Synthesis of Sulfonimidamide‐Based Amino Acid Building Blocks with Orthogonal Protecting Groups

Abstract

Herein, we report the synthesis of novel sulfonimidamides (SIAs) based on amino acid building blocks using a one‐pot method from tert‐butyldiphenylsilyl‐protected (TBDPS) sulfonamides, as well as exploration of orthogonal deprotection strategies. Among the several protecting groups investigated, TBDPS showed higher conversion, allowed UV detection and simple diastereomeric separation; in particular in combination with amino acid tert‐butyl esters. Moreover, we applied the present method to synthesize cyclic five‐membered acyl sulfonimidamides in two steps. The described synthesis of SIA‐based amino acid building blocks in combination with the orthogonal protection groups provide access to unnatural amino acid building blocks useful for further incorporation into larger molecules, such as peptide‐based transition‐state analogues and peptidomimetics. The chirality of the SIA group, as well as its additional point of diversity provided by the extra NH group, creates opportunities for the development of unique compound libraries that explore new chemical space, which is of considerable importance for the pharmaceutical and agrochemical industry.

Modern Stereoselective Synthesis of Chiral Sulfinyl Compounds

“…Sulfonimidamide derivatives of amino acids were prepared by chlorination of sulfonamides with Ph 3 PCl 2 , followed by the reaction with enantiopure amino acid esters. 372 Diastereomers formed in ca. 2:1 ratio were separated by column chromatography.…”

Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid–sulphonamide conjugates

“…For this reason, the development of novel classes of antimicrobial compounds with less side effect and improved selectivity is urgently needed. Therefore, synthesis of new sulphonamide derivatives is an active research topic for organic and pharmaceutical chemists 8, 9 . Both sulphonamides [10][11][12] and amino acids [13][14][15] have been reported to have various biological activities, but there are few reports of their successful combination in one molecule as a hybrid drug candidate [16][17][18] .…”

“…Due to their antimicrobial and CA inhibitory properties, both primary and secondary sulphonamide derivatives are under investigation to determine compounds possessing the highest activity with possibly few side-effects 19,20 . For this reason, many studies on sulphonamide derivatives have been done in recent years 3,8,9,12,18,21 . Moreover, our group previously observed the CA inhibitory properties of some primary sulphonamide derivatives incorporating dipeptide and amino acid moieties, which inhibited some pharmacologically relevant CA isoforms at nanomolar levels [16][17][18] .…”

Recovery, Purification, and Reusability of Building Blocks for Solid Phase Synthesis

“…[5,[8][9][10][11][12] For building blocks that have to be synthesized prior to SPS, for example, glycosylated building blocks or building blocks that are used in the SPS of synthetic polymers, the use of excess building blocks is a major limitation in terms of cost, time, and labor. Repetitive coupling of the same building block achieves full conversion; however, this comes at the cost of excess nonconjugated building blocks which end up in the waste.…”

“…Examples of such building blocks include non-natural amino acids, 13 C-and 15 N-labeled amino acids, and glycan donors. [5,[8][9][10][11][12] For building blocks that have to be synthesized prior to SPS, for example, glycosylated building blocks or building blocks that are used in the SPS of synthetic polymers, the use of excess building blocks is a major limitation in terms of cost, time, and labor. [13] Within the last decade, polymer chemists have successfully developed advanced strategies to introduce monomer sequence-control into synthetic polymers giving access to materials with new properties and applications such as drug delivery and data storage.…”