Acidities of sulfoximines and related oxosulfonium cations. Cyclopropyl effects and structures of .alpha.-sulfonyl-type carbanions

Bordwell, F. G.; Branca, John C.; Johnson, Carl R.; Vanier, Noel R.

doi:10.1021/jo01307a030

Cited by 70 publications

(30 citation statements)

References 5 publications

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“…This observation is in agreements that the acidity of alkylarylsulfoxides (p K a ~ 33)26 is much weaker than that of the corresponding sulfone (p K a ~ 29) 27. Like the sulfone, the sulfoxide group exerts a significant stereoelectronic effect on the barrier height.…”

Section: Resultssupporting

confidence: 74%

“…The experiments indicate that the sulfoxide analogue of SB-3CT is a linear competitive inhibitor of MMP2 that does not undergo ring opening, despite the structural similarity between these two species. The acidity of alkylarylsulfoxides (approximate p K a = 33)26 is significantly weaker than that of the corresponding sulfone (approximate p K a = 29) 27. This computational study tests whether the reduced carbon acidity of the sulfoxide analogue of SB-3CT could account for the fact that it is a poorer inhibitor of MMP2.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Matrix Metalloproteinase 2 (MMP2) Inhibition: DFT and QM/MM Studies of the Deprotonation-Initialized Ring-Opening Reaction of the Sulfoxide Analogue of SB-3CT

et al. 2009

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(4-Phenoxyphenylsulfonyl)methylthiirane (SB-3CT) is the selective inhibitor of matrix metalloproteinase 2 (MMP2). The inhibition mechanism of MMP2 by SB-3CT involves C–H deprotonation with concomitant opening of the three-membered heterocycle. In this study, the energetics of the deprotonation-induced ring opening of (4-phenoxyphenylsulfinyl)methylthiirane, the sulfoxide analogue of SB-3CT, are examined computationally using DFT and QM/MM calculations. A model system, 2-(methylsulfinylmethyl)thiirane, is used to study the stereoelectronic and conformational effects of reaction barriers in methanol. For the model system in methanol solution (using polarizable continuum model), the reaction barriers range from 17 to 23 kcal/mol with significant stereoelectronic effects. However, the lowest barriers of the (R, R) and (S, R) diastereomers are similar. Two diastereomers of the sulfoxide analogue of SB-3CT are studied in the active site of MMP2 by QM/MM methods with an accurate partial charge fitting procedure. The ring opening reactions of these two diastereomers have similar reaction energetics. Both are exothermic from the reactant to the ring opening product (thiolate). The protonation of the thiolate by a water molecule is endothermic in both cases. However, the deprotonation / ring opening barriers in the MMP2 active site using QM/MM methods for the (R, R) and (S, R) inhibitions are quite different (23.3 and 28.5 kcal/mol, respectively). The TSs identified in QM/MM calculations were confirmed by vibrational frequency analysis and reaction path following. The (R, R) diastereomer has hydrogen bond between the sulfoxide oxygen and the backbone NH of Leu191, while the (S, R) has hydrogen bond between the sulfoxide oxygen and a water molecule. The dissimilar strengths of these hydrogen bonds as well as minor differences in the TS structures contribute to the difference between the barriers. Compared to SB-3CT, both diastereomers of the sulfoxide analogue have higher reaction barriers, and have less exothermic reaction energies. This agrees well with the experiments that SB-3CT is a more effective inhibitor of MMP2 than its sulfoxide analogue.

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Section: Resultssupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase 2 (MMP2) Inhibition: DFT and QM/MM Studies of the Deprotonation-Initialized Ring-Opening Reaction of the Sulfoxide Analogue of SB-3CT

et al. 2009

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“…For conjugated carbanions, as in enolate ions that require the carbanion carbon to be planar, the cyclopropyl anions have lower stabilities than simple alkyl anions [17]. The crystal structure of a phenylsulfonylcyclopropyllithium shows a highly pyramidal carbanionic carbon [18]; yet the equilibrium acidity studies of Bordwell's group in DMSO show that cyclopropyl sulfones are generally less acidic than the corresponding methyl or isopropyl sulfones [19,20].…”

Section: Resultsmentioning

confidence: 99%

Carbon acidity. 97. Cesium ion pair acidity of some sulfones in cyclohexylamine

Streitwieser

Schriver

1997

Heteroatom Chem.

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“…Die Eigenschaften des Substituenten am Stickstoffatom haben einen ausgeprägten Einfluss auf die Säure/Base-Eigenschaften der Verbindung. [1,17] [19] Auf der Suche nach einer neuen Leitstruktur für antiasthmatische Wirkstoffe mit geringeren Nebenwirkungen und einem breiteren Wirkspektrum als bei klassischen Anticholinergika wie Atropin (6) oder Oxyphenoniumbromid (7; Abbildung 3) führte das…”

Section: Allgemeine Eigenschaften Von Sulfoximinenunclassified

Sulfoximine: Eine vernachlässigte Chance in der medizinischen Chemie

Lücking

2013

Angewandte Chemie

124

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Innovation ist häufig als der Schlüssel zur Wirkstoff‐Findung beschrieben worden. Doch in der täglichen Routine neigen Medizinalchemiker dazu, nur das Instrumentarium der funktionellen Gruppen und Strukturelemente zu verwenden, das sie bereits kennen und lieben. Das Blockbuster‐Krebsmedikament Velcade (Bortezomib) wurde beispielsweise von mehr als 50 Unternehmen abgelehnt, vermutlich wegen seiner ungewöhnlichen Boronsäuregruppe (“Only a moron would put boron in a drug!”). Auch im Entwicklungsprozess des pan‐CDK‐Inhibitors BAY 1000394 sorgte der unkonventionelle Vorschlag, eine Sulfoximingruppe in die Leitstruktur einzuführen, zunächst für Spott und Stirnrunzeln, da Sulfoximine selten in der medizinischen Chemie verwendet worden sind. Jedoch war es gerade die Sulfoximingruppe, die es schließlich ermöglichte, die fundamentalen Probleme des Projekts zu überwinden, und so zur Identifizierung des klinischen pan‐CDK‐Inhibitors BAY 1000394 führte. Der vorliegende Kurzaufsatz gibt einen Überblick über eine weithin vernachlässigte Chance in der medizinischen Chemie – die Sulfoximingruppe.

show abstract

Acidities of sulfoximines and related oxosulfonium cations. Cyclopropyl effects and structures of .alpha.-sulfonyl-type carbanions

Cited by 70 publications

References 5 publications

Matrix Metalloproteinase 2 (MMP2) Inhibition: DFT and QM/MM Studies of the Deprotonation-Initialized Ring-Opening Reaction of the Sulfoxide Analogue of SB-3CT

Matrix Metalloproteinase 2 (MMP2) Inhibition: DFT and QM/MM Studies of the Deprotonation-Initialized Ring-Opening Reaction of the Sulfoxide Analogue of SB-3CT

Carbon acidity. 97. Cesium ion pair acidity of some sulfones in cyclohexylamine

Sulfoximine: Eine vernachlässigte Chance in der medizinischen Chemie

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