Synlett 2019; 30(01): 77-81
DOI: 10.1055/s-0037-1611359
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Deacetoxytubuvaline Fragment of Pretubulysin and its Lipophilic Analogues for Enhanced Permeability in Cancer Cell Lines

Ramesh B. Reddy
a  Discipline of Chemistry, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore-453 552, India
,
Premansh Dudhe
a  Discipline of Chemistry, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore-453 552, India
,
Venkatesh Chelvam*
a  Discipline of Chemistry, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore-453 552, India
b  Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Simrol, Indore-453 552, India   Email: cvenkat@iiti.ac.in
› Author Affiliations
We would like to extend our sincere gratitude to the Science and Engineering Research Board, Department of Science and Technology, Government of India, for providing funding under the grant number EMR/2015/001764.
Further Information

Publication History

Received: 18 September 2018

Accepted after revision: 26 October 2018

Publication Date:
06 December 2018 (online)

Abstract

In the last two decades, tubulysins have emerged as alternatives to microtubule depolymerizing agents such as colchicine and vinblastine, which are well-established anticancer agents. However, the complex structure of tubulysins has always posed a challenge for synthetic chemists to scale up the production of these compounds. We report a new strategy for the practical gram-scale synthesis of a (4R)-4-[(tert-butoxycarbonyl)amino]-5-methylhexanoic acid through regioselective cleavage of a chiral aziridine ring with a vinyl Grignard reagent to afford tert-butyl [(1R)-1-isopropylbut-3-en-1-yl]carbamate, which was subjected to regioselective hydroboration–oxidation with 9-BBN. The resulting (4R)-4-[(tert-butoxycarbonyl)amino]-5-methylhexanoic acid was successfully transformed into the deacetoxytubuvaline fragment of pretubulysin or its highly lipophilic methyl-substituted thiazole and oxazole analogues for incorporation into pretubulysins. Increasing the lipophilicity of tubulysin or pretubulysin molecules should enhance their cell permeability and cytotoxicity in cancer cell lines.

Supporting Information

 
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