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

Abstract

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‐CONH2) and its descarbamoyl analogue 12‐H, respectively. Cyclic amidines 2 and 10‐H were generated from the amide N2‐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 = PhCH2OCO) followed by hydrolytic removal of both Z groups gave 5‐(carbamoylimino)proline amide 12‐CONH2 (via 2 and orthoamidine 11‐CONH2) in 70 % overall yield from 3.

Economic kilogram-scale synthesis of the novel antiepileptic drug brivaracetam utilizing porcine pancreatic lipase

“…The designed reaction proceeded smoothly in inorganic acid, and three major products were detected by LC-HRMS analysis of the crude reaction mixture including brivaracetam acid 10, brivaracetam ester 11 and brivaracetam imine 12. In addition to the major hydrolysis pathway, the cyclization of 2 might also proceed to the direct ammoniation of the alkyl nitrile [21][22][23][24][25][26] based on the result of the detected imine 12. Of note, 20% aq.…”

Bioactive natural products from Bacteroidetes

“…67 This has been addressed by total synthesis to investigate the structure–activity relationship (SAR). 69 A synthetic derivative with a methyl group on the proximal guanidine nitrogen was less potent (10-fold lower MIC) but the ED 100 was < 0.5 mg kg −1 (intravenous). 70…”