Sulfondiimidamides as new functional groups for synthetic and medicinal chemistry

Zhang, Ze-Xin; Willis, Michael C.

doi:10.1016/j.chempr.2022.02.013

Cited by 52 publications

(37 citation statements)

References 42 publications

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“…In addition to vigorous interest in the development of new synthetic procedures towards sulfonimidamides (Nandi & Arvidsson, 2018;Chen & Gibson, 2015;Wen et al, 2016;Izzo et al, 2017;Greed et al, 2020;Liu et al, 2021), activities towards the synthesis of sulfondiimides have recently just begun (Zhang et al, 2019;Bohmann et al, 2019). With the synthesis of stable sulfondiimidamides, Zhang & Willis (2022) introduced a new functional group for medicinal chemistry.…”

Section: Chemical Contextmentioning

confidence: 99%

Synthesis and crystal structure of rac-2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfondiimidoate: the first member of a new substance class

Friedrich¹,

Heinrich²,

Rosenberger³

et al. 2022

Acta Cryst E

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The title compound {systematic name: rac-2-[7-methyl-4-(4-methylphenyl)-4-(phenylimino)-6,6-bis(propan-2-yl)-3-oxa-4λ6-thia-5-aza-6-silaoct-4-en-1-yl]-2,3-dihydro-1H-isoindole-1,3-dione}, C32H41N3O3SSi, was synthesized by desoxychlorination of 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfonimidamide and subsequent reaction with 2-(2-hydroxyethyl)isoindoline-1,3-dione. The racemic compound was crystallized from isopropanol. The structural characterization by single-crystal X-ray diffraction revealed two double-bonded nitrogen atoms to the central sulfur atom and an overall crystal packing driven by its aromatic interactions.

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Section: Chemical Contextmentioning

confidence: 99%

Synthesis and crystal structure of rac-2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfondiimidoate: the first member of a new substance class

Friedrich¹,

Heinrich²,

Rosenberger³

et al. 2022

Acta Cryst E

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“…While sulfonamides 5 in particular, and to a lesser extent sulfones 2 and sulfoxides 1 (Figure 1), are found in many approved drugs, [1,2] a large variety of sulfur‐based functional groups has historically been neglected in drug discovery [3] . However, in recent years underexplored functional groups such as sulfoximines 3 , [3b,4] sulfondiimines 4 , [3b] sulfonimidamides 6 , [3b,5] sulfondiimidamides 7 [6] and sulfur fluorides like the pentafluorosulfanyl group (SF 5 ) 8 [7] have started to attract an increasing interest from drug designers.…”

Section: Introductionmentioning

confidence: 99%

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

Lücking¹

2022

Chemistry A European J

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Extension of the medicinal chemistry toolbox is in the vital interest of drug designers. However, the diffusion of an innovation can be a lengthy process. Along these lines, it took almost 70 years before the use of the sulfoximine group reached a critical mass in medicinal chemistry. Even though interest in this versatile functional group has increased exponentially in recent years, there is ample room for further innovative applications. This Review highlights emerging trends and opportunities for drug designers for the utilization of the sulfoximine group in medicinal chemistry, such as in the construction of complex molecules, proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and novel warheads for covalent inhibition.

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“…Sulfondiimidamides, the double aza-variants of sulfonamides, provide an exciting platform for the design of new bioactive molecules . Building on many of the favorable attributes of sulfonamides, the addition of two imidic N-groups presents multiple opportunities to manipulate their properties (Figure a).…”

Section: Introductionmentioning

confidence: 99%

“…Neither of these routes are amenable to discovery chemistry, in which the preparation of a diverse collection of molecules using simple, reliable procedures is needed. To address these shortcomings we recently reported a route to sulfondiimidamides starting from organometallic reagents and proceeding through key sulfondiimidoyl fluoride intermediates . The route is summarized in Figure c, and involves addition of organometallic reagents to an unsymmetrical sulfurdiimide ( 1a ), followed by N-nosyl-protection, providing sulfinamidines 3 .…”

Section: Introductionmentioning

confidence: 99%

Modular Two-Step Route to Sulfondiimidamides

et al. 2022

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Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.

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Sulfondiimidamides as new functional groups for synthetic and medicinal chemistry

Cited by 52 publications

References 42 publications

Synthesis and crystal structure of rac-2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfondiimidoate: the first member of a new substance class

Synthesis and crystal structure of rac-2-(1,3-dioxoisoindolin-2-yl)ethyl 4-methyl-N-phenyl-N′-(triisopropylsilyl)benzenesulfondiimidoate: the first member of a new substance class

New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**

Modular Two-Step Route to Sulfondiimidamides

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