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.

Metallaphotoredox catalysis enables facile (trifluoromethyl)thiolation of alkenyl iodides

“…50 Further product diversification was achieved via the transformation of the synthesized alkenyl sulfides to NH-sulfoximines via a one-pot N-and O-transfer, wherein treatment of 3b and 5a with H 2 -NCO 2 NH 4 and PhI(OAc) 2 yielded NH-sulfoximines 7a and 7b in moderate yield (Scheme 4, 49-53% yield). 51,52 Further reaction of the synthesized NH-sulfoximines was achieved via N-arylation and N-propargylation pathways. N-Arylation was carried out via reaction of 7a and 7b with para-trifluoromethylphenyl boronic acid under Cu-catalyzed conditions, yielding N-arylated alkenyl sulfoximes 8a and 8b in moderate yield (Scheme 4, 51-68% yield).…”

“…), click-chemistry, and their associated implications in late-stage functionalization efforts. 51,54,55 Photocatalytic stereochemical inversion of alkene geometry prototypically yields the contra-thermodynamic product, providing the less-stable Z isomer over its E counterpart. This process is mediated via a transient diradical species which is formed via EnT to the substrate (Scheme 5, inset).…”

Practical Asymmetric Synthesis of Chiral Sulfoximines via Sulfur-Selective Alkylation

“…Because allyl-substituted sulfoximine (R)-2j is readily isomerized to α,β-unsaturated sulfoximine (R)-6j by double bond migration under basic conditions as shown in Scheme 3, we conducted further optimization of the reaction conditions to obtain α,β-unsaturated sulfoximines preferentially. 19 In the presence of 1.1 equiv of NaOH, the reaction of (R)-1a with allyl bromide followed by addition of DBU (1.5 equiv) afforded α,β-unsaturated sulfoximine (R)-6j in 80% yield (Table 3). While application of the optimized conditions to (R)-2m afforded α,β-unsaturated sulfoximine (R)-6m in moderate yield, (R)-2k and (R)-2l did not afford the desired products (R)-6k and (R)-6l probably because they are thermodynamically less favored than the corresponding allylsubstituted sulfoximines.…”