An energy transfer mediated 4π spirocyclization intercepts the Staudinger β-lactam synthesis

Abstract

The Staudinger ketene-imine cyclization is a highly effective method for the synthesis of β-lactams, but a complete understanding of its mechanism remains elusive. Here we show that a visible light-mediated energy transfer spirocyclization to yield β-lactams proceeds via a zwitterionic ground state intermediate that undergoes thermal conrotatory cyclization via a TS with significant diradical character. The ring closure of this intermediate is directly analogous to that proposed in the ketene-imine cyclization, showing that open-shell singlet diradicals may be found on the potential energy surface of the Staudinger reaction. Confirmation of the presence of the zwitterion through crossover experiments validates a long-standing prediction of reversibility in its formation. This demonstrates that visible light may offer an alternative route to generate and interrogate high-energy zwitterionic intermediates.

Chemical Methods for the Construction of Spirocyclic β-Lactams and Their Biological Importance

“…Popescu and colleagues investigated visible light-driven energy transfer spirocyclization for β-lactam synthesis, proposing a zwitterionic ground state intermediate that undergoes thermal conrotatory cyclization through a transition state with significant diradical character. 30 This mechanism resembles that of ketene-imine cyclization and traditional Staudinger reaction, suggesting the presence of open-shell singlet diradicals. The existence of the zwitterionic intermediate was confirmed by crossover experiments, demonstrating the reversibility of zwitterion formation.…”