Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides

Abstract

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electrophilic chemical space. We demonstrate how late stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation. File list (2) download file view on ChemRxiv S&C Vinyl S(VI) ChemRxiv.pdf (2.21 MiB) download file view on ChemRxiv Supplementary S&C Vinyl S(VI) .pdf (15.81 MiB)

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

“…In contrast to sulfones and sulfonamides, the imine position of the sulfoximine group could, for instance, be utilized to tune the reactivity of the warhead via a substituent at the nitrogen. The concept of applying vinyl sulfoximines for the development of covalent inhibitors was recently highlighted by Armstrong, Bull and co‐workers in a publication describing various synthetic approaches to vinyl sulfoximines [65] . However, the only case study reported so far is a recent series of vinyl sulfoximines which activate the transcription factor Nrf2 [66] .…”

“…The concept of applying vinyl sulfoximines for the development of covalent inhibitors was recently highlighted by Armstrong, Bull and coworkers in a publication describing various synthetic approaches to vinyl sulfoximines. [65] However, the only case study reported so far is a recent series of vinyl sulfoximines which activate the transcription factor Nrf2. [66] While Nrf2 is considered the main target of the multiple sclerosis drug dimethyl fumarate (43, Figure 18), exploration of additional Nrf2-activating compounds is motivated by its significant off-target effects and low CNS penetration.…”

Synthesis and Transformations of NH‐Sulfoximines

“…reported several strategies for the preparation the vinyl sulfoximines. [57] Vinyl sulfoximines offer interesting potential as chiral electrophilic warheads in covalent inhibitors, that can also incorporate additional functionality through the nitrogen group to provide fully functionalized probes. Substituted vinyl sulfoximines 17 were generated directly from vinyl sulfides 16 , by NH and O transfer, again indicating the very high chemoselectivity of this reaction (Scheme 18 , a).…”

Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective

“…The concept of applying vinyl sulfoximines for the development of covalent inhibitors was recently highlighted by Armstrong, Bull and co-workers in a publication describing various synthetic approaches to vinyl sulfoximines. [63] However, the only case study reported so far is a recent series of vinyl sulfoximines which activate the transcription factor Nrf2. [64] While Nrf2 is considered the main target of the multiple sclerosis drug dimethyl fumarate (43, Figure 18), exploration of additional Nrf2-activating compounds is motivated by its significant off-target effects and low CNS penetration.…”