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 Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Committee Chair

Arun K. Ghosh

Date of Award

5-2018

Committee Member 1

Chittaranjan Das

Committee Member 2

Christopher Uyeda

Committee Member 3

Jean A. Chmielewski

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