Novel synthetic approaches toward procyanidins and biflavonoids - Achilonu, Matthew Chilaka (University of the Free State, 2009)
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.

Hierdie tesis ondersoek die verskillende metodes om die C-ring van flavono ede te funksionaliseer. Die resultate sluit in die vorming van ’n dubbelbinding in die C-ring, koppeling van ’n arielgroep op C-3 om biflavono ede te lewer, en arielkoppeling op C-4 wat aanleiding gee tot proantosianidiene. Ons het waargeneem dat die behandeling van tetra-O-metiel-3-O-mesielkatesjien met basis die ooreenstemmende flav-3-een lewer. Die reaksiekondisies is geoptimiseer en opbrengste van feitlik 100% is verkry (DBU, refluks in asetonitriel vir 24 uur, mesielderivaat). Retensie van konfigurasie by C-2 is waargeneem. Behandeling van tetra-O-metiel-3-O-tosielepikatesjien met DBU het ’n mengsel (ca 1:1 ratio) van die ooreenstemmende flav-2-een en flav-3-een in hoë opbrengste gelewer. Die C-2 waterstof van die C-3 gefunksionaliseerde epikatesjien (O-mesiel of O-tosiel) is trans relatief tot die mesiel/tosielgroep op C-3 en dit maak basisgekataliseerde trans eliminasie na die flav-2-een waarskynlik. In teenstelling hiermee, is die C-2 waterstof van die C-3 gefunksionaliseerde katesjien (O-mesiel of O-tosiel) cis relatief tot die mesiel/tosielgroep op C-3 en dus is trans eliminasie nie moontlik nie. Die C-4 waterstof is egter trans relatief tot die mesiel/tosielgroep op C-3 en dus word slegs die flav-3-een gevorm. Flav-2- en flav-3-ene is gewoonlik moeilik om te sintetiseer aangesien oksidasie na antosianidiene met gemak plaasvind. Ons het dus nie slegs die eerste stereoselektiewe sintese vir opties aktiewe flav-3-ene ontwikkel nie, maar die sintese lewer ook hoë opbrengste. Behandeling van tetra-O-metiel-3-oksokatesjien met tri-O-metielfloroglusinol in die teenwoordigheid van SnCl4 lewer die 3-ariel-3,4-dehidrokatesjien d.m.v. koppeling van die floroglusinolderivaat met C-3 via die vorming van ’n koolstof-koolstof binding. Die intermediêre C-3-fluoroglusinol alkoholderivaat is nie ge soleer nie. Eliminasie van water word waarskynlik bevorder deur die vorming van ’n stilbeen tipe gekonjugeerde sisteem tussen die elektronryk A- en D-ringe van die 3-ariel-3,4- dehidrokatesjien. Die retensie van konfigurasie by C-2 is bevestig deur SD data. Ons het dus die konsep vir die eerste stereoselektiewe sintetiese toegang tot I-3,II-6/8 biflavano ede bewys. Behandeling van tetra-O-metiel-3-oksokatesjien met tri-O-metielfloroglusinol in die teenwoordigheid van AgBF4 in THF het beide die C-4b- en C-4a-floroglusinol derivate gelewer met opbrengste van 45% en 13% onderskeidelik. Die 3-C karbonielgroep is vervolgens met waterige NaOH/MeOH gereduseer om die C-4b- en C-4a-arielflavan-3-ol derivate te lewer in feitlik kwantitatiewe opbrengste. ’n Oormaat AgBF4 word benodig vir die sintese en tydens die reaksie word ’n silwer spieël teen die wande van die reaksiefles gevorm (reduksie van Ag1 na Ag0). Hierdie twee waarnemings dui op ’n twee-elektron, oksidatiewe reaksiemeganisme. Geen selfkondensasie- of verdere kondensasie oligomere is waargeneem nie, waarskynlik omdat die nukleofiele eienskappe van die A-ring van die 3-oksokatesjien gedeaktiveer word via die enoliese tautomeer van die C-ring. The AgBF4 gekataliseerde kondensasiereaksie tussen tetra-O-metielkatesjien en tetra- O-metiel-3-oksokatesjien het die verwagte dimere [4b (38%) en 4a (6%)] gelewer met [2R,4S (C-ring):2R,3S (F-ring)] en [2R,4R (C-ring):2R,3S (F-ring)] konfigurasies onderskeidelik, gebaseer op KMR koppelingskonstantes en NOESY data. Ons het dus ’n nuwe en eenvoudige metode ontwikkel om ’n fenoliese eenheid aan die ongefunksionaliseerde C-4 van per-O-metielkatesjien te koppel en dus om prosianidien B-3 tipe dimeer derivate te sintetiseer. Hierdie metode het die volgende voordele: 1. Dit is nie nodig om die C-4 posisie van flavan-3-ols vooraf te funksionaliseer nie. Ons het ’n direkte oksidatiewe bindingsvorming tussen twee monomeriese flavano ede bewerkstellig. Geen vorige verwysings oor die gebruik van AgBF4 vir C-C-bindingsvorming is beskryf nie. 2. Selfkondensasie en homo-polimeervorming is nie waargeneem nie. Ons glo dat die karbonielgroep op C-3 van ons een uitgangstof met die aromatiese Aring konjugeer via die enol. Dit verlaag die HOMO energie en deaktiveer die A-ring sodoende dat dit nie as ’n nukleofiel kan optree nie. 3. Die sintetiese metodes wat tot dusver beskryf is maak staat op die elektrofiliese flavan-3-ol met ’n hidroksiegroep op C-3. Die konfigurasie van die hidroksiegroep op C-3 beheer die stereochemie van C-4 en die 3,4-trans proantosianidiene word gewoonlik as die hoofproduk ge soleer. Ons metode maak staat op die planêre C-3 wat sp2 gehibridiseer is en dus word die stereochemie op C-4 be nvloed deur die stereochemie op C-2 (i.e. op relatiewe stereochemie van die B-ring). Ons het dus toegang verkry tot beide die 3,4-cis en 3,4-trans proantosianidiene, afhangend van die konfigurasie op C-2. In die geval van katesjien derivate vorm die 3,4-cis produk dus as hoofproduk. Ons het dus ’n unieke en eenvoudige sintese van katesjien dimere ontwikkel wat C-4 funksionalisering uitskakel, kompeterende polimerisasie verhoed en die stapsgewyse vorming van hetero-oligomere moontlik maak. Hierdie metode, gebaseer op oksidatiewe C-C-interflavaniel bindingsvorming sal grootliks bydrae tot sintetiese toegang tot proantosianidien analoë, veral die prosianidiene met 3,4-cis stereochemiese katesjien ketting eenhede.
Thesis (Ph.D. (Chemistry))--University of the Free State, 2009
Keywords: Flavonoids; Tannins