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A general phase‐transfer catalyst (PTC) mediated enantioselective alkylation of N‐acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at −40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S‐(hetero)aryl and branched and unbranched S‐alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever‐increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free‐NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)‐sulfoximine stereoisomer. [ABSTRACT FROM AUTHOR]

A general one‐pot approach to diverse N‐acylsulfenamides from a common S‐phenethylsulfenamide starting material is reported. This approach was demonstrated by C−S bond formation utilizing commercially abundant (hetero)aryl iodides and boronic acids to provide sulfilimine intermediates that undergo thermal elimination of styrene. In contrast, all prior approaches to N‐acylsulfenamides rely on thiol inputs to introduce sulfenamide S‐substituents. A broad scope of reaction inputs was demonstrated including for approved drugs and drug precursors with dense display of functionality. Several different types of sulfur functionalization were performed on a sulfenamide derived from a complex precursor of the blockbuster anticoagulant drug apixaban, highlighting the utility of this approach for the introduction of high oxidation state sulfur groups in complex bioactive compounds. Mechanistic studies established that the key styrene elimination step proceeds by a concerted elimination that does not require reagents or catalysts, and therefore, this one‐pot approach should be applicable to the synthesis of N‐acylsulfenamides utilizing diverse electrophiles and reaction conditions for C−S bond formation. [ABSTRACT FROM AUTHOR]

A general phase-transfer catalyst (PTC) mediated enantioselective alkylation of N-acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at -40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S-(hetero)aryl and branched and unbranched S-alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever-increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free-NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)-sulfoximine stereoisomer., (© 2024 Wiley-VCH GmbH.)

A general one-pot approach to diverse N-acylsulfenamides from a common S-phenethylsulfenamide starting material is reported. This approach was demonstrated by C-S bond formation utilizing commercially abundant (hetero)aryl iodides and boronic acids to provide sulfilimine intermediates that undergo thermal elimination of styrene. In contrast, all prior approaches to N-acylsulfenamides rely on thiol inputs to introduce sulfenamide S-substituents. A broad scope of reaction inputs was demonstrated including for approved drugs and drug precursors with dense display of functionality. Several different types of sulfur functionalization were performed on a sulfenamide derived from a complex precursor of the blockbuster anticoagulant drug apixaban, highlighting the utility of this approach for the introduction of high oxidation state sulfur groups in complex bioactive compounds. Mechanistic studies established that the key styrene elimination step proceeds by a concerted elimination that does not require reagents or catalysts, and therefore, this one-pot approach should be applicable to the synthesis of N-acylsulfenamides utilizing diverse electrophiles and reaction conditions for C-S bond formation., (© 2023 Wiley-VCH GmbH.)