Efficient Synthesis of Spirolactams by Ring-Closing Olefin Metathesis

Abstract

Spirobicyclic cores play an important role in the development of new bioactive substances. This type of spiro system exists as a key framework of numerous steroids. Construction of spirocyclics can be achieved by intramolecular alkylation, cycloaddition reaction, radical cyclization and ring-closing metathesis reaction. Various approaches for the preparation of spirocyclics encountered problems related with functional group incompatibility at one or more stages, and they have been restricted to a single substitution pattern. Only in a few instances, the newly generated ring system was left with useful functional groups for further transformations. Therefore, there has been a continuous need to develop new methods for the preparation of spiro-linkage with additional functionality for further synthetic manipulation under mild condition. In this paper, we intend to report an efficient and versatile synthetic method for the preparation of spirolactams which involves zinc mediated allylation of cyclic imides followed by ring-closing metathesis using Grubbs catalyst. We previously reported that gem-diallylated precursors 3a-b can be prepared efficiently from cyclic imides 1a-b. Babier-type zinc mediated allylation of cyclic imides 1a-b with allyl bromide in the presence of catalytic amount of PbBr2 gave hydroxylactams 2a-b. Subsequent allylation of 2a-b with allyltributyltin in the presence of BF3·OEt2 afforded precursors 3a-b in good overall yield (Scheme 1).