Abstract
Asymmetric catalysis mediated by chiral N-heterocyclic carbenes (NHCs) represents a cornerstone of modern synthetic chemistry for constructing complex, enantioenriched architectures. However, traditional batch implementations often suffer from restricted mass and heat transfer, prolonged reaction periods, and progressive catalyst deactivation via off-pathway dimerization or oxidative degradation. Here, we report an integrated microfluidic continuous-flow methodology that interfaces chiral triazolium-derived NHC organocatalysis with microchannel reactors for the rapid, highly enantioselective synthesis of versatile pharmaceutical intermediates. By orchestrating precise fluidic mixing and fine control over residence times within a fluoropolymer-based microreactor, the formal asymmetric [3+2] annulation of α,β-unsaturated aldehydes with activated ketones proceeded to completion in under five minutes. The microfluidic architecture afforded functionalized chiral γ-butyrolactones in 88–96% isolated yields with up to 99% enantiomeric excess (ee), substantially outperforming batch counterparts that required 8 to 16 hours. Mechanistic interrogations reveal that the intense micro-mixing regime minimizes the steady-state accumulation of the transient Breslow intermediate, mitigating catalyst degradation and homocoupling side-reactions. The scalability of the protocol was validated through an automated multi-hour continuous run yielding over 25 grams of a chiral lactone precursor to therapeutic targets with an exceptional space-time yield of 4.12 kg·L⁻¹·h⁻¹. This work underscores the synergy between advanced chemical engineering and organic methodology, providing a robust, sustainable paradigm for fine-chemical manufacturing.
