Synthesis of tubuvaline (Tuv) fragment of tubulysin via diastereoselective dihydroxylation of homoallylamine

Abstract

Tubulysins are natural anticancer molecules that directly bind and inhibit tubulin polymerization in actively dividing cells leading to apoptosis and cell death. Structurally, tubulysins are linear tetrapeptides, constituted by a natural amino acid (Ile) and three non-canonical amino acids (Mep, Tuv, and Tup). Herein, we report a convenient strategy for the practical synthesis of tubuvaline fragment of tubulysin natural products. In this approach, we describe the regioselective ring opening of a chiral aziridine 7 with vinyl Grignard reagent to obtain (R)-tert-butyl(2-methylhex-5-en-3-yl)(tosyl)carbamate 8 which was further subjected to Sharpless asymmetric dihydroxylation with AD-mix-β resulting in the formation of (2 R,4R)-4-((tert-butoxycarbonyl)amino)-2-(methoxymethoxy)-5-methylhexanoic acid 3 that was finally transformed to tubuvaline by heterocyclization. © 2020 Taylor & Francis Group, LLC.