Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur–Fluorine Exchange (SuFEx) Reaction

Abstract

Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench‐stable, N‐Boc‐sulfinamide (Boc= tert ‐butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100 % es , es =enantiospecificity) generating sulfonimidamides with up to 99 % ee . Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.

Synthesis of Enantiopure Benzo Fused Cyclic Sulfoximines Through Stereoselective [3+2] Cycloaddition between N‐tert‐Butanesulfinyl [(2‐Pyridyl)sulfonyl]‐difluoromethyl Ketimines and Arynes

“…In the presence of Selectfluor , [36] sulfinamide 4 was converted to sulfonimidoyl fluoride 5 at room temperature as the sole diastereoisomer ( Scheme 3, a ). The absolute configuration at the stereogenic sulfur center is presumed to be retained as per previous report on electrophilic chlorination of chiral sulfinamides [37–39] . Sulfinamide 4 could also be further oxidized to cyclic sulfonamide 6 in 90 % yield by 3‐chloroperoxybenzoic acid ( m ‐CPBA) ( Scheme 3 ,b ).…”

Exploiting Configurational Lability in Aza‐Sulfur Compounds for the Organocatalytic Enantioselective Synthesis of Sulfonimidamides

“…These attributes have led to sulfonimidamides gaining traction in biological settings, [8] and as catalysts [9] . Consequently, there have been considerable efforts to develop new synthetic methods towards this functional group, [10] as well as routes to other underexplored aza‐sulfur derivatives, [11, 10h] including sulfinamidines ( E ), [12] sulfonimidoyl halides ( F ) [10c, 13] and sulfondiimines ( G ) [14] …”

“…For sulfinamides, asymmetric syntheses have traditionally relied on a chiral auxiliary approach, [16, 2] and only in recent years have catalytic methods emerged [17] . The ability to prepare a limited pool of enantioenriched sulfinamides has been capitalised upon, with these undergoing stereoselective conversion to several other aza‐sulfur motifs, notably sulfonimidoyl halides, [9b, 13, 18a,b] and recently sulfoximines [19]…”

How do we address neglected sulfur pharmacophores in drug discovery?

“…Imination methods have recently been successfully applied to sulfonimidamide syntheses [17,18]. Although sulfonimidamides are inherently chiral molecules, very few methods afford enantioenriched examples [19]. Enantioselectivity is particularly important because stereochemical configuration can have profound effects on drug potency.…”