On the Development of Pseudoephenamine and Its Applications in Asymmetric Synthesis

Pseudoephedrine is well established as a chiral auxiliary in the alkylation of amide enolates to form tertiary and quaternary carbon stereocenters. However, due to its facile transformation into the illegal narcotic methamphetamine, pseudoephedrine is either illegal or highly regulated in many countries, which limits its use in academic and industrial settings. To address this issue, pseudoephenamine has been developed as a replacement for pseudoephedrine in organic synthesis. This new auxiliary suffers no regulatory issues and exhibits several practical advantages over pseudoephedrine, including the high diastereoselectivities observed in alkylation reactions forming quaternary carbon stereocenters, the propensity for pseudoephenamine amides to be free-flowing crystalline solids, and the sharp, well-defined peaks that typically compose the 1H NMR spectra of these amides.Chemistry and Chemical Biolog

Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis

Pseudoephenamine is shown to be a versatile chiral auxiliary for asymmetric synthesis. It is free from regulatory restrictions and exhibits remarkable stereocontrol in alkylation reactions, especially those that form quaternary carbon centers. Amides derived from pseudoephenamine exhibit a high propensity to be crystalline substances and provide sharp, well-defined peaks in NMR spectra.Chemistry and Chemical Biolog

A Simple, Scalable Synthetic Route to (+)- and (−)-Pseudoephenamine

A three-step synthesis of pseudoephenamine suitable for preparing multigram amounts of both enantiomers of the auxiliary from the inexpensive starting material benzil is described. The sequence involves synthesis of the crystalline monomethylimine derivative of benzil, reduction of that substance with lithium aluminum hydride, and resolution of pseudoephenamine with mandelic acid

Synthesis of Quaternary α‑Methyl α‑Amino Acids by Asymmetric Alkylation of Pseudoephenamine Alaninamide Pivaldimine

The utility of pseudoephenamine as a chiral auxiliary for the alkylative construction of quaternary α-methyl α-amino acids is demonstrated. The method is notable for the high diastereoselectivities of the alkylation reactions, for its versatility with respect to electrophilic substrate partners, and for its mild hydrolysis conditions, which provide α-amino acids without salt contaminants. Alternatively, α-amino esters can be obtained by direct alcoholysis