Swim in the Chiral Pool: MDMA and MDA Enantiomers from Alanine-Derived Precursors

Abstract

A divergent two-step process has provided access to optically pure enantiomers of MDMA and MDA, clinically relevant phenylisopropylamine entactogens. Target compounds were synthesized from commercially available alanine-derived aziridines. Critical process parameters were identified, and the reactions were optimized to avoid chromatographic purifications toward gram-scale isolations, providing (R)-(-)-MDMA, (S)-(+)-MDMA, (R)-(-)-MDA, and (S)-(+)-MDA each in greater than 98% purity by UPLC, >99% enantiomeric excess, and net yields between 50 and 60% for the complete process.

Figure 1

Structures of MDMA (1), MDA (2), and corresponding stereoisomers.

Scheme 1. (A) Regiospecific Ring Opening of Tosyl-Protected Aziridine 4 As Described by Huot et al. and Nenajdenko et al.; (B) Chiral Pool Synthesis of Requisite boc-Aziridine R-6 from d-Alanine; and (C) Optimized Two-Step Divergent Route to 1 and 2 Employing boc-Aziridine 6 (This Work)

Figure 2

Overlaid chromatograms for isolated 7 (red), quenched Grignard solution 3 (blue), and labeled impurity peaks with putative structures 8 and 9 derived from 3.

Scheme 2. Byproduct Formation and Fate with Extended Reaction Times in the Formation of 7

Figure 3

Monitored intermediate in lithium aluminum hydride reduction of 7.