Synthesis of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogues

摘要

The preparation of C-3 coupled biflavonoids and C-3 coupled biflavonoid analogs occurs from flavan-3-ones that are contacted with a compound having a nucleophilic aromatic moiety, in the presence of a Lewis acid where an intermediate compound is formed with a C-3 hydroxy group. A flavan-3-ol can be converted to a flavan-3-one as required. The intermediate compound is dehydrated to a flavene with a C-3-C-4 double bond. The flavene compound undergoes hydroboration-oxidation hydration to introduce a C-4 hydroxy group that can be oxidized to an oxo group or can be dihydroxylation to introduce hydroxy groups at the C-4 and C-3 carbons and dehydrated to a biflavonoid or biflavonoid analog having an oxo group at its C-4 carbon and substituted by the selected nucleophilic aromatic moiety on its C-3 carbon.

主权项

1. A method for the preparation of a compound selected from the group consisting of C-3 coupled bioflavonoid compounds and C-3 coupled biflavonoid analogues from flavan-3-ols or flavan-3-ones, the method comprising the steps of:
(a) providing a flavan-3-one of Formula (I) or a corresponding flavan-3-ol: wherein each of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is independently selected from the group consisting of hydrogen, —OH, a hydrocarbyl group; a saccharide moiety and —OR10; wherein R10 is selected from the group consisting of a hydrocarbyl group, an acyl group and a benzyl group; and wherein, the hydrocarbyl group in any one of R1 to R10 and/or the acyl group contains from 1 to 10 carbon atoms; (b) optionally, converting the C-3 hydroxy group of the flavan-3-ol to an oxo group to form the flavan-3-one; (c) providing a compound having a nucleophilic aromatic moiety, selected from the group consisting of a flavonoid base structure: wherein carbon C-3 is optionally substituted with —OH; and carbons C-2′ to C-6′ and C-5 to C-8 are unsubstituted or independently substituted with —OH, a saccharide moiety, R11, OR11 or O—C(O)—R12, wherein R11 is a linear hydrocarbyl group selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl, or wherein R11 is a cyclic hydrocarbyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, or wherein OR11 is O-benzyl; wherein R12 is a linear hydrocarbyl group selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, or wherein R12 is a cyclic hydrocarbyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl; and 1, 3, 5-tri-O-methylphloroglucinol; (d) contacting the flavan-3-one provided by step (a) or obtained by step (b) with the compound containing having a nucleophilic aromatic moiety in the presence of a Lewis acid; (e) forming an intermediate compound, wherein the compound having the nucleophilic aromatic moiety has a flavonoid base structure, the oxo group on the C-3 carbon of the flavan-3-one is converted to a hydroxy group and a I-3, II-6 or a I-3, II-8 C—C bond is formed by nucleophilic addition of the compound containing a nucleophilic aromatic moiety to the C-3 carbon of the flavan-3-one; or forming an intermediate analogue compound, wherein the compound containing the nucleophilic aromatic moiety is 1, 3, 5-tri-methylphloroglucinol, the oxo group on the C-3 carbon of the flavan-3-one is converted to a hydroxy group and a I-3/1,3,5-tri-methylphloroglucinol C—C bond is formed by nucleophilic addition of the 1, 3, 5-tri-methylphloroglucinol to the C-3 carbon of the flavan-3-one; (f) subjecting the intermediate compound or intermediate analogue compound to dehydration to introduce a double bond between the C-3 carbon and C-4 carbon contributed by the flavan-3-one portion to form a flavene compound substituted by the nucleophilic aromatic moiety on the C-3 carbon; (g) optionally, subjecting the C-3 substituted flavene compound substituted by the nucleophilic aromatic moiety on the C-3 carbon of step (f) to hydroboration-oxidation hydration, thereby converting the double bond between the C-3 carbon and the C-4 carbon to a single bond and introducing a C-4 hydroxy group to form a C-4 hydroxy intermediate compound or C-4 hydroxy intermediate analogue compound; (h) optionally, oxidizing the C-4 hydroxy intermediate compound or C-4 hydroxy intermediate analogue compound, wherein the C-4 hydroxy group converts to a C-4 oxo group, to form a biflavonoid, or a biflavonoid analogue which comprises 1,3,5-tri-methylphloroglucinol, which is substituted by the selected nucleophilic aromatic moiety on the C-3 carbon; wherein the C-3 coupled biflavonoid is formed from the nucleophilic aromatic moiety that has the flavonoid base structure and C-3 coupled biflavonoid analogue is formed from the nucleophilic aromatic moiety that is the 1,3,5-tri-O-methylphloroglucinol; or alternatively to steps (g) and (h), (i) optionally subjecting the flavene compound substituted by the nucleophilic aromatic moiety on the C-3 carbon of step (f) to OsO4 dihydroxylation, forming a dihydroxylated intermediate compound or a dihydroxylated intermediate analogue compound comprising a C-3 hydroxy group and a C-4 hydroxyl group and a single bond between the C-3 and C-4 carbons; and (j) optionally subjecting the dihydroxylated intermediate compound or dihydroxylated intermediate analogue compound to dehydration, introducing a double bond between the C-3 carbon and C-4 carbon to form an enol that rearranges to form the C-3 coupled biflavonoid or the C-3 coupled biflavonoid analogue having a C-4 oxo group and substituted by the nucleophilic aromatic moiety on the C-3 carbon, wherein the C-3 coupled biflavonoid is formed from the nucleophilic aromatic moiety that has the flavonoid base structure and C-3 coupled biflavonoid analogue is formed from the nucleophilic aromatic moiety that is the 1,3,5-tri-O-methylphloroglucinol.