Development and Applications of the Palladium-Catalyzed Enantioselective Oxidation of Secondary Alcohols

Citation

Ebner, David Christopher (2009) Development and Applications of the Palladium-Catalyzed Enantioselective Oxidation of Secondary Alcohols. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/2KEA-TT16. https://resolver.caltech.edu/CaltechETD:etd-09192008-185009

Abstract

The development of new methods for the preparation of chiral alcohols is vital due to the presence of alcohols in natural products, pharmaceuticals, and a variety of synthetic materials, as well as their versatility as synthetic intermediates. Until recently, oxidative kinetic resolution has been a relatively underdeveloped strategy for obtaining enantioenriched alcohols.

The development of a palladium-catalyzed aerobic system for the enantioselective oxidation of secondary alcohols is described. This mild method utilizes (–)-sparteine as a chiral ligand to resolve a wide range of benzylic, allylic, and cyclopropylcarbinyl alcohols to high enantiomeric excesses with excellent selectivity. The resolution of pharmaceutical intermediates and the Claisen rearrangement of resolved allylic alcohols demonstrate the utility of the method.

Mechanistic insights have driven further catalyst development. Anionic ligand modification has provided more efficient catalysts for the resolution of a broader array of substrates. Neutral ligand studies have led to an enantioselective alcohol oxidation system with a diamine pseudo-enantiomeric to (–)-sparteine, allowing access to enantioenriched alcohols in either enantiomeric series.

This methodology has been applied to the enantioselective total synthesis of (–)-amurensinine via a selective C–H insertion, an aryne C–C insertion, and an oxidative kinetic resolution with (–)-sparteine. Use of an alternative diamine in the resolution results in a formal synthesis of (+)-amurensinine.

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