Stereoselective route to 15N-labeled-β-deuterated amino acids:: synthesis of (2S,3R)-[3-2H,15N]-phenylalanine

(2S,3R)-[3-H-2, N-15]-Phenylalanine hydrochloride was synthesized utilizing N-15-labeled 8-phenylmenthylhippurate as a chiral glycine equivalent. The key step in the synthesis was the alkylation of the glycine template with (S)-(+)-benzyl-alpha-d-mesylate. The doubly labeled alkylation product was obtained in 89% yield with 92% de at the alpha-carbon and 74% de at the beta-carbon. The nature of the electrophile employed in the alkylation step significantly affects the stereochemical outcome at the beta-carbon. Hydrolysis of the alkylation product under acidic conditions followed by recrystallization from isopropanol yielded the title compound as the hydrochloride salt. Analysis of the (-)-camphanamide derivative of the final product by NMR spectroscopy and HPLC revealed a 76% de at the alpha-carbon and a 72% de at the beta-carbon. The synthetic strategy described represents a simple yet versatile route to chirally deuterated beta-methylene unit containing amino acids. (C) 2002 Elsevier Science Ltd. All rights reserved.