Lossen Rearrangement of p-Toluenesulfonates of N-Oxyimides in Basic Condition, Theoretical Study, and Molecular Docking.

Piotr Stefanowicz,Mariusz Jaremko,Miłosz Siczek,Bartosz Setner,Mostafa A Hussien,Monika Kijewska,Abeer A Sharfalddin,Łukasz Jaremko,Marta Cal,Abdul-Hamid Emwas

doi:10.3389/fchem.2021.662533

Abstract

The sulfonic esters of N-oxyimides are a group of compounds with a wide range of biological activities, as well as a unique reactivity toward amines. They undergo this reaction with primary amines and other nucleophilic reagents according to a Lossen-like rearrangement. The reaction is initiated by nucleophilic attack on a carbonyl group in the succinimide ring followed by isocyanate formation, which next interacts with another nucleophile molecule forming an addition product (e.g., ureido or urethane derivative). However, the secondary amines are also susceptible to other reactions leading to products containing the maleimide ring formed by sulphonic acid elimination. In the case of tertiary amines, this reaction is predominant. To explain the phenomenon of the reactivity of the N- oxyimides toward different types of amines, we employed various spectroscopic and X-ray approaches as well as DFT calculation. Results suggest that the basicity of the amine used for the reaction plays a crucial role in the reaction mechanism that eventually dominates the entire chemical process. Moreover, we applied molecular docking to investigate the ability of the products to act as serine protease inhibitors using human leukocyte elastase (HLE).

Highlights

Non-protein amino acids play many essential roles in the biochemical pathways of living organisms
The sulfonic esters of N-oxyimides belong to a group of chemical compounds that is characterized by specific chemical and biological properties
The reactions between the sulfonic ester of N- hydroxyl imide based on aspartic acid or glutamic acid with selected primary and secondary amines were examined resulting in the formation of products via a Lossen-type rearrangement (Scheme 1)

Summary

Introduction

Non-protein amino acids play many essential roles in the biochemical pathways of living organisms. Identifying new non-protein amino acid derivatives can facilitate new important applications for this group of compounds, e.g., in medicine, as well as facilitating pathway investigations. It has been shown that sulfonic esters of N-oxyimides, in contrast to the carboxylic esters of the Noxyimides, react with the nucleophiles like amines through the carbonyl groups of the succinimidic ring to form ureido derivatives. The mechanism of these reactions, which is related with the Lossen rearrangement, has been previously described

Methods

Results

Conclusion