Asymmetric 'Clip-Cycle' synthesis of 3-spiropiperidines.

3-Spiropiperidines can be synthesized in up to 87% yield and 96 : 4 er using a two step 'Clip-Cycle' approach. The 'Clip' stage of this method is based on efficient and highly -selective cross metathesis of -Cbz-protected 1-amino-hex-5-enes with a thioacrylate. This is followed by the 'Cycle' step, in which an intramolecular asymmetric aza-Michael cyclization is promoted by a chiral phosphoric acid catalyst.

Asymmetric "Clip-Cycle" Synthesis of Pyrrolidines and Spiropyrrolidines.

The development of an asymmetric "clip-cycle" synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by "clipping" them to thioacrylate via an alkene metathesis reaction. Enantioselective intramolecular aza-Michael cyclization onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine.