syn/anti Diastereoselectivity in the Aldol Reaction of Aldehydes with the C(3) Carbanion of 1,3‐Dihydro‐2H‐1,4‐benzodiazepin‐2‐one

The aldol reaction of the C(3) carbanion of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (2) with a series of aromatic and aliphatic aldehydes at -78 degrees afforded threolerythro diastereoisomers 3-16 of 7-chloro-1,3-dihydro-3-(hydroxymethyl)-1-methyl-5-phenyl-2H-1,4-benzodiazepin ones, substituted at the C(3) side chain, in a ratio from 55:45 to 94:6 (Scheme 1). Lewis acids exhibited limited effect on the syn/ anti diastereoselectivity of this reaction, and kinetic control of the reaction was confirmed. H-1-NMR Data suggested the assignment of the threo relative configuration to the first-eluted diastereoisomers 3, 5, 7,and 9 on reversed-phase HPLC, and the erythro configuration to the second-eluted counterparts 4, 6, 8, and 10, respectively. The structures and relative configurations three and erythro of the diastereoisomers 5 and 6, respectively, were established by single-crystal X-ray analysis, confirming the assignment based on the H-1-NMR data. A tentative mechanistic explanation of the diastereoselectivity invokes the enolate anion of 1,3-dihydro-2H-1,4-benzodiazepin-2-one as the reactive species (Scheme 2). Acid-catalyzed hydrolytic ring opening of 3 afforded threo-beta-hydroxy-phenylalanine 17, whereas from 4, the N-(benzyloxy)carbonyl derivative 18 of erythro-beta-hydroxy-phenylalanine was obtained (Scheme 3); in both cases, neither elimination of H2O from the C(3)-CHOH moiety nor epimerization at C(3) were observed. This result opens a new pathway to various configurationally uniform alpha-amino-beta-hydroxy carboxylic acids and their congeners of biological importance.