University of Missouri - Saint Louis

The Graduate School

Announcement

An oral examination in defense of the dissertation for the degree

Doctor of Philosophy

Saibal Bandyopadhyay
M.S. in Chemistry, May, 2006, University of Missouri-St. Louis.
M.Sc. in Chemistry, August, 2002, Indian Institute of Technology, Kharagpur.

Approaches to the Synthesis of Cyclophostin and an Endophosphonate Analog

Abstract

Several approaches to the synthesis of a potent acetyl cholinesterase inhibitor, cyclophostin (1a) and an isosteric endophosphonate analog (2) were explored. The synthesis of the core structure of another series of natural products, cyclipostins (1b) was also explored. These bicyclic molecules posses a novel seven membered cyclic enolphosphate/phosphonate ring fused to a butyrolactone. Two basic synthetic strategies: a) lactonization followed by the seven membered ring formation and b) the seven membered ring synthesis followed by lactonization, were applied in these syntheses. The Pd(0) catalyzed nucleophilic substitution reaction of phosphono allylic carbonates was employed to prepare the key synthetic intermediates.

The synthesis of the endophosphonate analog, following strategy a, gave an unexpected lactone enol phosphonate molecule. However, the alternate strategy b was successful and the endophosphonate analog was obtained as a mixture of two diastereomers. The diastereomeric mixture was separated using column chromatography and the relative stereochemistry was assigned using X-ray diffraction.

Synthesis of cyclophostin by strategy a gave the natural product in very low yield. As an alternate approach to this synthesis, strategy b was followed using the enzymatic desymmetrization of a diacetate. A primary alcohol was obtained in this stereoselective enzymatic hydrolysis. Phosphorylation of the primary alcohol followed by an attempted C-acetylation resulted in an unanticipated formation of cyclopropane ring. Although, the total synthesis was unsuccessful, the study revealed that the preferred strategy b (seven membered followed by five membered ring synthesis) was superior to a.

Defense of Dissertation Committee