Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Smedley, Christopher J.; Li, Gencheng; Barrow, Andrew S.; Gialelis, Timothy L.; Giel, Marie‐Claire; Ottonello, Alessandra; Cheng, Yunfei; Kitamura, Seiya; Wolan, Dennis W.; Sharpless, K. Barry; Moses, John E.

doi:10.1002/ange.202003219

Cited by 36 publications

(18 citation statements)

References 74 publications

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“…In this view, alkynyl sulfonyl fluorides 38 provided particularly diverse patterns of heterocycles bearing the SO 2 F moiety (Scheme 18). [166,288]…”

Section: Synthesis Of (Hetero)aromatic 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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“…In this view, alkynyl sulfonyl fluorides 38 provided particularly diverse patterns of heterocycles bearing the SO 2 F moiety (Scheme 18). [166,288]…”

Section: Synthesis Of (Hetero)aromatic Sulfonyl Fluoridesmentioning

confidence: 99%

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

2021

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“…Sulfur fluoride exchange (SuFEx) (10), a new generation of click chemistry, has found diverse applications to chemical synthesis (11)(12)(13)(14)(15)(16), materials science (17)(18)(19)(20)(21)(22), chemical biology (23)(24)(25)(26)(27)(28), and drug discovery (29,30). In our previous studies, we demonstrated that SuFEx modification is a highly reliable approach for the late-stage functionalization of drugs and drug-like molecules to generate new compounds with improved properties (31,32).…”

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confidence: 99%

Identification of simple arylfluorosulfates as potent agents against resistant bacteria

Zhang

Zhao

Cappiello

et al. 2021

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

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Sulfur fluoride exchange (SuFEx), a next generation of click chemistry, opens an avenue for drug discovery. We report here the discovery and structure–activity relationship studies of a series of arylfluorosulfates, synthesized via SuFEx, as antibacterial agents. Arylfluorosulfates 3, 81, and 101 showed potency to overcome multidrug resistance and were not susceptible to the generation of resistance. They exhibited rapid bactericidal potency and selectively killed gram-positive bacterial strains. These compounds also exhibited the ability to disrupt established bacterial biofilm and kill persisters derived from biofilm. Furthermore, arylfluorosulfate 3 had a synergistic effect with streptomycin and gentamicin. In addition, their anti-MRSA potency was evaluated and determined by the Caenorhabditis elegans model.

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“…Sulfonyl fluoride reagents have been espoused by Sharpless as click reagents for the reaction with nucleophiles to form sulfonates and sulfonamides, in a process referred to as a SuFEx (sulfur-fluoride exchange) reaction. 5,6,7,28 As first demonstrated in seminal works by Steinkopf 29,30 and others, 31,32,33 the stronger and highly polarised S-F bond confers vastly increased stability to sulfonyl fluorides in comparison to sulfonyl chlorides. The fluoride ion is a poor leaving group and consequently sulfonyl fluorides are highly stable towards nucleophilic substitution as well as reductive and aqueous conditions.…”

Section: Resultsmentioning

confidence: 94%

Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides

et al. 2022

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Bioisosteres provide valuable design elements for medicinal chemists to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides, an extremely common pharmacophore, but are rarely examined due to the lack of available synthetic methods. Here, we describe a new class of reactions for sulfonyl fluorides to form aminooxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. An unprecedented defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared.Kinetic and computational studies support the formation of an oxetane carbocation as the rate determining step, followed by a chemoselective nucleophile coupling step.New reaction classes have enormous potential to access underexplored chemical space and influence molecular design. 1,2 A limited set of reliable and predictable reactions continue to have a disproportionate influence on the ability to construct medicinal and agrochemical compounds. 3 Such reactions can enable rapid access to derivatives, while also influencing, and limiting, molecular design. Most notably, click reactions have had an enormous impact in the chemical and biological sciences, which proceed on complex substrates without stringent conditions. 4,5,6,7 In drug discovery, amide bond formation continues to be the most common reaction, 3 exploiting vast amine and carboxylic acid libraries available to pharmaceutical companies. Amides are therefore prevalent in marketed pharmaceutical and agrochemical compounds, and display valuable features being more stable than other carbonyl derivatives, powerful H-bond donors and acceptors, and ubiquitous as critical bonding units in natural peptides and proteins. 8 Nonetheless, the amide sub-structure will frequently not provide the subtle balance of properties that is required for a successful active ingredient. Consequently, bioisosteres of amides are also common, providing a mimic of the features of the amide and adjusting the global properties of a compound. 9,10,11 While amidation is extensively investigated, with powerful, mostly stoichiometric coupling reagents, 12 the same cannot be said for amide-isosteres, which often require bespoke synthetic efforts (Fig. 1a).3,3-Disubstituted oxetanes have garnered considerable interest as carbonyl replacements, due to the similar dipole moments, hydrogen-bonding capacity, and oxygen lone pair orientation. 13,14 Their use as a bioisostere or replacement group also introduces a more 3-dimensional element to a drug compound that can have beneficial binding and solubility effects. 15 The motif is exemplified by antiviral Ziresovir, bear...

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Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Cited by 36 publications

References 74 publications

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

Identification of simple arylfluorosulfates as potent agents against resistant bacteria

Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides

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