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-benzyl-N-chloroacetyl amino acid derivatives is described. This study resulted in the first concise and versatile route to the preparation of 3-unsubstituted 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 and Leu derivatives afforded the corresponding beta-lactam derivatives with moderate enantioselectivity (up to 56%). It is suggested that, in these particular cases, the cyclization reaction proceeds by way of planar enolate intermediates, which possess dynamic chirality. The described sequence of reactions, that is compatible with commonly used protecting moieties for the alpha-carboxy group, cannot be applied to dipeptides, since the cyclization to the six-membered 2,5-diketopiperazine ring occurs preferentially.
Gerona-Navarro
G
G
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
Bonache
M A
MA
Herranz
R
R
García-López
M T
MT
González-Muñiz
R
R
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D001384:Azetidines / Q000138:chemical synthesis; D003500:Cyclization; D007769:Lactams / Q000138:chemical synthesis; D008968:Molecular Conformation
C116379:2-azetidinone; D000596:Amino Acids; D001384:Azetidines; D007769:Lactams