General Method for the Asymmetric Synthesis of N–H Sulfoximines via C–S Bond Formation

Matos, Priscilla M.; Lewis, William; Argent, Stephen P.; Moore, Jonathan C.; Stockman, Robert A.

doi:10.1021/acs.orglett.0c00761

Cited by 35 publications

(11 citation statements)

References 62 publications

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“…Sulfur-stereogenic sulfoximines particularly bearing free N-H units are important structural motifs, which are often found in pharmaceutical and agricultural chemicals, natural products and biologically active compounds (Figure A). − The enantioselective synthesis of sulfoximines with a stereogenic S-center , is therefore a long-standing research topic in the organic synthetic community. Currently, catalytic asymmetric approaches targeting these compounds mainly include kinetic resolution (KR) , and desymmetrization, and are still highly desirable. In sharp contrast to the KR, the desymmetrization through catalytic enantioselective transformations is one of the most economic and powerful methods to approach chiral molecules.…”

Section: Introductionmentioning

confidence: 99%

Access to S-Stereogenic Free Sulfoximines via Bifunctional Phosphonium Salt-Catalyzed Desymmetrization of Bisphenols

et al. 2021

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Sulfur-stereogenic sulfoximines particularly with a free N-H unit exhibit intriguing chemical and biological activities, and thus have received continuous attention from chemists. However, there are currently no examples of guiding catalytic asymmetric strategies available to directly access these molecules. Herein, we disclose an efficient and practical protocol for the direct enantioenrichment of free N-H sulfoximines, via a bifunctional phosphonium salt-catalyzed desymmetrization triggered by the Atherton–Todd reaction together with a further extended nucleophilic acyl substitution-type reaction. A series of free N-H sulfoximines bearing an assortment of aromatic groups (70 examples) are tolerated in this desymmetrization with incidentally involving minority kinetic resolution (KR). The desymmetrized products can be easily transformed into chiral sulfoxides and other classes of active sulfur-stereogenic compounds. Mechanistic studies provided insights into the reaction pathway particularly suggesting a desymmetrization/KR synergic process, and also offered support on hydrogen-bonding interactions as the key elements to successful stereocontrol.

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Section: Introductionmentioning

confidence: 99%

Access to S-Stereogenic Free Sulfoximines via Bifunctional Phosphonium Salt-Catalyzed Desymmetrization of Bisphenols

et al. 2021

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“…Considerable advances have been made in recent years in the synthesis of sulfoximines and sulfonimidamides by the Bolm and Bull groups, as well as others, which have simplified the imination of thioethers, 10 sulfoxides, 11 and sulfenamides. 12 Sulfonimidates 13 and sulfinamides 14 are also established as useful intermediates toward these targets. However, these methods share the fundamental limitation of ultimately needing thiol starting materials, which can be unpleasant to use due to their odor, oxidize to form disulfides in air, and are not widely commercially available.…”

Section: Introductionmentioning

confidence: 99%

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides

et al. 2020

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Sulfoximines and sulfonimidamides are promising compounds for medicinal and agrochemistry. As monoaza analogues of sulfones and sulfonamides, respectively, they combine good physicochemical properties, high stability, and the ability to build complexity from a three-dimensional core. However, a lack of quick and efficient methods to prepare these compounds has hindered their uptake in molecule discovery programmes. Herein, we describe a unified, one-pot approach to both sulfoximines and sulfonimidamides, which exploits the high electrophilicity of sulfinyl nitrenes. We generate these rare reactive intermediates from a novel sulfinylhydroxylamine (R–O–N=S=O) reagent through an N–O bond fragmentation process. Combining sulfinyl nitrenes with carbon and nitrogen nucleophiles enables the synthesis of sulfoximines and sulfonimidamides in a reaction time of just 15 min. Alkyl, (hetero)aryl, and alkenyl organometallic reagents can all be used as the first or second component in the reaction, while primary and secondary amines, and anilines, all react with high efficiency as the second nucleophile. The tolerance of the reaction to steric and electronic factors has allowed for the synthesis of the most diverse set of sulfoximines and sulfonimidamides yet described. Experimental and computational investigations support the intermediacy of sulfinyl nitrenes, with nitrene formation proceeding via a transient triplet intermediate before reaching a planar singlet species.

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“…Due to the growing interest in accessing biologically relevant sulfur-based structural motifs, , several advances in the reactivity of sulfur functionalities have been reported during the past decade. , As an example, Stockman disclosed the electrophilic character of sulfonimidates in reactions with organometallic reagents (Scheme , a) . In detail, the reaction of Grignard reagents with sulfonimidates resulted in the stereospecific preparation of sulfoximines via the formation of a new S–C bond, by a formal substitution of the alkoxy group linked to the sulfur(VI) atom . Similarly, attack of organometals to sulfonates and sulfinates esters enabled the preparation of sulfones and sulfoxides, respectively, again by breaking an S-OR bond through a formal nucleophilic substitution reaction (Scheme , b and c). , We recently described the synthesis of hardly accessible sulfinimidate esters and sulfinamidines through a nitrogen transfer to sulfenamides .…”

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confidence: 99%

Sulfinimidate Esters as an Electrophilic Sulfinimidoyl Motif Source: Synthesis of N-Protected Sulfilimines from Grignard Reagents

et al. 2021

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In this work we investigated, for the first time, the reactivity of sulfinimidate esters as an electrophilic sulfinimidoyl motif source. The reaction of such sulfinimidate esters with Grignard reagents enables the preparation of protected sulfilimines in high yields and with a remarkable structural variability. Moreover, the transformation can be performed in CPME (cyclopentyl methyl ether) as a green solvent under environmentally responsible conditions.

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General Method for the Asymmetric Synthesis of N–H Sulfoximines via C–S Bond Formation

Cited by 35 publications

References 62 publications

Access to S-Stereogenic Free Sulfoximines via Bifunctional Phosphonium Salt-Catalyzed Desymmetrization of Bisphenols

Access to S-Stereogenic Free Sulfoximines via Bifunctional Phosphonium Salt-Catalyzed Desymmetrization of Bisphenols

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides

Sulfinimidate Esters as an Electrophilic Sulfinimidoyl Motif Source: Synthesis of N-Protected Sulfilimines from Grignard Reagents

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