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Enantioselective syntheses of FR901464 and spliceostatin A: potent inhibitors of spliceosome.

ABSTRACT: Enantioselective syntheses of FR901464 and spliceostatin A, potent spliceosome inhibitors, are described. The synthesis of FR901464 has been accomplished in a convergent manner in 10 linear steps (20 total steps). The A-tetrahydropyran ring was constructed from (R)-isopropylidene glyceraldehyde. The functionalized tetrahydropyran B-ring was synthesized utilizing a Corey-Bakshi-Shibata reduction, an Achmatowicz reaction, and a stereoselective Michael addition as the key steps. Coupling of A- and B-ring fragments was accomplished via cross-metathesis.

SUBMITTER: Ghosh AK

PROVIDER: S-EPMC3827971 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Enantioselective syntheses of FR901464 and spliceostatin A: potent inhibitors of spliceosome.

Ghosh Arun K AK Chen Zhi-Hua ZH

Organic letters 20130919 19

Enantioselective syntheses of FR901464 and spliceostatin A, potent spliceosome inhibitors, are described. The synthesis of FR901464 has been accomplished in a convergent manner in 10 linear steps (20 total steps). The A-tetrahydropyran ring was constructed from (R)-isopropylidene glyceraldehyde. The functionalized tetrahydropyran B-ring was synthesized utilizing a Corey-Bakshi-Shibata reduction, an Achmatowicz reaction, and a stereoselective Michael addition as the key steps. Coupling of A- and ...[more]

PMID: 24050251

Similar Datasets

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

Project description: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 chain B was prepared from an optically active alcohol, followed by acetylation and hydrogenation over Lindlar's catalyst. The other densely functionalized tetrahydropyran C-ring was derived from readily available (R)-isopropylidene glyceraldehyde through a route featuring 1,2-addition, cyclic ketalization, and regioselective epoxidation. These fragments were coupled together at a late stage through amidation and cross-metathesis in a convergent manner. Six key diastereomers were then synthesized to probe the importance of specific stereochemical features of FR901464 and spliceostatin A, with respect to their in vitro splicing activity.

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Spliceostatin A inhibits spliceosome assembly subsequent to prespliceosome formation.

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Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue.

Project description:FR901464 is a potent anticancer natural product that lowers the mRNA levels of oncogenes and tumor suppressor genes. In this article, we report a convergent enantioselective synthesis of FR901464, which was accomplished in 13 linear steps. Central to the synthetic approach was the diene-ene cross olefin metathesis reaction to generate the C6-C7 olefin without the use of protecting groups as the final step. Additional key reactions include a Zr/Ag-promoted alkynylation to set the C4 stereocenter, a mild and chemoselective Red-Al reduction, a reagent-controlled stereoselective Mislow-Evans-type [2,3]-sigmatropic rearrangement to install the C5 stereocenter, a Carreira asymmetric alkynylation to generate the C4' stereocenter, and a highly efficient ring-closing metathesis-allylic oxidation sequence to form an unsaturated lactone. The decomposition pathways of FR901464's right fragment were studied under physiologically relevant conditions. Facile epoxide opening by beta-elimination gave two enones, one of which could undergo dehydration via its hemiketal to form a furan. To prevent this decomposition pathway, a right fragment was rationally designed and synthesized. This analogue was 12 times more stable than the right fragment of the natural product. Using this more stable right fragment analogue, an FR901464 analogue, meayamycin, was prepared in 13 linear steps. The inhibitions of human breast cancer MCF-7 cell proliferation by synthetic FR901464 and meayamycin were studied, and the GI50 values for these compounds were determined to be 1.1 nM and 10 pM, respectively. Thus, meayamycin is among the most potent anticancer small molecules that do not bind to either DNA or microtubule.

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