Synthesis of β-Lactams from Fluoroketenes and Imines: Ab Initio Potential Energy Surfaces in Gas Phase and in Solution

Abstract

3-Fluoroazetidinones are important as synthetic intermediates for the preparation of fluorinated β-lactam antibiotics and as building blocks for carbohydrates and amino acids. In this paper, possible mechanisms for the reaction between fluoroketene and formaldimine yielding a fluorinated β-lactam have been described. A deep analysis of the potential energy surface has been carried out at the ab initio computational level. Gas-phase and solution calculations have been performed. Free energy values have been estimated. A continuum solvent model has been employed that assumes a general cavity shape and a relative dielectric permittivity corresponding to a low polar medium (ε = 8.93). The role of the solvent has been found to be crucial since it modifies the reaction mechanism, which is concerted in the gas phase and stepwise in solution. A number of stationary points are described. They correspond to syn and anti attacks of the imine to fluoroketene. In each case, gauche and trans zwitterionic intermediates are obtained that are in general connected through a transition state. Planar cis structures with Cs symmetry have been also located and correspond to transition states connecting mirror images of gauche structures. Conrotatory and disrotatory motions in the ring closure are possible, although the former are more favorable. The large stereoselectivity of the reaction found experimentally is correctly predicted by the computations.