Enzymatic desymmetrization is a powerful transformation that can generate chiral nitrogen heterocycles exemplified by the commercial synthesis of Boceprevir. In an effort to access medicinally relevant 3,4-fused bicyclic piperidine derivatives, we relied on a desymmetrization and cycloisomerization sequence to rapidly synthesize the target chiral piperidines. Starting with achiral piperidine diketones, we identified a number of ketoreductase (KRED) enzymes capable of furnishing the desired desymmetrized stereodiad intermediates with high enantio- and diastereoselectivities under reaction conditions with low process mass intensity (PMI). To effect the subsequent ring closure, we have identified a number of cycloisomerization conditions, including an iron catalyst operating via a novel photoinduced mechanism.

Ketoreductase enabled synthetic strategy to chiral bicyclic piperidine building blocks

2019 Fall National Meeting

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