Diastereoselective Synthesis of alpha-Fluoro-gamma-Lactams via Difluorocarbene-Triggered Cyclization and Rearrangement

Abstract

We report a difluorocarbene-enabled, diastereoselective synthesis of α-fluoro-γ-lactams from readily accessible β-aminoketones and inexpensive, commercially available ethyl bromodifluoroacetate (EBDFA). Compared to established routes to this medicinally relevant motif, our strategy avoids the use of costly electrophilic fluorinating or deoxyfluorinating reagents, highlighting difluorocarbene as a versatile C1 and F building block. Density functional theory (DFT) calculations reveal that cyclization is the stereodetermining step, with observed diastereomeric ratios governed by Curtin-Hammett kinetics. In addition to activating EBDFA, the K2CO3 base enables the favourable formation of a transient hemiaminal epoxide intermediate, with subsequent C–F bond formation proceeding through a nucleophilic fluoride ring-opening pathway. Overall, this work not only delivers a direct and modular route to stereodefined α-fluoro-γ-lactams but more broadly expands our mechanistic understanding of difluorocarbene-mediated amine-carbonyl coupling reactions.