Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Abstract

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core “SuFExable” hubs—exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)—enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1 H -1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function – a key objective of click chemistry – of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Discovery of (E)-2-Methoxyethene-1-sulfonyl Fluoride for the Construction of Enaminyl Sulfonyl Fluoride

“…However, there are still many shortcomings to overcome: the use of the highly toxic and explosive sodium azide (NaN 3 ) in the preparation of BTESF; the generation of a certain amount of 4-phenyl-1 H -1,2,3-triazole as byproduct; tedious to separation and isolation of the desired product from byproducts; and the incompatibility of using aromatic amines for N -ESF synthesis. Recently, Sharpless and Moses reported N -ESF by Michael addition of amines with 2-(triisopropylsilyl) ethyne-1-sulfonyl fluoride (TIPS-SASF) in 2022 . However, the method still suffers from poor atomic economy, producing triisopropylsilane as a byproduct (Scheme , d).…”

“…Pleasingly, aromatic amines 1w – 1y including primary amines and secondary amines were also compatible. However, due to the poor nucleophilicity of aromatic amines, ,, the yields of using aromatic amines of 1w – 1y are relatively lower than those of using their aliphatic amine counterparts, providing their corresponding products 3w – 3y in 50%, 20%, and 36%, respectively, under acidic conditions.…”

Acid-Mediated Imidazole-to-Fluorine Exchange for the Synthesis of Sulfonyl and Sulfonimidoyl Fluorides

“…For example, in contrast to other S VI –X structures (with X = Cl or higher halogens), sulfonyl fluorides have no propensity to undergo reduction and are uniquely electrophilic at sulfur . However, under certain experimental conditions (i.e., in a protic solvent or by capture with an organosilane), the fluoro substituent becomes an excellent leaving group and fluoride is easily expelled under mild conditions. , This class of nucleophilic substitutions is coined as Sulfur­(VI)–Fluoride Exchange (SuFEx) chemistry and has found many applications in materials chemistry and chemical biology …”

A diversity oriented clicking strategy: the stereoselective synthesis of highly-functionalised olefins from 2-substituted-alkynyl-1-sulfonyl fluorides

“…The DOC strategy was later applied in the stereoselective synthesis of a library of SuFExable b-substituted alkenyl sulfonyl fluorides via Michael-addition pathways from SASFs by Sharpless and Moses, resulting in the discovery of a new class of covalent Human Neutrophil Elastase inhibitors. 2 The high yielding conjugate addition reactions proceeded smoothly to give products as single stereosiomers in just minutes. However, during reaction optimisation an interesting competing side reaction occurred with the SASF Michael acceptors when dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) were employed as reaction solvents which warranted further investigation.…”

“…Diversity Oriented Clicking (DOC) is a powerful synthesis strategy introduced by the Moses and Sharpless groups for the modular synthesis of functional molecules from discrete SuFExable connective hubs. 1,2 DOC merges the benefits of classical click chemistry 3 with the versatility of connective SuFEx hubs (see Fig. 1(A) for selected SuFEx hub examples), 4–24 enabling the discovery of diverse lead-like molecules using robust and reliable click transformations.…”