Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis

摘要

Pseudoephedrine is widely employed as a chiral auxiliary in diastereoselective alkylation reactions and provides ready access to enantiomerically enriched carboxylic acids, aldehydes, ketones, and alcohols. Because pseudoephedrine can be transformed into methamphetamine and other illegal drug substances, many countries restrict or ban its sale and distribution, thus complicating its use in industrial and academic settings. Herein we report that (1S,2S)- and (1R,2R)-2-methylamino-1,2-diphenylethanol (synonymously, (1S,2S)- and (1R,2R)-pseudoephenamine, respectively) have a broad range of utilities in asymmetric synthesis that meet or exceed those that previously characterized the pseudoephedrine system alone, with several advantages. Specifically, 1) these auxiliaries are free from regulatory restrictions and are not known to be transformable into illicit substances, 2) asymmetric alkylation reactions that employ pseudoephenamine as a directing group proceed with equal or greater diastereoselectivities in relation to the corresponding reactions that employ pseudoephedrine, with notable improvements in the selectivities of alkylation reactions that form quaternary stereocenters, and 3) amides derived from pseudoephenamine exhibit a greater propensity to be crystalline substances compared with the corresponding pseudoephedrine derivatives and provide sharp, well-defined signals in NMR spectra.