Novel synthetic approaches toward procyanidins and biflavonoids

In this thesis we investigate procedures to introduce functional groups into the C-ring of flavonoids. These include the introduction of a double bond, aryl coupling on the C-3 position to obtain biflavonoids and aryl coupling on the C-4 position to obtain proanthocyanidins.We observed that treatment of tetra-O-methyl-3-O-mesylcatechin with base yielded the corresponding flav-3-ene. We optimized conditions to obtain yields close to 100% (DBU, reflux in acetonitrile for 24 hours, mesyl derivative). Retention of configuration at C-2 was observed. Treatment of tetra-O-methyl-3-O-tosylepicatechin with 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/mesyl group at C-3 and base catalysed trans elimination to a flav-2-ene is feasible. This contrasts with tetra-O-methyl-3-O-mesylcatechin where the C-2 hydrogen is cis relative 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 normally difficult to synthesize due to the ease with which they oxidize to anthocyanidins. We have thus developed an efficient and high yielding method that yields the first stereoselective access to optically active flav-3-enes. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in the presence of SnCl4 affords facile coupling of the phloroglucinol analogue at C-3 via a carbon-carbon bond to give the 3-aryl-3,4-dehydrocatechin. The 3-arylcatechin intermediate could not be isolated, presumably because water elimination is encouraged by the formation of a stilbene-type conjugated system between the electron rich A-and D-rings. CD data confirm retention of configuration at C-2. We have thus developed proof of concept for the first stereoselective synthetic access to I- 3,II-6/8 biflavonoids. This represents a significant contribution towards flavonoid synthesis. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in the presence 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 in aqueous NaOH/MeOH afforded the C-4b and C-4a arylflavan-3-ol derivatives in 98% 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 self condensation or further condensation products were evident, probably due to the deactivation of the nucleophilic properties of the A-ring of the 3-oxocatechin via the enolic tautomer of the C-ring. The AgBF4-catalyzed condensation reaction between tetra-O-methyl-3-oxocatechin and 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 constants and NOESY data. We thus developed a novel and facile method for the introduction of a phenolic unit at unfunctionalized 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 two flavonoid monomers. We could not find any previous usage of AgBF4 to effect C-C bond formation. 2. Self condensation and the formation of homo-polymers are not observed. We believe that the carbonyl group on the C-3 position of our one starting material conjugates with the aromatic A-ring via its enol. This lowers the HOMO energy and deactivates the A-ring to such an extent that it does not act as a nucleophile. 3. The synthetic methods described so far rely on an electrophilic flavan-3-ol with a hydroxy group at C-3. The configuration of the hydroxy group at C-3 controls 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 sp2 carbonyl and the stereochemistry at C-4 is controlled by the stereochemistry at C-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 derivatives that circumvents the need for C-4 functionalization, avoids competing polymerization and allows stepwise formation of hetero-oligomers. This method, based upon oxidative C-C interflavanyl bond formation will contribute significantly to ready synthetic access to proanthocyanidin analogues, especially procyanidins with 3,4-cis congifured catechin chain extension units.