C-23 oxidation reported by Baldwin's group requires the use of stoichiometric palladium salts (Figure 3A). For the above reasons, designing synthetic strategies has become an important issue in terpenoid synthesis.

[0008] In the past decades, directing group-assisted C-H bond functionalization strategies have emerged. Monodentate amides, pyridines, or imines, and bidentate directing groups with Lewis base properties that can control regioselectivity are utilized. In most cases, the directing groups are covalently bonded 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 non-directing C-H activation are developed to meet the needs of economic efficiency.

[0009] Among the various directing groups mentioned above, bidentate transient directing groups show their niche in C-H 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 auxiliaries. During the past decades, bidentate directing groups have been widely used in transition metal-catalyzed C-H bond functionalization reactions due to their easier metal coordination and tunable coordination properties compared with monodentate ones. In 2020, Yu et al. (Site-selective C-H hydroxylation of pentacyclic triterpenoids directed by transient chiral pyridine-imino groups. Nat. Commun. 2020, 11, 4371.) successfully established the site-selective functionalization of triterpenoids by utilizing the chiral directing group (R / S)-(pyridin-2-yl)ethan-1-amine (Figure 3B). By forming a temporary 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. Summary of the Invention

[0010] The present disclosure utilizes a temporary N,N-position orientation strategy to access the CH bond hydroxylation of oleanane-type terpenoids. This strategy can reduce the synthesis steps due to the characteristics of easy removal and high selectivity. By combining two CH activations, the present disclosure provides an environmentally friendly and industrially practical method for the synthesis of quillaric acid instead of the traditional extraction method to obtain quillaric acid.

[0011] The present disclosure provides a process for preparing a triterpenoid compound of formula (I), comprising converting a compound of formula (II) to a compound of formula (I). [ka] 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.

[0012] In one exemplary embodiment of the present disclosure, the method further comprises converting the 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 attaching a protecting group to one oxygen atom of the carboxyl group. [ka] In the formula, R3 is 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 Aryl acyl 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) arylsilyl groups, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of hydroxyl, cyano, halo, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C1-C6)alkylthio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C1-C6 alkoxy.

[0013] In one exemplary embodiment of the present disclosure, the method further comprises converting the compound of formula (III) to the compound of formula (IV) via sequential epimerization, deprotection and oxidation. [ka]

[0014] In one exemplary embodiment of the present disclosure, the method further comprises the steps of epimerizing compound of formula (III) at the carbon to which the hydroxyl group is attached to form compound of formula (VI), and converting compound of formula (VI) to compound of formula (IV) via sequential 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 comprises converting the compound of formula (IV) to a compound of formula (I) by a deprotection reaction. [ka] In the deprotection step, R3 is removed from the compound of formula (IV).

[0016] In one exemplary embodiment of the present disclosure, the method further comprises converting compound of formula (VII) to compound of formula (II) via sequential directing group introduction and CH activation. [ka]

[0017] In another exemplary embodiment of the present disclosure, the method further comprises converting the compound of formula (VII) to the compound of formula (VIII) by reacting the compound of formula (VII) with the compound of formula (a) via directing group introduction, and converting the compound of formula (VIII) to the compound of formula (II) by CH activation. [ka] During the ceremony, R6 is, [ka] Represents, W is H or a C1-C8 alkyl group; X and Y are independently hydrogen, a hydroxyl group, a cyano group, a halo, a C6-C 12 Aryl group or C5-C 12 represents a heteroaryl group, Compounds of formula (a) are [ka] Represents.

[0018] In another exemplary embodiment of the present disclosure, the method further comprises converting oleanolic acid to the compound of formula (VII) via sequential halolactone oxime formation, C-H activation, protecting group attachment 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) via sequential reduction and optional protecting group attachment. [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 attachment. [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) via halolactone oxime formation. [ka]

[0022] In another exemplary embodiment of the present disclosure, the method further comprises converting hederagenin to a compound of formula (VII) via sequential protecting group attachment, reduction and oxidation. [ka]

[0023] In another exemplary embodiment of the present disclosure, the method further comprises the step of oxidizing the compound of formula (XI) to a 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 Aryl acyl 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 ) arylsilyl groups, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of hydroxyl, cyano, halo, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C1-C6)alkylthio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C1-C6 alkoxy.

[0024] In another exemplary embodiment of the present disclosure, the method further comprises reducing the compound of formula (XII) to a 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 Aryl acyl 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 ) arylsilyl groups, each of which is substituted by 0 to 4 substituents independently selected from the group consisting of hydroxy 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 converting hederagenin to a compound of formula (XII) by attaching a protecting group to a hydroxyl group of hederagenin. [ka] [Brief description of the drawings]

[0026] [Figure 1a] The major representative structures of triterpenoid saponins are shown.

[0027] [Figure 1b] The major representative structures of steroidal saponins are shown.

[0028] [Diagram 2] The representative structure of oleanane-type saponins is shown below.

[0029] [Figure 3A] A strategy for triterpenoid C-23 oxidation is presented.

[0030] [Figure 3B] FIG. 1 shows a scheme in which C-22 and C-16 in the triterpenoid D / E ring are directly hydroxylated by using a bidentate directing group.

[0031] [Figure 4] FIG. 1 shows a scheme using a bidentate directing group to improve C-16 oxidation.

[0032] [Diagram 5] 1 shows a scheme for synthesizing quillaric acid from compound 6 according to one embodiment of the present disclosure.

[0033] [Figure 6] FIG. 1 shows a scheme for synthesizing compound 6 from oleanolic acid according to another embodiment of the present disclosure.

[0034] [Figure 7] 1 shows a scheme for synthesizing compound 15 from hederagenin according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] The following disclosure provides many different embodiments or examples for implementing different features of the present disclosure. Hereinafter, in order to simplify the present disclosure, specific examples of components and arrangements are described. Of course, these are merely examples and are not intended to be limiting. Furthermore, the present disclosure may repeat reference numbers and / or letters in various examples. This repetition is for the purpose of brevity and clarity and does not in itself limit the relationship between the various embodiments and / or configurations discussed.

[0036] The term "alkyl group" as used herein refers to a straight or branched chain 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. In this specification, unless otherwise specified, alkyl groups may be optionally substituted.

[0037] "Alkenyl group" refers to a straight or branched chain 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 2-8, 2-6, or 2-4 carbon atoms. The double bond of an alkenyl group may be unconjugated or may be conjugated with another unsaturated group. Non-limiting examples of alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, and cyclopent-1-en-1-yl. In this specification, unless otherwise specified, an alkenyl group may be optionally substituted.

[0038] The term "alkynyl group" refers to a straight or branched chain 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, which have 2-8, 2-6, or 2-4 carbon atoms, respectively. The triple bond of an alkynyl group may be unconjugated or may be conjugated with another unsaturated group. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. In this specification, unless otherwise specified, an alkynyl group may be optionally substituted.

[0039] A "cycloalkyl group" is a group that contains one or more saturated and / or partially saturated rings, including, for example, all ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, and partially saturated variants of the above, such as cyclohexenyl.

[0040] As used herein, "alkoxy" refers to an alkyl group attached through an oxygen bridge. Alkoxy groups include C1-C8 alkoxy groups and C1-C4 alkoxy groups, having 1 to 8 or 1 to 4 carbon atoms, respectively. Particular alkoxy groups are 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 containing at least 6 carbon atoms or 6-12 carbon atoms and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system and may include fused or bridged ring systems. Non-limiting examples of aryl groups include aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and triphenylene. In this specification, unless otherwise specified, aryl groups may be optionally substituted.

[0042] The term "heteroaryl group" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic or polycyclic ring group incorporating one or more (e.g. 1 to 4, particularly 1, 2 or 3) heteroatoms 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 usually 5 to 10 ring members. Heteroaryl groups may be 5- or 6-membered monocyclic rings, or 9- or 10-membered bicyclic rings, e.g., fused 5- and 6-membered rings or a bicyclic structure formed from two fused 6-membered rings. Each ring may contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur and oxygen. Typically, heteroaryl rings contain up to 3 heteroatoms, more usually up to 2 heteroatoms, e.g., 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 an imidazole or pyridine, or essentially non-basic, as in an indole or pyrrole. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, will be less than five.

[0043] The term "substituted" refers to the independent replacement of one, two, or more hydrogen atoms with a substituent, said substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, -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-heterocycloalkyl, -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 aryl, heteroaryl, alkyl, cycloalkyl, and methylthiomethyl groups include, but are not limited to, cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, and methylthiomethyl. It is understood that the aryl, heteroaryl, alkyl, cycloalkyl, and the like groups may be further substituted. In one embodiment of the present disclosure, the substituents may be selected from the group consisting of hydroxy, cyano, halo, halo(C1-C6)alkyl, halo(C1-C6)alkyloxy, (C1-C6)alkylthio, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, and C1-C6 alkoxy groups.

[0044] The phrase "substituted with 0-X substituents" is also referred to as "optionally substituted," which refers to unsubstituted or substituted with other than hydrogen at one or more available positions, typically 1, 2, 3, 4, 5, or 6 positions, by one or more suitable groups (which may be the same or different), where X is the maximum number of permissible substituents. Certain optionally substituted groups are substituted with 0-2, 3, or 4 independently selected substituents (i.e., unsubstituted or substituted with up to the maximum number of substituents listed). Other optionally substituted groups are substituted with at least one substituent (e.g., substituted with 1-2, 3, or 4 independently selected substituents).

[0045] The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0046] The term "protecting group" refers to any protecting group for alcohols known in the art. Non-limiting examples include 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthyl methyl 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", "deprotecting" and the like refer to removing a protecting group by any conventional means known by one of ordinary skill in the art. It will be readily apparent that the conditions for deprotection will depend on what protecting group is used.

[0048] The term "CH activation" (also known as CH bond activation and sometimes used interchangeably with CH functionalization) refers to a set of mechanistic processes in which stable carbon-hydrogen bonds in organic compounds are broken. The purpose is to enable the functionalization of these molecules, leading to the synthesis of more complex intermediate or product compounds, often containing C-O, C-C and C-N bonds. The ability to break C-H bonds allows the conversion of inexpensive feedstock molecules into commercially valuable molecules. Directed C-H activation allows for selectivity and specificity in the synthesis of important and more complex molecules in 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. The term is usually applied to the CH activation of hydrocarbons and is defined as "a coordinating moiety (internal ligand) that directs a metal catalyst into the vicinity of a particular C-H bond."

[0050] The term "halolactone" refers to the formation of lactones with the addition of halogen by halolactonization. Halolactonization 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 a compound of the structure R2C=NOH derived from the condensation of an aldehyde or ketone with a hydroxylamine. Oximes derived from aldehydes can be called aldoximes and those derived from ketones can 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 the halolactone oxime formation, a halogenating agent (such as N-bromosuccinimide (NBS)) used for halolactonization, an oxidizing agent (such as trichloroisocyanuric acid (TCCA)) used for oxidation of C-3-OH, and an oximating agent (such as hydroxylamine hydrochloride (HONH2·HCl)) used for oxime formation are added sequentially 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 (X). In one embodiment of the present disclosure, a halogenating agent is added and stirring is continued for 1 to 2 hours (e.g., 1 hour, 1.5 hours, and 2 hours), an oxidizing agent is added and stirring is continued for 1.5 to 2.5 hours (e.g., 1.5 hours, 2 hours, and 2.5 hours), and an oximating agent is added and stirring is continued 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 formula (IX) compound can be prepared by sequential CH activation and protecting group attachment according to Scheme 2. The formula (X) compound is dissolved in a co-solvent (e.g., acetic anhydride (Ac2O) / acetic acid (AcOH)), and then a palladium metal catalyst (e.g., but not limited to, PdCl2, Pd(allyl)Cl2, and Pd(OAc)2) and an oxidizing agent (e.g., phenyliodine(III) diacetate (PIDA)) are added sequentially at 40-50°C (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50°C). The mixture is then added with a co-solvent (e.g., tetrahydrofuran (THF) / acetone) in the presence of an acid, e.g., HCl, at 50-60°C (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60°C) to obtain the formula (IXa) compound. The compound of formula (IXa) is dissolved in a solvent (e.g., dimethylformamide (DMF), dichloromethane (DCM) or dimethylsulfoxide (DMSO)) under N2 atmosphere. Imidazole and a protecting group 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 stirring is continued for 1 to 2 minutes (e.g., 1 minute, 1.5 minutes, and 2 minutes), an oxidizing agent is added and stirring is continued for 7.5 hours to 8.5 hours (e.g., 7.5 hours, 8 hours, and 8.5 hours), an acid is added and stirring is continued for 7.5 hours to 8.5 hours (e.g., 7.5 hours, 8 hours, and 8.5 hours), and an imidazole and a protecting group compound are added and stirring is continued for 3.5 hours 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 attachment 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 then the mixture is cooled to about -82°C to -75°C (e.g., -82, -81, -80, -79, -78, -76, or -75°C), and Add a reducing agent (e.g., diisobutylaluminum hydride (DIBAL-H)). Add catalyst AcOH / Zn at 45-55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55°C) and cool 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., 1,2-dichlorophenyl) under N2 atmosphere. For example, dimethylformamide (DMF), dichloromethane (DCM) or dimethyl sulfoxide (DMSO) is dissolved in the imidazole and protecting group compound (for example, tert-butyldimethylsilyl chloride (TBSCl)) are added sequentially between -4 and 4°C (for example, -4, -3, -2, -1, 0, 1, 2, 3 or 4°C), and then the reaction is continued at 15 to 30°C (for example, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 10 and 30° C.) to obtain a compound of formula (VII). In one embodiment of the present disclosure, a reducing agent is added and stirring is continued for 0.5 to 2 hours (e.g., 0.5, 1, 1.5, and 2 hours), a catalyst is added and stirring is continued for 0.5 to 1.5 hours (e.g., 0.5, 1, and 1.5 hours). In one embodiment of the present disclosure, imidazole and a protecting group compound are added and stirring is continued for 3.5 to 4.5 hours (e.g., 3.5, 4, and 4.5 hours). [ka]

[0056] In one embodiment of the present disclosure, the method further includes the steps of converting the formula (VII) compound to the formula (VIII) compound by reacting the formula (VII) compound with the formula (a) compound via directing group introduction according to scheme 4, and converting the formula (VIII) compound to the formula (II) compound by CH activation. The formula (VII) compound is reacted with the formula (a) compound in the presence of a solvent (e.g., toluene), and heated to 75 to 85°C (e.g., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 and 85°C) to obtain the formula (VIII) compound. A copper salt (e.g., Cu(OTf)2 or (CuOTf)2·C6H6) and sodium ascorbate are added to a mixture of the formula (VIII) compound, 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 bubbled with an O2 balloon and warmed to 45-55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55°C) to obtain the formula (II) compound. The formula (a) compound can be obtained from commercial sources, can be synthesized from commercially available precursors using established protocols known in the art of synthetic organic chemistry, or can be modified as would be understood by one of skill in the art. In one embodiment of the present disclosure, the compound of formula (a) is added and stirring is continued for 1.5 hours 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 stirring is continued for 1.5 hours to 2.5 hours (e.g., 1.5 hours, 2 hours, and 2.5 hours). [ka]

[0057] In another embodiment of the present disclosure, the method further includes converting the formula (VII) compound to the formula (VIII) compound by reacting the formula (VII) compound with the formula (a) compound via directing group introduction according to scheme 4-1, and converting the formula (VIII) compound to the formula (II) compound by CH activation. A mixture containing the formula (VII) compound and an organic soluble acid catalyst (e.g., p-toluenesulfonic acid monohydrate (TsOH)) is reacted with the formula (a) compound 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 the formula (VIII) compound. A mixture of a cupric salt (e.g., copper(II) nitrate trihydrate (Cu(NO3)2·3H2O)) and a 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 a compound of formula (II). In one embodiment of the present disclosure, the cupric salt and the compound of formula (VIII) are added and stirred for 0.5 hours to 1.5 hours (e.g., 0.5 hours, 1 hour, and 1.5 hours), and the oxidizing agent is added and stirred for 23 hours to 25 hours (e.g., 23 hours, 24 hours, and 25 hours). [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 by oxidation and forming an oxygen protecting group by attaching an oxygen protecting group to one oxygen atom of the carboxyl group according to Scheme 5. The compound of formula (II) dissolved in a solvent (e.g., DMSO / tert-butanol) is added to a solution containing an oxidizing agent (e.g., NaClO2) and a buffering agent (e.g., NaH2PO4·H2O) 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 acidified with a solution (e.g., aqueous HCl) to obtain a crude mixture. The crude mixture is dissolved in a solvent (e.g., THF / HO), and then a protecting group reagent (e.g., allyl bromide), a catalyst (tetra-n-butylammonium iodide) and a reaction reagent (e.g., KCO) are added sequentially at 60-70°C (e.g., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69-70°C) to obtain a compound of formula (III). In one embodiment of the present disclosure, an oxidizing agent is added and stirring is continued for 3.5 hours to 4.5 hours (e.g., 3.5 hours, 4 hours and 4.5 hours), and a protecting group reagent is added and stirring is continued for 3.5 hours 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 method further comprises epimerizing the compound of formula (III) at the carbon to which the hydroxyl group is attached to form the compound of formula (VI), and converting the compound of formula (VI) to the compound of formula (IV) by sequential deprotection and oxidation according to Scheme 6. The compound of formula (III) is dissolved in a solvent (dimethylformamide (DMF), dichloromethane (DCM) or dimethylsulfoxide (DMSO)), and then an oxidizing agent (Dess-Martin 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 give the compound of formula (VI). The compound of formula (VI) is dissolved in a solvent (e.g., THF) containing a deprotecting reagent (e.g., tetra-n-butylammonium fluoride (TBAF)) at 45-55°C (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 or 55°C) to give the compound of formula (VIa). The compound of formula (VIa) is dissolved in a solvent (e.g., dimethylformamide (DMF), dichloromethane (DCM) or dimethylsulfoxide (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 oxidizing agent is added and stirred for 1.5 hours to 2.5 hours (e.g., 1.5 hours, 2 hours and 2.5 hours), and the reducing agent is added and stirred for 3.5 hours to 4.5 hours (e.g., 3.5 hours, 4 hours and 4.5 hours). In one embodiment of the present disclosure, the deprotection reagent is added and stirring is continued for 3.5 hours to 4.5 hours (eg, 3.5 hours, 4 hours, and 4.5 hours).In one embodiment of the present disclosure, the catalyst and oxidizing agent are added and stirred for 3.5 to 4.5 hours (eg, 3.5 hours, 4 hours, and 4.5 hours). [ka]

[0061] In one embodiment of the present disclosure, the formula (I) compound can be prepared by a deprotection reaction according to Scheme 7. The formula (IV) compound 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 formula (I) compound. In one embodiment of the present disclosure, the protecting group scavenger is added and stirring is continued for 2.5 hours to 3.5 hours (e.g., 2.5 hours, 3 hours and 3.5 hours). [ka]

[0062] In one embodiment of the present disclosure, the method further comprises 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 (e.g., dimethylformamide (DMF), dichloromethane (DCM) or dimethyl sulfoxide (DMSO)) containing a strong base (e.g., NaH) 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 group compound is added and stirred for 11 to 13 hours (for example, 11 hours, 12 hours, and 13 hours). [ka]

[0063] In one embodiment of the present disclosure, the method further comprises 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 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). In one embodiment of the present disclosure, the strong base is added and stirring is continued for 14 to 16 minutes (e.g., 14 minutes, 15 minutes and 16 minutes). [ka]

[0064] In one embodiment of the present disclosure, the method further comprises oxidizing the compound of formula (XI) to 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 dimethylsulfoxide (DMSO)), and then an oxidizing agent (e.g., Dess-Martin 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 of formula (VII). In one embodiment of the present disclosure, the oxidizing agent is added and stirring is continued for 1.5 hours to 2.5 hours (e.g., 1.5 hours, 2 hours and 2.5 hours). [ka] EXAMPLES

[0065] The following examples are provided to illustrate some aspects of the present disclosure and should not be construed as limiting the scope of the present disclosure.

[0066] In this embodiment, the preparation processes of Examples 1 to 6 may refer to the preparation scheme of Figure 6. The preparation processes of Examples 7 to 12 may refer to the preparation scheme of Figure 5. In addition, the preparation processes of Examples 13 to 17 may refer to the preparation scheme of 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 turned into a clear yellow solution upon stirring at room temperature. 48 g of NBS was added and stirring was continued at room temperature for 1.5 h. 48.8 g of trichloroisocyanuric acid (TCCA) was added and stirring was continued at room temperature for 2 h (beware of gas evolution). After complete conversion, 32 mL of IPA was added to the mixture and stirring was continued at room temperature for 1 h to quench the excess TCCA. 58.2 g of HONH2·HCl was added to the mixture and stirring was continued at room temperature for 4 h.

[0069] To remove excess reagents after the reaction, the mixture was diluted with 1200 mL of DCM and extracted with 4050 mL of 1 M HCl. Then, water was back-extracted with 1500 mL of DCM. The combined organic layer was then 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 give compound 1 as a pale yellow solid (132.1 g, 94.3% yield).

[0070] Example 2: Preparation of Compound 2

[0071] Compound 1 (39.4 g) as a pale yellow solid from the previous step was dissolved in Ac2O:AcOH=1:1 co-solvent (400 mL). After stirring at 45°C for 90 min, 2.5 g of Pd(OAc)2 and 35.7 g of phenyliodo(III) diacetate were added sequentially and stirring was continued at 45°C for 8 h. The solvent was then removed under reduced pressure and the mixture was added with THF:acetone:1M HCl=1:1:1 co-solvent (600 mL) and stirred at 55°C for 8 h. After acid catalysis, the mixture was diluted with 650 mL of ethyl acetate and extracted three times with water (650 mL). After drying over anhydrous magnesium sulfate and filtration, the organic layer was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:hexane=1:10) to give compound 2 as a white foam (15.3 g, 37.7% yield). 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) as a white foam from the previous step was dissolved in DMF (60 mL) under 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 h. The mixture was diluted with ethyl acetate (750 mL) and quenched by dropwise addition of NaHCO3 (sat) (950 mL). The aqueous layer was extracted twice with ethyl acetate (750 mL). After drying over anhydrous magnesium sulfate and filtration, the organic layer was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:hexane=1:20) to give compound 3 as a white foam (15.9 g, 86.2% yield). 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 N2 atmosphere and stirred at room temperature. After 1 h, the mixture was cooled to -78 °C and diisobutylaluminum hydride (1.72 mL, 20 wt%) was added dropwise and stirring was continued for 90 min. Excess hydride was quenched by dropwise addition of MeOH (3.5 mL) before warming to room temperature. AcOH (30 mL) and Zn powder (2.7 g) were added sequentially and the mixture was sonicated for 1 min. It was then stirred at 50 °C for 1 h and cooled to room temperature for 16 h. The mixture was diluted with 60 mL of ethyl acetate and extracted three times with 50 mL of water. After drying over anhydrous magnesium sulfate and filtration, the organic layer was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:hexane = 1:20) to give 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 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 h. The mixture was diluted with ethyl acetate (120 mL) and quenched by dropwise addition of NaHCO3 (sat) (150 mL). The aqueous layer was extracted twice with ethyl acetate (120 mL). After drying over anhydrous magnesium sulfate and filtration, the organic layer was concentrated under reduced pressure and purified by column chromatography (ethyl acetate:hexane=1:200) to give 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] Compound 5 (2.06 g) was placed in a round bottle under N2 atmosphere. Anhydrous toluene (30 ml) and (S)-1-pyridin-2-yl-ethylamine (0.73 g) were added sequentially. The reaction was then warmed to 80° C. and stirred for 2 hours. Excess solvent was removed by vacuum to give compound 6 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 bubbled by an O2 balloon for 30 minutes. The mixture was then warmed 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 give 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 C 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] + The calculated value is 701.5355 and the actual value is 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 a solution of NaClO2 (6.96 g) and NaH2PO4·H2O (9.24 mg) in water (51.8 mL) was added. The reaction was stirred at room temperature for 4 h. The mixture was diluted with 10% aqueous NaOH (until pH=9) and the aqueous phase was extracted with hexane. The aqueous phase was then acidified with 1N aqueous HCl (until 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 in vacuo to give the 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 was stirred at 65 °C for 4 h. THF was removed by vacuum. After diluting the mixture 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 give 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 Dess-Martin periodinane (12.4 g) and NaHCO3 (1.84 g) were added. After stirring at 25 °C for 2 h, the excess reagent was quenched with saturated aqueous 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 in vacuo to give a white foam compound without further purification.

[0087] The white foam compound from the previous step was dissolved in ethanol (73 mL) and sodium borohydride (2.8 g) was added. The reaction was stirred at room temperature for 4 h. The reaction was quenched with H2O (100 mL) and then the ethanol was removed by vacuum. After diluting the mixture with DCM (100 mL), the layers were separated and 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 give compound 9 as a white foam (3.4 g, yield=60.4%, 2 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 (2.3 g) was dissolved in THF (60 mL) and TBAF (7.8 g, 1 M solution in THF) was added. The reaction was stirred at 50° C. for 4 h. THF was removed by vacuum. After diluting the mixture with DCM (80 mL), the layers were separated and the aqueous layer was extracted three times with DCM (80 mL). The combined organic layers were washed with brine (80 mL), 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 give compound 10 as a white foam (1.32 g, yield=83.3%). 1H NMR (600 MHz, CDCl3) δ 5.90-5.84 (m, 1H, internal alkenyl CH), 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 solution of NaOCl (848.6 mg) in 5% aqueous NaHCO3 (0.035 M) was added. The reaction was stirred vigorously at room temperature for 4 h. 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 give aryl quinoline 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 Quillaric Acid

[0093] Allyl quilacic acid (800 mg) was dissolved in 1,4-dioxane (20 mL). The reaction was carried out by adding the allyl quilacic acid solution to a mixture of Pd(OAc)2 (34 mg) and triphenylphosphine (0.2 g) dissolved in 1,4-dioxane (13 mL). Piperidine (260 mg) was added to the reaction mixture and stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate:hexane=1:15) to give quilacic acid as a white foam (502.7 mg, yield=68%). 1 H NMR (600 MHz, methanol-d4) δ 9.30 (s, 1H, H-23), 5.30(1H, alkenylCH), 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); 13C 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 added portionwise at 0° C. After the addition was complete, stirring was continued for another 12 h at room temperature under N2 atmosphere, after which ethyl acetate (20.0 mL) was added to dilute the reaction mixture. The resulting mixture was thoroughly washed with water (2×20 mL) and brine (20 mL), then the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (EtOAc / hexane=1:100) to give compound 11 as a white foam (6.9 g, 73.8% yield).

[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 to a solution of lithium aluminum hydride (0.929 g, 24.0 mmol) in anhydrous THF (10 mL) at 0° C. The solution was heated to 50° C. After the reaction was completed, the mixture was cooled to 0° C. and excess LiAlH4 was inactivated by adding water (10 mL). 1N aqueous sodium hydroxide solution (10 mL) was added and the mixture was stirred for 15 min. 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 / EtOAc=20:1), compound 12 was obtained as a white foam (3.28 g, 64.2% yield).

[0098] Example 15: Preparation of Compound 13

[0099] To a stirred solution of compound 12 (2.0 g, 3.1 mmol) in CHCl (4.0 mL) was added Dess-Martin periodinane (2.63 g, 6.2 mmol). After stirring at 25° C. for 2 h, the excess reagent was quenched with saturated aqueous NaSO (5.0 mL) and the resulting mixture was extracted with EtOAc (3×5.0 mL). The combined organic phase was washed with brine (4.0 mL), dried over anhydrous MgSO, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc / hexanes=1:50) to give compound 13 as a white foam (1.3 g, 63% yield). 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] 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) in a flame-dried flask was added the amine (S)-1-pyridin-2-yl-ethylamine (28.8 μL, 0.48 mmol). The mixture was heated to 80° C. until the formation of the imine was complete as monitored by TLC. The mixture was cooled to 25° C. and concentrated in vacuo to give 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 stirred vigorously for 1 h. 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 a blue-green solution. The reaction mixture was then stirred at room temperature for 24 h. Saturated aqueous Na4EDTA solution (3.0 mL) was then added and the mixture was stirred for 1 h. 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 (EtOAc / hexanes=1:20) to give 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] Although the present disclosure has been described in considerable detail with reference to certain embodiments thereof, other embodiments are possible, and therefore the scope of the claims is not limited to the description contained in the embodiments herein.

[0105] It will be apparent to those skilled in the art that various modifications and variations can be made to the structure of the present disclosure without departing from the scope of the present disclosure. In view of the above, it is intended that the present disclosure cover modifications and variations of the present disclosure provided they fall within the scope of the appended claims.

Claims

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】 Wherein, R １ and R ２ 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 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, tri(C ６ -C １２ arylsilyl group, -C(O)R ７ and -C(O)OR ８ represent a protecting group selected from the group consisting of, each of which is a hydroxy group, a cyano group, 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 substituted with 0 to 4 substituents selected from the group consisting of, 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.

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】

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】

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.

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】

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.

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.

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】

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】

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 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, and is substituted with 0 to 4 substituents independently selected from the group consisting of.

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】 In the formula, R ５ 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 al koxy group, and is independently substituted with 0 to 4 substituents selected from the group consisting of.

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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