Issue 48, 2023, Issue in Progress

Electronic origins of the stereochemistry in β-lactam formed through the Staudinger reaction catalyzed by a nucleophile

Abstract

This paper evaluates the electronic effects of molecular substituents on the stereoselectivity of the umpolung Staudinger catalytic reaction. This is especially important because experimental studies on constructing the β-lactam ring, a core structure of most antibiotics, through catalyzed Staudinger reactions have been massively progressing over the last century. Yet, there is a necessity for an in-depth understanding of the reaction mechanisms to help chemists, working on the well-established discoveries, improve these to optimize the stereoselectivity and yield of synthetic methods. Access to practical and effective advancements in forming optically pure β-lactam is paramount in the field of medical chemistry. This paper specifically investigates how changing the N-protecting group in the imine fragment can switch the stereoselectivity of the PPY-catalyzed Staudinger reaction. To do so, we employed the density functional theory (DFT) for geometry optimization and electronic analysis at the B3LYP/6-31G(d) level of theory to examine and compare the role of N-tosyl (N-Ts) and N-triflyl (N-Tf) imine on the mechanism pathways, i.e., imine-first or ketene-first, and stereochemistry of the reaction, i.e., cis or trans β-lactam. Our results show that the reaction mechanism pathway cannot be simply switched from ketene-first to imine-first by changing the substituent on the imine nitrogen atom, which is contrary to the reported experimental results, and both imines go through the ketene-first mechanism with different stereochemistries, which is cis selective for imine-Ts and trans selective for imine-Tf. Based on electronic analyses, the reversal in diastereoselectivity in the N-triflyl imine system could be attributed to the charge transfers and electron-density distribution over the transition states. Therefore, the cis/trans selectivity of the PPY-catalyzed Staudinger reaction could be effectively controlled by the electronic characteristics of the molecular substituents in the reactants. A N-protecting group in imine with a more electron-withdrawing nature seems to accelerate the stereo-determining step, ring closure, and increase the stabilization charge transfers in the transition state, leading to a preference for trans β-lactam formation. It seems that using a N-substituent with a higher electron-withdrawing nature can initially activate the imine by the nucleophilic catalyst in competition with ketene, i.e., imine-first versus ketene-first. These results can provide an insight into select proper substituents for the fragments to synthesis β-lactam with a desired stereochemistry. Also, a comprehensive comparison was performed between calculations with and without dispersion.

Graphical abstract: Electronic origins of the stereochemistry in β-lactam formed through the Staudinger reaction catalyzed by a nucleophile

Supplementary files

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Article information

Article type
Paper
Submitted
04 Aug 2023
Accepted
31 Oct 2023
First published
16 Nov 2023
This article is Open Access
Creative Commons BY license

RSC Adv., 2023,13, 33654-33667

Electronic origins of the stereochemistry in β-lactam formed through the Staudinger reaction catalyzed by a nucleophile

F. Pahlavan, S. S. Moosavi, A. R. Zolghadr and N. Iranpoor, RSC Adv., 2023, 13, 33654 DOI: 10.1039/D3RA05286A

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