Those containing tertiary hydroxy groups exhibit potent anti-HIV activity in the sesquiterpyridine alkaloids. A novel enantioselective strategy for the synthesis of the diester derivative of hydroxywilfordic acid, a key fragment of anti-HIV sesquiterpene pyridine alkaloids, was developed. Asymmetric cyanation using Jacobsen’s (R,R)-aminothiourea and hydrolysis were performed to afford chiral α-hydroxy-α-methyl acid as the (S)-isomer. Naturally derived hydroxywilfordate prepared by methanolysis of wilfortrine was found to be the (R)-isomer upon comparison with the synthetic compound. Asymmetric cyanosilylation of the α,β-unsaturated ketone using Jacobsen’s (R,R)-amino-thiourea was performed to synthesize the (S)-isomer. The stereochemistry of the tertiary alcohol in naturally occurring hydroxywilfordic acid could be assigned as the (R)-configuration. Currently, synthetic strategies for regioselective/chemoselective esters or amide formation from hydroxywilfordic acid are under investigation as a means to obtaining simplified analogs of sesquiterpene pyridine alkaloids and evaluating the biological activities of their derivatives.

Enantioselective synthesis and absolute configuration determination of hydroxywilfordic acid in sesquiterpene pyridine alkaloids

2019 Fall National Meeting

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