Synthesis of isoflavonoid-neoflavonoid oligomers

[摘要] English:A recent phytochemical study on the heartwood of the Purplewood Dalbergia (Dalbergianitidula) in our laboratories led to the isolation of the first pterocarpan-neoflavonoid dimers, Daljanelins A-C, and an isoflavan-neoflavonoid dimer, Daljanelin D. Although the structureof Daljanelin C has been confirmed by synthesis previously, synthetic evidence regarding theexact structures of Daljanelins A, Band D was still pending. This dissertation outlines thetotal syntheses of Daljanelins Band D, as well as the preparation of a suitable precursor toDaljanelin A.The crucial step in the retrosynthesis of Daljanelin B is the nucleophilic coupling of a suitablyfunctionalized pterocarpan precursor with a benzofuranone. The electrophilic methylenebridge required at C-4 of (6aS, llaS)-medicarpin was introduced via 3-0-allylation, Claisenrearrangement, isomerization and oxidative cleavage of the olefin, benzylic reduction and insitu bromination, affording (6aS, llaS)-4-bromomethylmedicarpin.The requisite benzofuranone synthon was synthesized from vanillin by Dakin oxidation,Houben-Hoesch acylation, cyclization, protection of the hydroxy group and conversion to thetert-butyldimethylsilyl enol ether.The subsequent coupling of the pterocarpanoid and benzofuranoid fragments was achieved bymeans of desilylation of the latter with a strongly siliconophilic fluoride source. Grignardreaction of the resulting dimer with phenyl magnesium bromide and subsequent acidcatalyzed dehydration and deprotection then afforded synthetic Daljanelin B, which exhibitedthe same IH NMR and CD properties as the natural product.Reductive cleavage of the pterocarpan C-ring in Daljanelin B afforded Daljanelin D, identicalto the natural compound. It should be noted that the standard method for benzylic ethercleavage, i.e. hydrogenolysis on Pd(O) catalysts, was ineffectual. Good results were obtained,however, with a Na(CN)BHr TFA system.A suitable precursor to Daljanelin A, i.e. a 2-ethoxycarbonyl-substituted medicarpin, wassynthesized from (6aS, llaS)-medicarpin via 2,8-dibromination, 3-0-methoxymethylation,selective lithium-bromine exchange and carboxylation at C-2, followed by 8-debromination.Reduction of the resulting ethyl benzoate, in situ bromination, benzylic coupling to abenzofuranoid, Grignard reaction and phenolic deprotection, as used in the synthesis of Daljanelin B, should prove instrumental in affording the desired dimer.Over and above structural elucidation, this research project has led to the following significantresults:o The introduction of a hydroxy methyl group to position 4 of the pterocarpan skeletonconstitutes an unusual accomplishment, since substitution on resorcinol-type pterocarpanA-rings is usually hampered by low aromatic nucleophilicity, as well as sensitivity of theC-ring towards the typically employed Bronsted and/or Lewis acids.o Electrophilic aromatic substitution on such A-rings, if observed at all, takes place in lowyields at position 2. An analogue situation is encountered in natural and synthetic5-deoxyflavonoids, where A-ring substitution is found exclusively at position 6. It is thushoped that the protocol developed for the synthesis of Daljanelin B will alleviate thesedifficulties.o Although the yields In the bromination-carboxylation-debromination protocol towardsDaljanelin A are still low, an alternative route for C-2-alkylation ofpterocarpans has beenestablished.The novel synthetic routes towards Daljanelins A and B may thus collaborate incircumventing some of the problems typically associated with flavonoid and isoflavonoidA-ring functionalization.

[发布机构] University of the Free State