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

Article abstract of DOI:10.1016/S0957-4166(02)00487-1

(2S,3R)-[3-²H,¹⁵N]-Phenylalanine hydrochloride was synthesized utilizing ¹⁵N-labeled 8-phenylmenthylhippurate as a chiral glycine equivalent. The key step in the synthesis was the alkylation of the glycine template with (S)-(+)-benzyl-α-d-mesylate. The doubly labeled alkylation product was obtained in 89% yield with 92% de at the α-carbon and 74% de at the β-carbon. The nature of the electrophile employed in the alkylation step significantly affects the stereochemical outcome at the β-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 α-carbon and a 72% de at the β-carbon. The synthetic strategy described represents a simple yet versatile route to chirally deuterated β-methylene unit containing amino acids.