Development of Pseudoephenamine as a Chiral Auxiliary for Asymmetric Synthesis

Pseudoephedrine (Figure 1) has been well-established as a chiral auxiliary for the asymmetric, alkylative construction of carbon-carbon bonds. Unfortunately, due to the ease of its transformation into methamphetamine, pseudoephedrine is highly regulated or banned in many countries, complicating its use in academic and industrial research settings. As such, pseudoephenamine has been developed as an alternative chiral auxiliary that possesses several practical advantages over pseudoephedrine, including its freedom from regulatory restrictions, the high diastereoselectivities of amide alkylation reactions forming α-quaternary centers, and the high propensity for pseudoephenamine amides to be crystalline solids.

Figure 1: A comparison of pseudoephedrine to pseudoephenamine. — **Figure 1:** A comparison of pseudoephedrine to pseudoephenamine.

Figure 2: Asymmetric alkylation of pseudoephenamine amides to form tertiary and quaternary carbon centers. — **Figure 2:** Asymmetric alkylation of pseudoephenamine amides to form tertiary and quaternary carbon centers.

Pseudoephenamine amides are readily alkylated to form both α-tertiary and α-quaternary amide products (Figure 2). Alkylations forming α-quaternary centers show remarkable improvement in diastereoselectivity in comparison to similar reactions employing pseudoephedrine. Additionally, the vast majority of these alpha-quaternary amides are crystalline solids, while their pseudoephedrine analogs are typically oils. All pseudoephenamine amides are readily transformed into a variety of valuable synthetic building blocks, including carboxylic acids, ketones, and primary alcohols.

Figure 3: Asymmetric synthesis of quaternary amino acids. — **Figure 3:** Asymmetric synthesis of quaternary amino acids.

In a recent extension of this alkylation methodology, pivaldimines derived from pseudoephenamine alaninamide have been found to undergo highly diastereoselective alkylations to generate quaternary amino amides in high yield (Figure 3). These quaternary amino amides are easily hydrolyzed to give the free quaternary amino acids, which are of interest in a number of biological applications.