Synthesis of Spliceostatin E and Decytospolide A and B and Progress Toward the Synthesis of Thailanstatin A
Abstract
The first stereoselective total synthesis of spliceostatin E has been accomplished. The left hand δ-lactone subunit was constructed from commercially available (R)-glycidyl alcohol through a ring-closing metathesis as the key reaction. The central-functionalized tetrahydropyran ring was synthesized as done in the synthesis of spliceostatin A. An olefin cross-metathesis of the δ-lactone and the central tetrahydropyran ring provided spliceostatin E. Spliceostatin E was originally reported to exhibit potent antitumor activity, however, our biological evaluation of synthetic spliceostatin E revealed that it did not inhibit in vitro spicing and did not impact speckle morphology in cells. A stereoselective total synthesis of thailanstatin A methyl ester, a semi-synthetic derivative of the natural product thailanstatin A, has been achieved. By synthesizing thailanstatin A methyl ester, we were only one step away from making the natural product, however, after many attempts, we were unable to successfully purify thailanstatin A. Both the left-hand and the central tetrahydropyran ring were constructed from readily available tri-O-acetyl-D-glucal. Notable reactions in this synthesis include a stereoselective allylation, a directed epoxidation, a Claisen rearrangement and a substrate-controlled asymmetric Michael addition. Thailanstatin A and thailanstatin A methyl ester were both originally reported to possess potent antitumor activity, with thailanstatin A methyl ester exhibiting greater potency of the two. A biological evaluation of thailanstatin A methyl ester is currently underway. A stereoselective total synthesis of the small natural products decytospolide A and B was accomplished. The synthesis features a Friedel-Crafts acylation, an asymmetric Noyori transfer hydrogenation, and an Achmatowicz rearrangement as the key reactions. A discovered concomitant reduction to directly provide the reduced tetrahydropyran ring shortened the synthesis.
Degree
Ph.D.
Advisors
Ghosh, Purdue University.
Subject Area
Chemistry
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