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Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and
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-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of
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-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the
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-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.
N/O-Heterocycles are widely spread in natural products and drug candidates. Here, the authors report a modular access to bridged piperidine-γ-butyrolactones via Cu/Ir-catalyzed asymmetric allyation and
aza
-Prins cyclization/lactonization sequences.