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US-12617746-B2 - Method of preparing triterpenoid compound

US12617746B2US 12617746 B2US12617746 B2US 12617746B2US-12617746-B2

Abstract

A method of preparing a triterpenoid compound of formula (I): including a step of converting a compound of formula (II) into the compound of formula (I), wherein R 1 and R 2 independently represent hydrogen or a protecting group selected from the group consisting of C 1 -C 8 alkyl, allyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 6 -C 12 )aryl(C 1 -C 8 )alkyl, tri(C 1 -C 8 )alkylsilyl, di(C 1 -C 8 )alkyl(C 6 -C 12 )arylsilyl, di(C 6 -C 12 )aryl(C 1 -C 8 )alkylsilyl ,tri(C 6 -C 12 )arylsilyl, —C(O)R 7 , and —C(O)OR 8 , and each of which is substituted with from 0 to 4 substituents independently selected from the group consisting of hydroxy, cyano, halo, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and C 1 -C 6 alkoxy, wherein R 7 and R 8 are independently C 1 -C 8 alkyl or C 6 -C 12 aryl.

Inventors

  • Pi-Hui Liang

Assignees

  • NATIONAL TAIWAN UNIVERSITY

Dates

Publication Date
20260505
Application Date
20230331

Claims (12)

  1. 1 . A method of preparing a triterpenoid compound of formula (I), comprising: a step of converting a compound of formula (II) into a compound of formula (III) through sequentially oxidizing an aldehyde group of formula (II) to a carboxyl group by oxidation, and forming an oxygen protecting group on one oxygen atom of the carboxyl group by attaching a protecting group, a step of converting the compound of formula (III) into a compound of formula (IV) through epimerization, deprotection and oxidation sequentially, and a step of converting the compound of formula (IV) into the compound of formula (I) with deprotecting reaction, wherein R 1 and R 2 independently represent hydrogen or a protecting group selected from the group consisting of C 1 -C 8 alkyl, allyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 6 -C 12 )aryl(C 1 -C 8 )alkyl, tri(C 1 -C 8 )alkylsilyl, di(C 1 -C 8 )alkyl(C 6 -C 12 )arylsilyl, di(C 6 -C 12 )aryl(C 1 -C 8 )alkylsilyl, tri(C 6 -C 12 )arylsilyl, —C(O)R 7 , and —C(O)OR 8 , and each of which is substituted with from 0 to 4 substituents independently selected from the group consisting of hydroxy, cyano, halo, halo(C 1 -C 6 ) alkyl, halo(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and C 1 -C 6 alkoxy, wherein R 7 and R 8 are independently C 1 -C 8 alkyl or C 6 -C 12 aryl, wherein R3 is a protecting group selected from the group consisting of C1-C8 alkyl, C2-C8alkenyl, C2-C8 alkynyl, (C6-C12)aryl(C1-C8)alkyl, C6-C12 arylacyl, tri(C1-C8)alkylsilyl, di(C1-C8)alkyl(C6-C12)arylsilyl, di(C6-C12)aryl(C1-C8)alkylsilyl and tri(C6-C12)arylsilyl, and each of which is substituted with from 0 to 4 substituents independently 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.
  2. 2 . The method of claim 1 , further comprising a step of subjecting the compound of formula (III) to epimerization at the carbon position where a hydroxyl group is attached to form a compound of formula (VI), and a step of converting the compound of formula (VI) to a compound of formula (IV) with deprotection and oxidation sequentially,
  3. 3 . The method of claim 1 , further comprising a step of converting a compound of formula (VII) into the compound of formula (II) through directing group introduction and C—H activation sequentially,
  4. 4 . The method of claim 3 , further comprising a step of converting the compound of formula (VII) into a compound of formula (VIII) by reacting the compound of formula (VII) with a compound of formula (a) through directing group introduction, and a step of converting the compound of formula (VIII) into the compound of formula (II) with C—H activation, wherein R 6 represents W is H or C 1 -C 8 alkyl group and X and Y independently represent hydrogen, hydroxy, cyano, halo, C 6 -C 12 aryl or C 5 -C 12 heteroaryl, and wherein the compound of formula (a) represents
  5. 5 . The method of claim 3 , further comprising a step of converting oleanolic acid to the compound of formula (VII) through halolactone oxime formation, C—H activation, attaching protecting group and reduction sequentially,
  6. 6 . The method of claim 4 , wherein the compound of formula (VII) is obtained by converting a compound of formula (IX) into the compound of formula (VII) through reduction and optionally attaching protecting group sequentially, wherein Rx is F, Cl, Br or I.
  7. 7 . The method of claim 6 , wherein the compound of formula (IX) is obtained by converting a compound of formula (X) into the compound of formula (IX) with C—H activation and attaching protecting group sequentially, wherein Rx is F, Cl, Br or I.
  8. 8 . The method of claim 7 , wherein the compound of formula (X) is obtained by converting Oleanolic acid into the compound of formula (X) with halolactone oxime formation,
  9. 9 . The method of claim 3 , further comprising a step of converting Hederagenin into the compound of formula (VII) through attaching a protecting group, reduction and oxidation sequentially,
  10. 10 . The method of claim 3 , further comprising a step of oxidizing a compound of formula (XI) into the compound of formula (VII), wherein R 4 is hydrogen or a protecting group selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 6 -C 12 )aryl(C 1 -C 8 )alkyl, C 6 -C 12 arylacyl, tri(C 1 -C 8 )alkylsilyl, di(C 1 -C 8 )alkyl(C 6 -C 12 )arylsilyl, di(C 6 -C 12 )aryl(C 1 -C 8 )alkylsilyl and tri(C 6 -C 12 )arylsilyl, each of which is substituted with from 0 to 4 substituents independently selected from the group consisting of hydroxy, cyano, halo, halo (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and C 1 -C 6 alkoxy.
  11. 11 . The method of claim 10 , further comprising a step of reducing a compound of formula (XII) to the compound of formula (XI), wherein R 5 is hydrogen or a group selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (C 6 -C 12 )aryl(C 1 -C 8 )alkyl, C 6 -C 12 arylacyl, tri(C 1 -C 8 )alkylsilyl, di(C 1 -C 8 )alkyl(C 6 -C 12 )arylsilyl, di(C 6 -C 12 )aryl(C 1 -C 6 ) alkylsilyl and tri(C 6 -C 12 )arylsilyl, each of which is substituted with from 0 to 4 substituents independently selected from the group consisting of hydroxy, cyano, halo, halo (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkylthio, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl and C 1 -C 6 alkoxy.
  12. 12 . The method of claim 11 , wherein comprising a step of converting Hederagenin into the compound of formula (XII) through attaching protecting groups on the hydroxyl groups of Hederagenin,

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This Application claims priority to U.S. Provisional Application No. 63/325,792, filed on Mar. 31, 2022. The entirety of the above-mentioned patent application is hereby incorporated by reference herein and made a part of this specification. BACKGROUND 1. Technical Field The present disclosure is related to a method of preparing of triterpenoid compound. More particularly, the present disclosure is related to a method of preparing of quillaic acid for triterpenoid saponin-based vaccine-adjuvant. 2. Description of Related Art The name “saponin” is derived from the Latin word sapo, meaning soap-like foam generating ability, and the amphiphilic properties derived from the structure containing an isoprenoid-derived aglycone (a sapogenin), attached to one or more sugar chains by either an ether or ester linkage. Structural classification of saponins is primarily based on their sapogenin skeletons, which can be divided into two main groups, triterpenoid saponins and steroid saponins. Triterpenoid saponins are broadly distributed in dicotyledons, including four major skeletons, such as pentacyclic oleanane, ursane, lupane, and tetracyclic dammarane (FIG. 1a). Steroid saponins are mostly derived from monocotyledons, comprising of four major skeletons, such as tetracyclic cholestane, hexacyclic spirostane, pentacyclic furostane, and lactone-bearing cardenolide (FIG. 1b). Sugar-bearing sapogenins are categorized by numbers of sugar residue into monodesmosidic (one sugar residue), bidesmosidic (two sugar residues), and polydesmosidic saponins (three or more sugar residues). In nature, saponins are found in plants and marine animals, where they are implicated in host defense against pathogens and herbivores. Since saponins are presented in many medicinal plants and Chinese herbal medicines, exhibiting a plethora of biological activities, including anti-fungal, antimicrobial, antiviral, anti-inflammatory, anticancer, antioxidant, and immunomodulatory effects, they can serve as a good starting point for the development of natural product-derived drugs. However, the mechanism and structure-activity-relationship (SAR) of saponins are poorly understood, and the isolation from plant to get appropriate amounts is sometimes troublesome and laborious due to microheterogeneity and scarcity of the molecules. As a result, applying organic synthesis method to generate artificial saponins is a promising way to efficiently expand the structure library and search for highly active compounds. Oleanane type saponins are the most studied synthetic saponins, due to their promising pharmacological effects and high natural abundance. Referring to FIG. 2, common oleanane type skeletons modified with chemical approach are oleanolic acid, hederagenin, and quillaic acid. They have been isolated from enormous plant species as either a free triterpenoid or a saponin, and are particularly rich in Oleaceae family. Oleanane type saponins are reported to exhibit multiple biological activities, especially in antitumor, antiviral and immunomodulatory effect. However, toxicity triggered by hemolytic and membrane lysis effect is the major challenge in drug development, and the understanding of structure-toxicity-relationships is still in the early stage. The saponins with immunomodulatory effects were categorized into upregulation and downregulation. Immune upregulation activities were majorly evaluated in quillaic-saponins, which were extensively studied for the enhancement of serum IgG production compared to GPI-0100 and QS-21 for the development of vaccine adjuvant and various derivatives based on quillaic acid have been developed. QS-21 is an FDA-approved vaccine-adjuvant, which is widely used in treating infectious diseases and cancers. Contrary to versatile uses of QS-21, its natural source was limited. The traditional quillaic acid isolation methods need to extract from roots or barks. To preserve the natural source and make the application more sustainable, chemical synthesis of quillaic acid is necessary. However, chemical synthesis of quillaic acid started from protoescigenin was reported, it was 24-steps process to quillaic acid (Zeng et al., Chemical synthesis of quillaic acid, the aglycone of QS-21. Org. Chem. Front. 2021, 8, 748-753.). Besides 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 alternative source of quillaic acid by starting the synthesis with the metabolite of β-amyrin. By transforming the S. cerevisiae strain BY-bAS with the CYP716A567 and CYP72A262 genes, it can produce 314.01 mg/L of quillaic acid. However, the method needed to clone the specific RNA sequences of CYP716A567 and CYP72A262 and could not be scaled up currently. The versatile C—H activation equips us with a new platform in pharmaceutical industry. Among terpenoid and steroid C—H functionali