Convenient Entry to α‐Amino‐β‐hydroxy‐γ‐methyl Carboxylic Acids. Diastereoselective Formation and Directed Homogeneous Hydrogenation of 3‐(3‐Aryl‐1‐hydroxy‐2‐methylprop‐2‐enyl)‐1,4‐benzodiazepin‐2‐ones

Abstract

Aldol reaction of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (1) with 4-substituted a-methylcinnamaldehydes 2 ± 5 afforded a mixture of threo-and erythro-3-(3-aryl-1-hydroxy-2-methylprop-2-enyl)-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-ones 6 ± 13. The chromatographically separated threo diastereoisomers 6, 8, 10, and 12 and erythro diastereoisomers 7, 9, 11, and 13 were submitted to −directed× homogeneous hydrogenation catalyzed by [Rh I (cod)(diphos-4)]ClO 4 (cod cycloocta-1,5-diene, diphos-4 butane-1,4-diylbis [diphenylphosphine]. From the erythro-racemates 9, 11, and 13, the erythro,erythro/erythro,threo-diastereoisomer mixtures 16/17, 20/21, and 24/25 were obtained in ratios of 20 : 80 to 28 : 72 (HPLC), which were separated by chromatography. From the threo racemates 8, 10, and 12, the threo,threo/threo,erythro-diastereoisomer mixtures were obtained in a ratio of ca. 25 : 75 ( 1 H-NMR). The relative configurations were assigned by means of 1 H-NMR data and X-ray crystal-structure determination of 21. Hydrolysis of 21 afforded the diastereoisomerically pure N-(benzyloxy)carbonyl derivative 27 of a-amino-bhydroxy-g-methylpentanoic acid 26, representative of the novel group of polysubstituted a-amino-bhydroxycarboxylic acids. 2248 1 ) The descriptors erythro/threo are used in the traditional (carbohydrate) sense to describe the relative configurations at the two stereogenic N-and OH-substituted centers or at the two stereogenic OH-and Me-substituted centers. 2 ) Arbitrary numbering according to Fig. 1 (see also Scheme 3).