Synthesis of the potent antimycobacterial agent evocarpin

Evocarpin, originally isolated from the fruits of the Chinese medicinal plant Evodia rutaecarpa (Juss.) Benth. (Rutaceae) displayed a potent antimycobacterial activity on fast growing strains of mycobacteria [1,2]. As part of our on going project, we have prepared evocarpin from the cheaply available unsaturated fatty acid, oleic acid (1). The synthesis was started by Wittig reaction of an aldehyde ester, which was readily prepared by ozonolysis of methyl oleate with pentyltriphenylphosphonium bromide which was obtained by the reaction between bromopentane and triphenylphosphine. The resulting unsaturated ester underwent alkaline hydrolysis to afford the corresponding unsaturated acid, and subsequent methylation of the acid with methyllithium afforded an unsaturated methyl ketone. Further treatment of this methyl ketone with N-methylisatoic acid anhydrid (2) under strong basic conditions gave evocarpine and its trans isomer (2:1) [3], which was subjected to preparative HPLC to give evocarpin (3).

Acknoledgements: We are grateful for financial support by the Austrian Science Fund (FWF), Project No. P21152.

References: [1] Adams, M. et al. (2005) Int. J. Antimicrob. Agent. 26:262–264.

[2] Adams, M. et al. (2006) Patent. Int WO 2006/094327 A1.

[3] Coppola, G.M. (1985)J. Heterocyclic Chem. 22:491–494.