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Enantiocontrolled Synthesis of 2,6-Disubstituted Piperidines by Desymmetrization of meso-η-(3,4,5)-Dihydropyridinylmolybdenum Complexes. Application to the Total Synthesis of (−)-Dihydropinidine and (−)-Andrachcinidine

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posted on 12.02.2003, 00:00 by Chutian Shu, Lanny S. Liebeskind
A conceptually new approach to the enantiocontrolled synthesis of 2,6-disubstituted piperidines was achieved by desymmetrization of meso-2,6-dimethoxy-η-(3,4,5)-dihydropyridinylmolybdenum complexes. After protection of the piperidine nitrogen as a urethane derived from (+)- or (−)-trans-2-(α-cumyl)cyclohexyl (TCC), a sequential, one-pot methoxide abstraction/nucleophilic addition/methoxide abstraction/nucleophilic addition generated good yields of 2,6-disubstituted-η-(3,4,5)-dihydropyridinylmolybdenum complexes. This sequence proceeds by way of a highly diastereoselective methoxide abstraction (>40:1). High yielding protodemetalation and N-deprotection provided a simple and enantiocontrolled synthetic entry to a variety of 2,6-disubstituted piperidines. This new method was used for the total synthesis of (−)-dihydropinidine and (−)-andrachcinidine.