SuFExable Isocyanides for Ugi Reaction: Synthesis of Sulfonyl Fluoro Peptides

Xu, Shuheng; Cui, Sunliang

doi:10.1021/acs.orglett.1c01734

Cited by 14 publications

(10 citation statements)

References 59 publications

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“…An alternative strategy to obtain peptido sulfonyl fluorides offers the use of fluorosulfonyl isocyanides in an Ugi reaction . However, it shares similar limitations, especially with regard to substituted β-amino sulfonyl fluorides.…”

Section: Introductionmentioning

confidence: 99%

EnT-Mediated N–S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides

et al. 2023

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Sulfur(VI) fluoride exchange (SuFEx) gives rise to a plethora of high-valent sulfur linkages; however, the availability of (aliphatic) sulfonyl fluoride manifolds lag behind, owing to the limited sources of introducing the SO2F moiety via a classical two-electron approach. Recently, radical-based methodologies have emerged as a complementary strategy to increase the diversity of accessible click partners. In this work, synthesis of a bench-stable sulfamoyl fluoride reagent is presented, which may undergo sigma-bond homolysis upon visible-light-induced sensitization to form protected β-amino sulfonyl fluorides from alkene feedstocks. Notably, this offers an appealing strategy to access various building blocks for peptido sulfonyl fluorides, relevant in a medicinal chemistry context, as well as an intriguing entry to β-ammonium sulfonates and β-sultams, from alkenes. Densely functionalized 1,3-sultones were obtained by employing allyl alcohols as substrates. Surprisingly, allyl chloride-derived β-imino sulfonyl fluoride underwent S–O bond formation and ring closure to yield rigid cyclopropyl β-imino sulfonate ester under SuFEx conditions. Furthermore, by engaging a thiol-based hydrogen atom donor in the reaction, the reactivity of the same reagent can be tuned toward the direct synthesis of aliphatic sulfonyl fluorides. Mechanistic experiments indicate an energy transfer (EnT)-mediated process. The transient sulfonyl fluoride radical adds to the alkene and product formation occurs upon either radical–radical coupling or hydrogen atom transfer (HAT), respectively.

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Section: Introductionmentioning

confidence: 99%

EnT-Mediated N–S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides

et al. 2023

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“…Another feature unique to SuFEx is the growing number of versatile SuFExable hubs, including SO 2 F 2 , SOF 4 , ESF, BESF, and SASFs, [1, 16–21] that serve as robust connectors for creating diverse functional molecules and expanding the ever‐growing applications of click chemistry (Figure 1 b). [21–26] …”

Section: Introductionmentioning

confidence: 99%

Accelerated SuFEx Click Chemistry For Modular Synthesis**

et al. 2021

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SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S−O linkages upon exchange of S−F bonds with aryl silyl‐ether substrates, and while near‐perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs. We demonstrate Barton's hindered guanidine base (2‐tert‐butyl‐1,1,3,3‐tetramethylguanidine; BTMG) as a superb SuFEx catalyst that, when used in synergy with silicon additive hexamethyldisilazane (HMDS), yields stable S−O bond linkages in a single step; often within minutes. The powerful combination of BTMG and HMDS reagents allows for catalyst loadings as low as 1.0 mol % and, in congruence with click‐principles, provides a scalable method that is safe, efficient, and practical for modular synthesis. ASSC expands the number of accessible SuFEx products and will find significant application in organic synthesis, medicinal chemistry, chemical biology, and materials science.

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“…Isocyanide-substituted variants have also been reported and have been exploited in 4-component Ugi reactions to provide a-amino amide substituted sulfonyl fluorides (FIG. 4G) 124 . In 2019 and 2021, the Willis and Liao laboratories reported the synthesis of structurally diverse alkenylsulfonyl fluorides, respectively 33,70 .…”

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

169

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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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SuFExable Isocyanides for Ugi Reaction: Synthesis of Sulfonyl Fluoro Peptides

Cited by 14 publications

References 59 publications

EnT-Mediated N–S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides

EnT-Mediated N–S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides

Accelerated SuFEx Click Chemistry For Modular Synthesis**

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

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