Date of Award

Winter 2005

Project Type

Dissertation

Program or Major

Chemistry

Degree Name

Doctor of Philosophy

First Advisor

Charles K Zercher

Abstract

The Tandem Chain Extension-Aldol (TCEA) Reaction of beta-keto esters with aliphatic and aromatic aldehydes yields gamma-keto-beta'-hydroxy esters with significant syn-selectivity. A control Reformatsky reaction with a methyl 2-iodo-5,5-dimethyl-4-oxo-hexanoate 53 and methyl 2-iodo-5,5-dimethylhexanoate 65 indicates that the presence of a gamma-keto-functionality in the zinc-organometallic intermediate in the TCEA reactions is key to the syn-selectivity that is observed. The gamma-keto-functionality, through complexation to zinc, may direct the bias of the reaction toward a transition state that results in the syn-product. An investigation of the zinc-organometallic intermediate with Nuclear Magnetic Resonance Spectroscopy has supported the theory that the intermediate's gamma-keto-group is coordinated to zinc-species on the reaction mixture.

Use of protected alpha-hydroxyacetaldehydes in the TCEA reaction results in an erosion in the syn-selectivity of the TCEA reaction. A study, in which the steric bulk of the hydroxyacetaldehyde's protecting group was varied, has indicated that the erosion in syn-selectivity is likely due to complexation of the aldehydes hydroxy-functionality to zinc in the transition state of the TCEA reaction.

Finally, in an attempt to develop an approach toward the synthesis of CJ-12,954 114a, the TCEA reaction has been successfully applied to the synthesis of spiroketal units, via the generation of dihydroxy-keto synthons.

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