A Novel Rearrangement of Cyclic Glutamine Derivatives: Ring Contraction in 3,6-Diamino-2,3,4,5-tetrahydropyridin-2-ones to Yield 5-Iminoproline Amides

A new rearrangement of the cyclic L-glutamine derivative (S)-6-carbamoylamino-3-(methylamino)-2,3,4,5-tetrahydropyridin-2-one (2) and its descarbamoyl analogue 10-H was found to yield enantiomerically pure 5-carbamoylimino-1-methyl-L-proline amide (12-CONH(2)) and its descarbamoyl analogue 12-H, respectively. Cyclic amidines 2 and 10-H were generated from the amide N(2)-ZGlnOEt 3 in seven and six steps, respectively. Deprotection of (S)-6-amino-3-[(N-benzyloxycarbonyl-N-methyl)amino]-2,3,4,5-tetrahydropyridin-2-one (8) led directly to 5-iminoproline amide 12-H (via 10-H and the bicyclic orthoamidine 11-H) in 66% overall yield from 3. Carbamoylation of 8 with ZNCO (Z = PhCH(2)OCO) followed by hydrolytic removal of both Z groups gave 5-(carbamoylimino)proline amide 12-CONH(2) (via 2 and orthoamidine 11-CONH(2)) in 70% overall yield from 3.