Issue 37, 2024

Retro-Cope elimination of cyclic alkynes: reactivity trends and rational design of next-generation bioorthogonal reagents

Abstract

The retro-Cope elimination reaction between dimethylhydroxylamine (DMHA) and various cyclic alkynes has been quantum chemically explored using DFT at ZORA-BP86/TZ2P. The purpose of this study is to understand the role of the following three unique activation modes on the overall reactivity, that is (i) additional cycloalkyne predistortion via fused cycles, (ii) exocyclic heteroatom substitution on the cycloalkyne, and (iii) endocyclic heteroatom substitution on the cycloalkyne. Trends in reactivity are analyzed and explained by using the activation strain model (ASM) of chemical reactivity. Based on our newly formulated design principles, we constructed a priori a suite of novel bioorthogonal reagents that are highly reactive towards the retro-Cope elimination reaction with DMHA. Our findings offer valuable insights into the design principles for highly reactive bioorthogonal reagents in chemical synthesis.

Graphical abstract: Retro-Cope elimination of cyclic alkynes: reactivity trends and rational design of next-generation bioorthogonal reagents

Supplementary files

Article information

Article type
Edge Article
Submitted
25 Jun 2024
Accepted
20 Aug 2024
First published
27 Aug 2024
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., 2024,15, 15178-15191

Retro-Cope elimination of cyclic alkynes: reactivity trends and rational design of next-generation bioorthogonal reagents

S. E. Beutick, S. Yu, L. Orian, F. M. Bickelhaupt and T. A. Hamlin, Chem. Sci., 2024, 15, 15178 DOI: 10.1039/D4SC04211E

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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