A LARGE-SCALE PREPARATION OF )-3-(TERT-BUTOXYCARBONYL)AMINO-4-METHYLPYRROLIDINE AND ITS ANALOGS FROM L-ASPARTIC ACID

)-3-(tert-Butoxycarbonyl)amino-4-methylpyrrolidine (12a) was synthesiz ed from L-aspartic acid (4) on a large scale. Methylation of dimethyl (2S)-N-benzyl-N-(9-phenylfluoren-9-yl)aspartate (5), easily derived fr om 4, a with methyl iodide gave (3R)-3-methylaspartate (6a) in 91% yie ld with high diastereoselectivity. Reduction of 6a with lithium alumin um hydride, followed by hydrogenolysis, protection with di-tert-butyl dicarbonate, and mesylation gave 10a in 89% overall yield. Subsequentl y, reaction of 10a with benzylamine under a nitrogen atmosphere at roo m temperature, followed by hydrogenolysis, gave the target compound (1 2a) in 65% overall yield. In a similar manner to that described for th e preparation of 12a from 5, compound 5 was converted into 4-ethyl and 4-propyl derivatives (12b,c) in 34% and 38% overall yields.