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Issue 2, 2021
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Cyclization of interlocked fumaramides into β-lactams: experimental and computational mechanistic assessment of the key intercomponent proton transfer and the stereocontrolling active pocket

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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

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Article information


Submitted
19 Oct 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

Chem. Sci., 2021,12, 747-756
Article type
Edge Article

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

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