Development of the Enantioselective Oxidation of Secondary Alcohols and Natural Products Total Synthesis

Author: Bagdanoff, Jeffrey Thomas

Year: 2006

Degree: Dissertation (Ph.D.)

Advisor: Stoltz, Brian M.

Committee Members: Grubbs, Robert H.; Stoltz, Brian M.; Tirrell, David A.; Hsieh-Wilson, Linda C.

Option: Chemistry

DOI: 10.7907/Z94F1NQK

Abstract

Oxidation is a fundamental process in chemistry and biology. In synthetic chemistry, there are several methods for the asymmetric oxidation of organic substrates. Classically, these methods have focused on the delivery of a heteroatom from a reagent or catalyst to a prochiral substrate. What have historically been underdeveloped are enantioselective oxidation methods that do not involve the transfer of a heteroatom, but rather are defined by the enantioselective dehydrogenation of an organic substrate. This type of oxidative transformation was investigated using a palladium(II) catalyst system.

A palladium-catalyzed oxidative kinetic resolution of secondary alcohols was developed. Key features of the catalytic system include the use of (–)-sparteine as the source of chiral relay, and molecular oxygen as the sole stoicheometric oxidant. Under the described catalytic system, a number of benzylic and allylic alcohols have been oxidized in an enantioselective manner, to provide a ketone and residual alcohol in high enantiomeric excess and excellent yield.

Subsequent to the original system, the systematic investigation of a number of mechanistic hypotheses involving the role of exogenous bases and H-bonding additives prompted the discovery of new reaction conditions displaying greatly enhanced reactivity, selectivity, atom economy, and generality. The net result of these improvements was a catalytic system effective in oxidative desymmetrization of a number of complex meso-diols. Ultimately, these advances have permitted our method to be applied towards a number of synthetic endeavors, including the key step in the total synthesis of the natural product alkaloid (–)-lobeline.

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