TY - JOUR AU - Reddy, Ramesh B.; Dudhe, Premansh; Chelvam, Venkatesh TI - Synthesis of the Deacetoxytubuvaline Fragment of Pretubulysin and its Lipophilic Analogues for Enhanced Permeability in Cancer Cell Lines SN - 0936-5214 SN - 1437-2096 PY - 2019 JO - Synlett JF - Synlett LA - EN VL - 30 IS - 01 SP - 77 EP - 81 ET - 2018/12/06 DA - 2018/12/14 KW - amino acid KW - deacetoxytubuvaline KW - tubulysin KW - pretubulysin KW - medicinal chemistry AB - 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. PB - © Georg Thieme Verlag DO - 10.1055/s-0037-1611359 UR - http://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0037-1611359 ER -