Studies towards a total synthesis of alkaloids manzamine A and cylindrospermopsin and development of a complex example of the Dowd-Beckwith rearrangement

by Havas, Fabien

Abstract (Summary)
This dissertation describes efforts towards a total synthesis of manzamine A and cylindrospermopsin, and the development of a novel variant of the Dowd rearrangement. Manzamine A is a marine sponge alkaloid with a complex structure and potentially valuable biological activity. This thesis describes an approach to a manzamine A substructure involving an asymmetric Birch reductive alkylation of the amide derived from (L)-prolinol methyl ether and 2-methoxybenzoic acid as a key step. Another key step was projected to be a diastereoselective Keck allylation, however a novel Dowd-Beckwith rearrangement occurred instead, producing a substituted 2-oxabicyclo[3.3.0]octan-3,6-dione in good yield. A study of the scope and limitations of this process is described herein. This study illustrated that the rearrangement can be efficient and stereoselective, and culminated in a nontrivial synthesis of a bicyclo[3.3.0]octanone containing three contiguous quaternary stereocenters. Cylindrospermopsin is a highly toxic cyanobacterial guanidinium alkaloid. The work presented herein describes a synthesis of advanced intermediates in a projected synthesis of cylindrospermopsin. Key steps include a Roush crotylation reaction to establish several key stereogenic centers, an intramolecular conjugate addition to form a piperidine ring, a Curtius rearrangement with internal trapping to provide a hexahydroimidazo[1,5-a]pyridine-3-3one, and a Sonogashira coupling to attach the incipient D-ring pyrimidine. Whereas a synthesis was not accomplished, a 14-step synthesis of an intermediate that may serve as a cylindrospermopsin precursor is described.
Bibliographical Information:


School:The Ohio State University

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:alkaloids total synthesis manzamine a cylindrospermopsin dowd beckwith rearrangement


Date of Publication:01/01/2004

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