Issue 2, 2021

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

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
19 Okt. 2020
Accepted
10 Nov. 2020
First published
11 Nov. 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 747-756

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

A. Martinez-Cuezva, A. Pastor, M. Marin-Luna, C. Diaz-Marin, D. Bautista, M. Alajarin and J. Berna, Chem. Sci., 2021, 12, 747 DOI: 10.1039/D0SC05757F

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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