Small nitrogen heterocycles are ubiquitous targets for myriad biological applications. Using a complementary synthetic approach of transition metal- and enzyme-catalyzed reactions, the enantioselective syntheses of (–)-coniine, DAB-1, and nectrisine are reported. The easily-obtained oxynitrilase enzyme was used to set the initial cyanohydrin stereocenter with &gt;99% enantiomeric excess. Ruthenium-catalyzed cross- and ring-closing metathesis reactions were used to overcome functional limitations of the natural oxynitrilase enzyme. Highly stereospecific and regioselective palladium catalysis via chiral π-allyl intermediates was used for allylic transposition of the enzyme-derived stereocenters with high fidelity. The resulting highly-functionalized enantiopure intermediates were carried forward to the titular piperidine and pyrrolidine natural products as proof-of-concept for this combined catalytic strategy. It is anticipated that this approach could be applied to the enantioselective synthesis of other highly-functionalized piperidine and pyrrolidine alkaloids.

Combined enzyme- and transition metal-catalyzed strategy for the syntheses of nitrogen heterocycles: (–)-coniine, DAB-1, and nectrisine

ACS Spring 2022

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