Document Type

Dissertation

Degree

Doctor of Philosophy

Major

Chemistry

Date of Defense

8-2-2011

Graduate Advisor

Chris Spilling

Committee

Alexie V. Demchenko

Cynthia M. Dupureur

Eike Bauer

Abstract

This work is divided into 2 parts: a) total synthesis of (±)-cyclophostin, (±)-cyclipostin P and their monocyclic analogs b) development of a metathesis based methodology for transformation of vinyl phosphonates. Cyclophostin (1) and cyclipostins (2) are bioactive natural bicyclic organophosphates. Cyclophostin is a powerful inhibitor of acetyl cholinesterase (AChE), whereas members of the cyclipostins are potent inhibitors of hormone sensitive lipase (HSL). Cyclophostin (1) and cyclipostin (2) have the same structural core unit, but different phosphate ester substituents. While cyclophostin is a methyl ester, the members of the cyclipostins are phosphate esters of different alkyl groups of various length and structure at the phosphate center. First total synthesis of (±)-cyclophostin (1) and 14 monocyclic phosphonate analogs is reported. Similarly, synthesis of the natural product (±) cyclipostin P was achieved via a novel, high yielding one-pot transesterification of diastereomer of (±)-cyclophostin. This method acts as bridge from cyclophostin to any member of cyclipostins. The conversion can also be carried out with monocyclic phosphonate analogs. (±)-Cyclophostin and 14 monocyclic phosphonate analogs were tested against different members of the serine hydrolase family of enzymes at UMSL and at CNRS-Marseilles in France. The biological evaluation of these analogs was helpful in understanding the relationship between the structure and biochemistry of the molecules towards the inhibition of various enzymes. Vinyl phosphonates have the potential to be useful intermediates in organic synthesis. However, there are only a limited number of transformations reported for vinyl phosphonates. Although terminal vinyl phosphonates easily undergo cross metathesis reaction, internal vinyl phosphonate do not. A method for cross metathesis of allyl vinyl phosphonates based on relay process has been developed.

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Chemistry Commons

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