Organocatalysts for the Asymmetric Neber reaction: Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

Several novel organocatalysts derived from beta- and gamma-lactamfused thiazolidines and L-phenylalanine-based thiazolidines were efficiently synthetized. These organocatalysts, as well as other previously developed thiazolidine-derived thioureas, were tested in the asymmetric one-pot Neber reaction of beta-ketoxime-1H-tetrazoles towards chiral 2-(tetrazol-5-yl)-2H-azirines. The results obtained when using thioureas only differing in the lactam ring size demonstrate that the presence of the 6 beta-lactam ring in the catalysts is a requirement to achieve high enantioselectivity in the studied transformation. The new 6 beta-aminopenicillanic acid-derived thiourea afforded the R enantiomer of 3-phenyl-2-(tetrazol-5-yl)-2H-azirine with > 99% ee.