Pseudoephenamine: a practical chiral auxiliary for asymmetric synthesis.

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. Both enantiomeric forms of pseudoephenamine are easily prepared with well-established methods (Scheme 1). In 1951, Tishler and co-workers at Merck reported a process for the transformation of erythro-1,2-diphenyl-2-aminoethanol (1R,2S or 1S,2R) into the corresponding threo diastereomer (1S,2S or 1R,2R, respectively) by N-formylation with formamide, invertive cyclization to form the corresponding oxazoline using thionyl chloride, and hydrolytic ring-opening under acidic conditions. By employing a small but important modification (that is, the use of formamide containing approximately 0.2 equivalents ammonium formate for Nformylation rather than pure formamide, the use of which leads to a reduced yield and yellowing of the product), we have applied the Tishler protocol for large-scale synthesis of both enantiomers of threo-1,2-diphenyl-2-aminoethanol from the appropriate erythro-diastereomer (both erythro diastereomers are commercially available in enantiomerically pure form and are widely used as chiral auxiliaries themselves, for example, in the Williams amino acid synthesis). Subsequent N-methylation of threo-1,2-diphenyl-2-aminoethanol was achieved in 97% yield by N-formylation with acetic formic anhydride followed by reduction with lithium aluminum hydride. The product was recrystallized from hot ethanol to produce large, orthorhombic, colorless crystals (m.p. 109–110 8C). We have routinely prepared 20–40 g batches of (1R,2R)or (1S,2S)-pseudoephenamine by the described four-step sequence, which proceeds in 87% yield and requires no column chromatography. X-ray crystallographic analysis revealed that pseudoephenamine adopts a conformation identical to pseudoephedrine in the solid state, with gauche orientations between both the aminomethyl and hydroxy substituents as well as the two phenyl substituents (Figure 1). Amide derivatives of pseudoephenamine were prepared from the corresponding carboxylic acid chlorides or anhydrides by routine methods and, in most cases, were crystalline solids (see the Supporting Information). Pseudoephenamine Scheme 1. Synthesis of ( )-(1S,2S)-pseudoephenamine by a modified Tishler protocol followed by N-methylation.