Flow Chemistry Enabled Asymmetric Total Synthesis of (+)-Biotin through Pseudocatalytic Strategy

Continuous-flow chemistry has greatly expanded the capacity for tailored molecular construction, yet the multistep synthesis of natural products and small-molecule pharmaceuticals remains constrained by solvent and reagent incompatibilities, byproduct accumulation, reactor clogging, and mismatched time scales. Through the deliberate integration of multiple purpose-devised tubular continuous extractors, in-line liquid/liquid separators, fixed-bed drying units, and in-line waste-gas vent devices, we have established a fully coupled continuous-flow regime that enables the 13-step asymmetric total synthesis of (+)-biotin with a 43% overall yield and a total residence time of only 121.5 min. The process telescopes a newly developed chiral auxiliary-controlled desymmetrization to construct (3aS,6aR)-lactone in a pseudocatalytic closed-loop cycle through a customized continuous recycling system of the chiral auxiliary, enabling multiple equivalents of chiral product to be produced per molecule of auxiliary, together with a Pd-catalyzed Fukuyama coupling for rapid side-chain assembly, and a final one-flow debenzylation/ring-opening and ring-closing sequence. This work establishes a new paradigm in asymmetric flow chemistry by integrating closed-loop recycling of a chiral auxiliary with unified reaction-separation modules, transforming multistep synthesis into a seamless and sustainable platform for complex molecule production.