Synthesis of Novel Saccharin Derivatives

Sally-Ann Poulsen,Gregory M Rankin

doi:10.3390/molecules22040516

Abstract

The synthesis of saccharin (1,2-benzisothiazol-3-one-1,1-dioxide) derivatives substituted on the benzene ring has seen limited development despite the longevity of this compound’s use as an artificial sweetener. This type of saccharin derivative would however present attractive properties for the development of new bioactive, drug-like small molecule compounds. Here we report the derivatisation of the benzene ring of saccharin using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) to synthesise a diverse library of novel saccharin-1,2,3-triazole conjugates. All library compounds retain the capability for interactions with biomolecules via the unmodified sulfonamide and lactam groups of the parent saccharin core heterocycle. The compounds also encompass alternate orientations of the 1,2,3-triazole heterocycle, thus further adding diversity to the potential hydrogen bonding interactions of these compounds with biomolecules of therapeutic interest. Our findings demonstrate that specifically functionalized derivatives of saccharin may be prepared from either saccharin azide or saccharin alkyne building blocks in high yield using CuAAC.

Highlights

Several different synthetic routes have been applied to construct the heterocyclic compound1,2-benzisothiazol-3-one-1,1-dioxide, commonly known as saccharin (1, Figure 1), a synthetic calorie-free sugar substitute [1,2]
In addition to N- and O-alkylation, compounds derivatised on the benzene moiety of 1 are desirable, as these compounds retain both the cyclic sulfonamide and lactam groups which can participate in strong noncovalent interactions with biomolecular targets such as enzymes
We further elaborated this finding through the design and synthesis of a small library of compounds based on 1 that retain the cyclic sulfonamide core with the addition of a ‘tail’ group to the benzene ring of 1 [10]

Summary

Introduction

Several different synthetic routes have been applied to construct the heterocyclic compound1,2-benzisothiazol-3-one-1,1-dioxide, commonly known as saccharin (1, Figure 1), a synthetic calorie-free sugar substitute [1,2]. In addition to N- and O-alkylation, compounds derivatised on the benzene moiety of 1 are desirable, as these compounds retain both the cyclic sulfonamide and lactam groups which can participate in strong noncovalent interactions with biomolecular targets such as enzymes The synthesis of the latter derivatives is reliant on the application of synthetic acumen to introduce a latent handle on the benzene moiety of 1 for subsequent derivatisation; this modification’s methodology is much less developed than the straightforward alkylation of 1. Klebe and Supuran first demonstrated that the metal binding characteristics of 1 could be utilised to target metalloenzyme inhibition, the zinc metalloenzyme carbonic anhydrase (CA) [9] We further elaborated this finding through the design and synthesis of a small library of compounds based on 1 that retain the cyclic sulfonamide core (allowing for zinc binding) with the addition of a ‘tail’ group to the benzene ring of 1 [10].

Methods

Results

Conclusion