Development of a Method for the Copper-Catalyzed Asymmetric Propargylation of Oxime Esters

Citation

Chan, Katie Marie (2018) Development of a Method for the Copper-Catalyzed Asymmetric Propargylation of Oxime Esters. Master's thesis, California Institute of Technology. doi:10.7907/Z9CR5RJC. https://resolver.caltech.edu/CaltechTHESIS:12272017-150231015

Abstract

Alkynes represent a significant motif in natural products and pharmaceutical drugs, and the wide variety of reactions they can undergo makes them a handy tool in total synthesis. They can be introduced readily in various manners, including via propargylations of ketones and aldehydes. However, one reaction that remains to be examined is the propargylation of oximes to give a propargyl hydroxylamine. Current enantioselective propargylations of oximes typically require a chiral auxiliary and/or rare metals such as palladium or indium. Having an enantioselective propargylation of oximes which could use an external ligand and more commonly available metals would facilitate use of the product in total synthesis, as well as potentially as an unnatural amino acid. Unusual amino acids including alkynes are desirable for their use in copper(I)-catalyzed azide-alkyne [3+2] dipolar cycloadditions, a common bioorthogonal reaction.

Herein, the development of a copper-catalyzed propargylation of oxime esters is described. Initial efforts to induce enantioselectivity using a zinc nucleophile-based system proved fruitless. Although some Lewis acids could raise the yield, the enantioselectivity remained very low. Therefore, new reaction conditions using a boronate nucleophile were investigated. The use of a copper catalyst with a diphosphine ligand gave the desired product in high enantioselectivity, albeit low yield.

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