Asymmetric Synthesis of Substituted Pyrrolidines via Kinetic Resolutions

The pyrrolidine ring is present in a large number of alkaloid natural products and in many pharmaceutical drugs. Building on the asymmetric ‘Clip-Cycle’ synthesis of spiropyrrolidines, this thesis details our study into the kinetic resolution of racemic ‘Clip-Cycle’ substrates to give enantioenriched chiral pyrrolidines.
Scheme 1: 'Clip-Cycle' asymmetric reaction
‘Clip-Cycle’ involves an unsaturated Cbz-protected ‘allyl’ amine being ‘clipped’ with an activating unsaturated thioester group by an alkene metathesis reaction, followed by a chiral phosphoric acid (CPA) catalyzed aza-Michael ‘cycle’ reaction. Racemic 2-, and 3-substituted cyclisation precursors were cyclized using (R)-TRIP and the conversion monitored until 50% of the substrate had been consumed. Analysis of the reaction mixture by chiral HPLC indicated that kinetic resolution had occurred in all cases studies with up to 90% ee and s=122.

Scheme 2: Asymmetric kinetic resolution reaction