Enantioselective total syntheses of FR901464 and spliceostatin A and evaluation of splicing activity of key derivatives.

ABSTRACT: FR901464 (1) and spliceostatin A (2) are potent inhibitors of spliceosomes. These compounds have shown remarkable anticancer activity against multiple human cancer cell lines. Herein, we describe efficient, enantioselective syntheses of FR901464, spliceostatin A, six corresponding diastereomers and an evaluation of their splicing activity. Syntheses of spliceostatin A and FR901464 were carried out in the longest linear sequence of 9 and 10 steps, respectively. To construct the highly functionalized tetrahydropyran A-ring, we utilized CBS reduction, Achmatowicz rearrangement, Michael addition, and reductive amination as key steps. The remarkable diastereoselectivity of the Michael addition was specifically demonstrated with different substrates under various reaction conditions. The side ch

SUBMITTER: Ghosh AK 

PROVIDER: S-EPMC4066912 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature