Synthetic Studies Towards the Enamido Natural Products Microcionamide B and Miyakamide A1

Abstract

A diverse aray of phenyl or indole enamido alkaloids have been reported from natural sources, with many of the natural products exhibiting interesting biological activities. Synthetic routes to such enamides include amide/carbonyl condensation, alkyne hydroamidation and vinyl halide amidation. Microcionamide B (30), an enamide-containing cyclic peptide, was isolated in 2004 from a marine sponge and found to exhibit significant cytotoxic activity against human breast cancer cell lines MCF-7 and SKBR-3. The alkyne hydroamidation methodology reported by Gooßen et al., was employed for the preparation of a model linear enamide. Two different routes were trialled: one where the enamide was formed from an amino acid amide followed by solution phase coupling with the remaining peptide chain, and the other, where the enamide was formed by reaction with a complete amido-peptide chain. Enamide synthesis via both routes proved challenging as reacting phenylacetylene (162) with any protected amino acid amide or peptide larger than N-Ac-Gly-NH2 (172) resulted in only trace amounts of product forming. However, all the model di-, tri- and septapeptides 185, 186, 187 and 188 were successfully synthesised using solid-phase peptie synthesis proving the effectiveness of that half of the synthesis. With these results in mind the focus of the project moved on to attempting the synthesis of miyakamide A1 (108), a microbial indolic dipeptide enamide that possesses insecticidal, nematocidal and antimicrobial activities. Synthesis was attempted using a vinyl halide amidation protocol reported by Cheung and Buchwald. Coupling of β-bromostyrene with N-Me-Phe-NH2 (193) yielded the desired model enamide, which was then coupled with N-Ac-Phe (191) to afford a phenyl enamide analogue of miyakamide A1, albeit in low yield. Similar coupling methodology using an E/Z mixture of tert-butyl-3- (2-iodovinyl)-1H-indole-1-carboxylate (192) successfully afforded a Boc derivative of miyakamide A1, again in low yield. Future studies directed towards optimisation of the coupling steps will provide access not only to miyakamide A1, but an additional array of structurally related natural products.