| The conversion of acyclic precursors to substituted heterocycles holds an important position in organic synthesis. Wasserman and co-workers have demonstrated the ability to accomplish such a task by the thermal rearrangement of substituted ;The synthetic utility of the bicyclic oxazolidine reduction strategy, in substituted piperidine synthesis, was demonstrated by the successful total synthesis of (;The imine-epoxide rearrangement was further extended to ;Attempted reversal of the trans-selectivity observed in the bicylic oxazolidine reduction, to provide cis-2,6-disubstituted piperidines, met with little success. However, a formal "cis-reduction" could be accomplished by addition of Grignard reagents to N-benzyl-6-oxa-8-azabicyclo(3.2.1) octane. In all Grignard addition cases studied, the cis-2,6-disubstituted piperidinemethanol was the exclusive product.;It was envisioned that reduction of bicyclic oxazolidines, generated via an imine-epoxide rearrangement, would provide a general method for substituted piperidine synthesis. It was found, in a subsequent reduction study, that N-benzyl-5-methyl-6-oxa-8-azabicyclo(3.2.1) octane could be reduced with a number of hydride reagents. Furthermore, it was observed that in all cases studied, the predominant product of reduction was the trans-2,6-disubstituted piperidinemethanol.;Thus it has been established that a new, stereoselective method of substituted piperidine synthesis has been developed. The preparation of N-benzyl-6-oxa-8-azabicyclo(3.2.1) octanes and their subsequent reduction provides a route to either trans-2,6-disubstituted or threo-monosubstituted piperidines. Cis-2,6-disubstituted piperidines can be synthesized by Grignard addition to oxatropanes. |
