Novel synthetic approaches toward procyanidins and biflavonoids

[摘要] English: In this thesis we investigate procedures to introduce functional groups into the C-ringof flavonoids. These include the introduction of a double bond, aryl coupling on theC-3 position to obtain biflavonoids and aryl coupling on the C-4 position to obtainproanthocyanidins.We observed that treatment of tetra-O-methyl-3-O-mesylcatechin with base yieldedthe corresponding flav-3-ene. We optimized conditions to obtain yields close to 100%(DBU, reflux in acetonitrile for 24 hours, mesyl derivative). Retention ofconfiguration at C-2 was observed. Treatment of tetra-O-methyl-3-O-tosylepicatechinwith DBU gives a mixture (ca 1:1 ratio) of the corresponding flav-2-ene and flav-3-ene in high yield. The C-2 hydrogen of epicatechin is trans relative to the tosyl/mesylgroup at C-3 and base catalysed trans elimination to a flav-2-ene is feasible. Thiscontrasts with tetra-O-methyl-3-O-mesylcatechin where the C-2 hydrogen is cisrelative to the tosyl/mesyl group at C-3 and the only available trans hydrogen is at C-4, resulting in the flav-3-ene exclusively. Flav-2-enes and flav-3-enes are normallydifficult to synthesize due to the ease with which they oxidize to anthocyanidins. Wehave thus developed an efficient and high yielding method that yields the firststereoselective access to optically active flav-3-enes. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in thepresence of SnCl4 affords facile coupling of the phloroglucinol analogue at C-3 via acarbon-carbon bond to give the 3-aryl-3,4-dehydrocatechin. The 3-arylcatechinintermediate could not be isolated, presumably because water elimination isencouraged by the formation of a stilbene-type conjugated system between theelectron rich A-and D-rings. CD data confirm retention of configuration at C-2. Wehave thus developed proof of concept for the first stereoselective synthetic access to I-3,II-6/8 biflavonoids. This represents a significant contribution towards flavonoidsynthesis. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in thepresence of AgBF4 in THF afforded the C-4b- and C-4a phloroglucinol-3-oxocatehin adducts in 45% and 13% yields, respectively. Subsequent reduction with NaBH4 inaqueous NaOH/MeOH afforded the C-4b and C-4a arylflavan-3-ol derivatives in98% and 95% yields, respectively.The requirement of an excess of AgBF4 and the observation of a silver mirror(reduction of Ag1 to Ag0) indicate a two-electron oxidative mechanism. No selfcondensation or further condensation products were evident, probably due to thedeactivation of the nucleophilic properties of the A-ring of the 3-oxocatechin via theenolic tautomer of the C-ring. The AgBF4-catalyzed condensation reaction between tetra-O-methyl-3-oxocatechinand tetra-O-methylcatechin afforded the anticipated C-4b and C-4a dimers in 38%and 6% yields, respectively, with [2R,4S (C-ring):2R,3S (F-ring)] and [2R,4R (Cring):2R,3S (F-ring)] configurations, respectively, based on NMR coupling constantsand NOESY data. We thus developed a novel and facile method for the introduction of a phenolic unit atunfunctionalized C-4 of per-O-methylcatechin and hence to synthesize procyanidin B-3 type dimer derivatives. Our method has the following advantages:1. It does not require pre-functionalization of the C-4 position of flavan-3-ols.We have developed direct oxidative C-6/8 C-4 bond formation between twoflavonoid monomers. We could not find any previous usage of AgBF4 toeffect C-C bond formation.2. Self condensation and the formation of homo-polymers are not observed. Webelieve that the carbonyl group on the C-3 position of our one starting materialconjugates with the aromatic A-ring via its enol. This lowers the HOMOenergy and deactivates the A-ring to such an extent that it does not act as anucleophile. 3. The synthetic methods described so far rely on an electrophilic flavan-3-olwith a hydroxy group at C-3. The configuration of the hydroxy group at C-3controls the stereochemistry at C-4 and 3,4-trans proanthocyanidins are usually isolated as the major product. In our method, C-3 is a planar sp2carbonyl and the stereochemistry at C-4 is controlled by the stereochemistry atC-2 (configuration of the B-ring). We thus have access to both 3,4-cis and 3,4-trans proanthocyanidins depending on the configuration of the B-ring at C-2. We have thus developed a unique and facile synthesis of catechin dimer derivativesthat circumvents the need for C-4 functionalization, avoids competing polymerizationand allows stepwise formation of hetero-oligomers. This method, based uponoxidative C-C interflavanyl bond formation will contribute significantly to readysynthetic access to proanthocyanidin analogues, especially procyanidins with 3,4-ciscongifured catechin chain extension units.

[发布机构] University of the Free State