Direct synthesis of pterocarpans via aldol condensation

[摘要] English: Pterocarpans, representing the second largest group of natural isoflavonoids, havereceived considerable interest on account of their medicinal properties over the last fewyears. These phytoalexins not only serve as antitoxins but also display antifungal,antiviral and antibacterial properties. Despite this, the study of these metabolites arerestricted by their limited availability from natural sources. Furthermore, syntheticprotocols allowing ready access to these compounds are restricted by the lack ofavailability of suitable starting materials and the potential introduction ofstereoselectivity. Owing to the demand for enantiopure pterocarpans a directstereoselective synthetic approach, based on the aldol condensation between appropriatephenylacetates and benzaldehydes, was developed.2-Hydroxybenzaldehydes, protected as 2-0-methoxymethyl ethers, and 2-hydroxyphenylacetates, protected as TBDMS ethers, were subjected to aldolcondensation employing lithium diisopropylamide, to afford the 2,3-diphenyl-3-hydroxypropanoates (40-76%, de = 22-100%). Subsequent reduction (LiAIH4), followedby Lewis acid (SnCI4, BnSH) deprotection of the 2'-O-MOM ethers, yielded the 3-benzylsulfanyl-2,3-diphenylpropanols (29-56%). Improved yields of these propanolswere obtained by simply reversing the order of reactions (54-81%). B-ring formationusing Mitsunobu conditions (TPP-DEAD) afforded the isoflavan silyl ethers in goodyields (80-97%). The 2'-O-TBDMS derivatives were smoothly deprotected (TBAF) toyield the 2'-hydroxyisoflavans in excellent yields (96-99%). Finally, thiophilic Lewisacid (AgBF4, AgOTf or DMTSF) cyclisation produced the cis-pterocarpans in moderateto good yields (39-82%).Initial C-ring cyclisation (AgBF4) of the methyl 3-benzylsulfanyl-2,3-di(2-hydroxyphenyl)propanoates, followed by reduction (LiAIH4) and Mitsunobu (TPPDEAD)B-ring formation, afforded for the first time a trans-pterocarpan in a moderateoverall yield of 12%.In order to address the issue of stereo control, we first attempted to introducestereoselectivity during the aldol condensation. Stereoselective aldolisation employingdiisopropylethylamine and chiral boron triflates, was evaluated utilizing achiraldibutylborontriflate. This system, though capable of effecting aldolisation, wasineffective to incorporate a broad range of substrates. Secondly, we converted the methylpropanoates to chiral derivatives of imidazolidin-2-one, bornane-l0,2-sultam and(lR,2S)-p-tol-N-norephedrine. Steric shielding of the enolates generated from thesederivatives, prevented aldol condensation. Thirdly, using (-)-sparteine as chiral baseafforded achiral products. Finally, in an effort to employ stereoselective epoxidation,attempts were made to synthesize 2-propenoates. All attempts to introduce the doublebond gave disappointing yields. Although our attempts to introduce chirality failed,several alternatives still needs to be investigated in future endeavours.We have thus developed a highly efficient synthesis of cis-pterocarpans and succeeded inmodifying this protocol to the novel synthesis of Irans-pterocarpanoids. Also, thissynthetic protocol was modified to permit the stereoselective synthesis of 6ahydroxypterocarpansin high overall yields. The ease with which these protocolsaccommodate highly oxygenated substrates, featured by most natural pterocarpans,should contribute substantially to assess the chemical and physiological characteristicsthat may promote application of this class of phenolics as pharmaceutical or agriculturalchemicals.

[发布机构] University of the Free State