Cyclization of interlocked fumaramides into β-lactams: experimental and computational mechanistic assessment of the key intercomponent proton transfer and the stereocontrolling active pocket

A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides to give beta-lactams is described. The mechanistic analysis comprises the experimental evaluation of the structure-reactivity relationship for a wide range of fumaramides [2]rotaxanes (Hammet-plots), KIE studies with deuterium-labelled interlocked fumaramides and computational analysis of two alternative mechanistic pathways for the cyclization process. The obtained results confirm that: (a) the rate-determining step is the deprotonation of the N-benzyl group of the thread by the amidate group of the macrocycle generated by the external base, (b) the polyamide macrocycle plays an important role not only as activating element but also as the stereodifferenciating factor responsible for the observed diastereoselection and (c) the higher flexibility of the adamantyl core speeds up the cyclization process in diadamantyl-derived rotaxanes.

Automated summary

This study investigates the CsOH-promoted diastereoselective cyclization of interlocked fumaramides to form beta-lactams. Experimental evaluation, KIE studies, and computational analysis indicate that the rate-determining step involves deprotonation of the N-benzyl group by the amidate group from the macrocycle. The polyamide macrocycle plays a crucial role in both activation and diastereoselection. Additionally, increased flexibility of the adamantyl core accelerates the cyclization process in diadamantyl-derived rotaxanes.