Ring strain and substituent effects in oxyanion-promoted Myers and Schmittel cyclizations

Michelle Kimberly Waddell, Purdue University

Abstract

A series of acetoxy-substituted enyne-allenes, fused to cyclopentene and cyclohexene ring systems, were synthesized and treated with methyllithium to generate the corresponding oxyanion-substituted enyne-allenes. It was found that, whereas the cyclohexannulated examples underwent either C2-C 7 (Myers-Saito) cycloaromatization or C2-C6 (Schmittel) cyclization depending on their terminal substituents, the cyclopentannulated examples either failed to cyclize altogether or underwent C2-C7 cyclization. Both of these results lie in contrast to the behavior of their benzannulated analogues, which underwent exclusive C2-C6 cyclization independent of substituents. These findings are rationalized on the basis of both ring strain effects and the steric encumbrance of the terminal alkynyl and allenyl substituents. As a continuation of an exploration of the Myers cyclization, a bicyclo[8.4.0]tetradecendiynone system was designed and synthesized. This fused ring system was investigated as a potential prodrug. The purpose of this molecule was to mimic the reactivity of ene-diyne antibiotics while minimizing their cytotoxicity. The fused ring system proved to be stable to cyclization in abiotic conditions. This was attributed to the stability of the ring system. The unnatural amino acid (αR,βR)-3-azido-β-methoxytyrosine methyl ester was synthesized. This amino acid was designed to be incorporated into the macrocyclic framework of the cyclic depsipeptides callipeltin A and papuamide A via solid-phase synthesis. Currently, the mechanism by which they inhibit the infectivity of the HIV-1 virus is unknown. The use of a photoaffinity label to covalently label biological targets of these natural products could provide insight into their biological mode of action.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry

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