Entry to new conformationally constrained amino acids. First synthesis of 3-unsubstituted 4-alkyl-4-carboxy-2-azetidinone derivatives via an intramolecular N-alpha-C-alpha-cyclization strategy

A systematic study on the base-assisted intramolecular alkylation of N-benz yl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of S-unsubstitu ted 4-alkyl-4-carboxy-2-azetidinones, to be included into the scarce family of beta -lactams with quaternary centers at the C-4 position. Particularly noteworthy is that the intramolecular N-alpha-C-alpha-cyclization of Phe a nd Leu derivatives afforded the corresponding beta -lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these pa rticular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of r eactions, that is compatible with commonly used protecting moieties for the alpha -carboxy group, cannot be applied to dipeptides, since the cyclizati on to the six-membered 2,5-diketopiperazine ring occurrs preferentially.