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.

Graphical Abstract

Keywords:

• γ-Amino acid
• Sharpless dihydroxylation
• tubuvaline
• tubulysin

Acknowledgments

We thank Sophisticated Instrumentation Centre (SIC), IIT Indore for compound characterization facilities.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

The authors are thankful to Ministry of Human Resource Development (MHRD), Government of India, Indian Institute of Technology (IIT) Indore, India, for research student’s fellowship. We would like to extend our sincere gratitude to Science and Engineering Research Board, Department of Science and Technology, Govt. of India for providing funding under the grant [number EMR/2015/001764].