N-Phenyl substituent controlled diastereoselective synthesis of β-lactam-isatin conjugates

Abstract

Unprecedented diastereoselective synthesis of novel β-lactam-isatin conjugates via a Staudinger [2+2] cycloaddition is described. The electronic nature of substituents on the imine N-phenyl moiety induced high levels of stereocontrol and plausibly controlled the competition between direct ring closure (conrotatory) and isomerization of the azabutadiene intermediate. The presence of electron-donating groups (OCH3 and CH3) at the para-position of the imine N-phenyl moiety increases the electron density of the imine nitrogen atom. This in turn increases direct conrotatory ring closure favoring the cis-isomer. On the other hand, electron-withdrawing groups (NO2 and CF3) at the para-position gave the thermodynamically more stable trans-isomer as the major products by promoting isomerization of the azadiene zwitterionic intermediate presumably due to a decrease in the electron density on the imine nitrogen atom. A varied diastereoselective behavior was observed for meta-position substituents, where OCH3, CH3 and NO2 groups favored the cis-isomer, hence indicating the additional role of steric hindrance in the observed diastereoselectivity. Additionally, the transition states of these reactions computed at the density functional theory (DFT) level were in accordance with the experimental results.