A Simple Protocol for the Stereoselective Construction of Enaminyl Sulfonyl Fluorides

Leng, Jing; Tang, Wenjian; Fang, Wan‐Yin; Zhao, Chuang; Qin, Hua‐Li

doi:10.1021/acs.orglett.0c01360

Cited by 17 publications

(21 citation statements)

References 48 publications

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“…This new synthesis compliments Hyatt and Krutak's MnO 2 mediated dehydrogenation of β-fluorosulfonylethylamines (46) reaction of the 1-bromo-2-triazolethane-1-sulfonyl fluoride connective hub with amines reported by Qin et al (47). The assigned E-stereochemistry is consistent with the previously reported syntheses (46,47) and supported by trans-coupling constants J HA-HB ranging from 12.3 to 12.7 Hz. Replacing the -SO 2 F group of 5 with the corresponding-SO 2 CF 3 also led to desilylated products, ruling out the involvement of fluoride ions in the desilylation process.…”

Section: Resultssupporting

confidence: 89%

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Cheng

Smedley

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core “SuFExable” hubs—exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)—enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1 H -1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function – a key objective of click chemistry – of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

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Section: Resultssupporting

confidence: 89%

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Cheng

Smedley

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…[130] Important methods with a broad applicability to aliphatic, aromatic, and heterocyclic amines rely on the use of Ca(NTf 2 ) 2 in tert-amyl alcohol, [155] DABCO in THF, [156] DMAP, [157,158] and N-hydroxybenzotriazole (HOBt) with organosilicon additives (e. g. 1,1,3,3-tetramethyldisiloxane). [159] Synthesis of sulfonates via the SuFEx strategy included the use of both aliphatic alcohols (with Cs 2 CO 3 [160] or DBU [161] ) and phenols (with K 2 CO 3 , [162,163] Cs 2 CO 3 , [150,160,164,165] or DBU and NaHCO 3 [151] ). A general and efficient method applicable to both aliphatic and aromatic substrates was designed for O-silylated (TMS or TBDMS) derivatives including their reaction with sulfonyl fluorides in the presence of DBU in MeCN [166][167][168][169][170] or TBAF in THF.…”

Section: Applications In Synthetic and Medicinal Chemistrymentioning

confidence: 99%

“…[299] Promising building blocks could be obtained from bulk amino esters used. [294] BTESF (45, 1-bromo-2-(triazol-1-yl)ethanesulfonyl fluoride) [165] represents an example of a versatile building block that can be obtained by the "click" reaction of 2-azido-1bromoethane-1-sulfonyl fluoride (46) and ethynylbenzene (Scheme 21, A). BTESF reacts with amines to give functionalized enamines via the E 2 elimination reaction of the triazolyl residue after the initial elimination of HBr and the Michael addition (B).…”

Section: Synthesis Of αβ-Unsaturated Sulfonyl Fluoridesmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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Current medicinal chemistry relies heavily on the quality of building blocks, i. e. reagents used to introduce chemical diversity into the target molecules. The last decade witnessed an emergence of many novel (or well-overlooked old) chemotypes for drug discovery, which is related to adapting new synthetic methodologies, designing new sp 3 -enriched bioisosteres, paying attention to previously underrated (or even unwanted) structural motifs, or combination thereof. In this review with 532 references, a survey of selected chemotypes that emerged recently in medicinal chemistry is provided, with a focus on the synthesis of the corresponding building blocks. Thus, saturated (hetero)aliphatic boronates, sulfonyl fluorides, sulfinates, non-classical sp 3 -enriched benzene isosteres, bicyclic morpholine/piperidine/piperazine analogs, as well as gemdifluorinated cycloalkanes (as an example of emerging fluorinated motifs) are discussed.

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“…Derivatives of ESF have also been studied 2, [116][117][118][119][120] . Bromination of the alkene produced 1,2-dibromoethane-1-sulfonyl fluoride (DESF), and subsequent elimination yielded 1-bromoethene-1-sulfonyl fluoride (BESF) 117,118 .…”

Section: Multifunctional Sulfonyl Fluoride Reagentsmentioning

confidence: 99%

Sulfonyl fluorides as targets and substrates in the development of new synthetic methods

Lou

Willis²

2022

Nat Rev Chem

120

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The advent of sulfur(VI)-fluoride exchange (SuFEx) processes as transformations with click-like reactivity has invigorated research into electrophilic species featuring a sulfur-fluorine bond. Amongst these, sulfonyl fluorides have emerged as the work-horse functional group, with diverse applications being reported. Sulfonyl fluorides are used as electrophilic warheads by both medicinal chemists and chemical biologists. The balance of reactivity and stability that is so attractive for these applications, particularly the resistance of sulfonyl fluorides to hydrolysis under physiological conditions, has provided opportunities for synthetic chemists. New synthetic approaches that start with sulfur-containing substrates include the activation of sulfonamides using pyrilium salts, the deoxygenation of sulfonic acids, and the electrochemical oxidation of thiols. Employing non-sulfur containing substrates has led to the development of transition-metal-catalysed processes based on palladium, copper and nickel, as well as the use of SO2F2 gas as an electrophilic hub. Selectively manipulating molecules that already contain a sulfonyl fluoride group has also proven to be a popular tactic, with metal-catalysed processes again at the fore. Finally, coaxing sulfonyl fluorides to engage with nucleophiles, when required, and under suitable reaction conditions, has led to new activation methods. This review provides an overview of the challenges in the efficient synthesis and manipulation of these intriguing functional groups.

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A Simple Protocol for the Stereoselective Construction of Enaminyl Sulfonyl Fluorides

Cited by 17 publications

References 48 publications

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Sulfonyl fluorides as targets and substrates in the development of new synthetic methods

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