Development of a Flexible Approach to Nuphar Alkaloids via Two Enantiospecific Piperidine-Forming Reactions

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (−)-deoxynupharidine ((−)-2), (−)-castoramine ((−)-3), and (−)-nupharolutine ((−)-4) via intermediate lactam 7 is delineated.