Cyclization of interlocked fumaramides into β-lactams: experimental and computational mechanistic assessment of the key intercomponent proton transfer and the stereocontrolling active pocket |
| |
| Authors: | Alberto Martinez-Cuezva Aurelia Pastor Marta Marin-Luna Carmen Diaz-Marin Delia Bautista Mateo Alajarin Jose Berna |
| |
| Institution: | Department of Organic Chemistry, Faculty of Chemistry, University of Murcia, Regional Campus of International Excellence “Campus Mare Nostrum”, 30100 Murcia Spain.; ACTI, University of Murcia, 30100 Murcia Spain |
| |
| Abstract: | A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides to give β-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.A mechanistic study of the diastereoselective cyclization of interlocked fumaramides to give β-lactams unveils the key factors for successfully taming the process. |
| |
| Keywords: | |
|
|
