Serhii Zhersh

An efficient sulfuryl fluoride‐enabled synthesis of benzo[ e ][1,2,3]oxathiazine‐4(3 H )‐one‐2,2‐dioxides from salicylic amides is described. Salicylamides were prepared on a multigram scale, and the corresponding cyclic sulfamates were synthesized via operationally simple one‐pot Et ₃ N‐promoted [5 + 1] cyclization. In some cases, intermediate products of O ‐sulfonylation (fluorosulfates) were isolated. The method was suitable for both primary and secondary salicylic amides, albeit the use of a stronger base was necessary for sterically hindered substrates. The synthetic utility of the obtained heterocycles was demonstrated by their further chemical transformations. In particular, 4‐chloro derivatives were obtained by deoxochlorination and converted into various cyclic aminosulfamates on a multigram scale. Derivatives bearing a bromine atom in the benzene ring were subjected to Pd‐catalyzed couplings without affecting the sulfamate ring. Physicochemical properties of a representative virtual library derived from the synthesized scaffolds met the criteria of lead‐likeness guidelines.

Alkenyl fluorosulfates are evaluated as the partners of palladium-catalyzed cross-coupling reactions and alternative to more common triflates and halides. Efficient protocols for the multigram synthesis of title reactants using reaction of carbonyl compounds with SO ₂ F ₂ were documented. Reactivity of alkenyl fluorosulfates in Suzuki, Sonogashira, Heck, Stille, and Buchwald-Hartwig reactions, as well as Miyaura borylation under typical conditions was studied, and limitations of the methods were established. It was found that alkenyl flurosulfates have similar or even higher reactivity in the cross-coupling reactions as compared to alkenyl triflates.

A robust and scalable synthetic platform that provides broad access to thietane-based building blocks is disclosed, covering three oxidation states of sulfur, S(II), S(IV), and S(VI). Starting from readily available thietan-3-one or epithiochlorohydrin, a diverse series of 3-substituted and 3,3-disubstituted thietanes were prepared, including carboxylic acids, primary and secondary amines, alcohols, hydrazines, alkyl halides, sulfonyl halides, etc. The synthetic utility of these fragments was illustrated by the synthesis of thietane-based analogs of a marketed N-acyl sulfonamide drug. Furthermore, a systematic study of the physicochemical properties of the new thietane building blocks was performed in direct comparison with oxetane, azetidine, and cyclobutane analogs. The pKa data for amines and carboxylic acids, along with LogD measurements for model benzamides and anilides, revealed clear structure-property trends depending on the oxidation state of the sulfur atom. While S (II) thietane derivatives remained close to cyclobutane in terms of lipophilicity, S (IV) and S (VI) counterparts were markedly less lipophilic and more acidic/less basic as compared to other model derivatives, even surpassing oxetane in polarity. These findings support the concept of thietane as a versatile “three-in-one” fragment, which sulfur oxidation state can be used to finely modulate ionization state and lipophilicity, enabling the rational design of sp³-rich, polarity-tuned building blocks for modern drug discovery.

In 2012, bicyclo[1.1.1]pentanes were demonstrated to be bioisosteres of the benzene ring. Here, we report a general scalable reaction between alkyl iodides and propellane that provides bicyclo[1.1.1]pentane iodides in milligram, gram and even kilogram quantities. The reaction is performed in flow and requires just light; no catalysts, initiators or additives are needed. The reaction is clean enough that, in many cases, evaporation of the reaction mixture provides products in around 90% purity that can be directly used in further transformations without any purification. Combined with the subsequent functionalization, >300 bicyclo[1.1.1]pentanes for medicinal chemistry have been prepared. So far, this is the most general and scalable approach towards functionalized bicyclo[1.1.1]pentanes.

The chemoselectivity of halo(het)arene sulfonyl halide aminations is studied thoroughly under parallel synthesis conditions, and the scope and limitations of the method are established. It is shown that S_NAr-reactive sulfonyl halides typically undergo sulfonamide synthesis during the first step; the second amination is also possible provided that the S_NAr-active center is sufficiently reactive. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper control. Further sulfur-fluoride exchange (SuFEx) is also possible, which can be especially valuable for some sulfonyl halide classes. The developed two-step parallel double amination protocol provides access to a 6.67-billion compound synthetically tractable REAL-type chemical space (76% expected synthesis success rate).

Запропоновано препаративний підхід до синтезу низки нових насичених нітрогеновмісних гетероциклічних сульфінатів — перспективних біфункціональних будівельних блоків для потреб органічної та медичної хімії. Метод ґрунтується на використанні як вихідних речовин N-Boc-захищених гетероциклічних аміноспиртів і передбачає їх перетворення на тіопіримідильні похідні, подальше окиснення та основне розщеплення утворених сульфонів. Для кожної із стадій проведено оптимізацію умов перебігу процесу з огляду на необхідність одержання багатограмових кількостей цільових сполук. Після незначної модифікації підхід виявився придатним для синтезу оптично чистих сполук. Перспективи використання синтезованих сульфінатів продемонстровано їх перетворенням на відповідні сульфонамідні похідні.

Advances in chemoproteomic technology have revealed covalent interactions between small molecules and protein nucleophiles, primarily cysteine, on a proteome-wide scale. Most chemoproteomic screening approaches are indirect, relying on competition between electrophilic fragments and a minimalist electrophilic probe with inherently limited proteome coverage. Here we develop a chemoproteomic platform for direct electrophile-site identification based on enantiomeric pairs of clickable arylsulfonyl fluoride probes. Using stereoselective site modification as a proxy for ligandability in intact cells, we identify 634 tyrosines and lysines within functionally diverse protein sites, liganded by structurally diverse probes. Among multiple validated sites, we discover a chiral probe that modifies Y228 in the MYC binding site of the epigenetic regulator WDR5, as revealed by a high-resolution crystal structure. A distinct chiral probe stimulates tumour cell phagocytosis by covalently modifying Y387 in the recently discovered immuno-oncology target APMAP. Our work provides a deep resource of ligandable tyrosines and lysines for the development of covalent chemical probes.

In 2012, bicyclo[1.1.1]pentanes were demonstrated to be bioisosteres of the phenyl ring. Today, after more than a decade, the difficulty in their large-scale preparation is still a problem, that often outweighs the corresponding derivatives to becoming clinical candidates. Here, we report a practical general reaction that gives bicyclo[1.1.1]pentanes on mg- to kg-quantities using just light. No additional additives or catalysts are needed. Using this strategy, we have prepared >300 functionalized bicyclo[1.1.1]pentanes on a (multi)gram scale. So far, this is the most general and practical approach to bicyclo[1.1.1]pentanes. Many of these molecules, which were previously commercialized, are already being used in drug discovery by pharmaceutical companies Gilead Sciences, Hoffman-La Roche, Idorsia, Merck, Janssen Pharm., etc. This work should ease the transition of bicyclo[1.1.1]pentane-containing bioactive compounds to clinical candidates, and subsequently to drugs.

Saturated bicyclic sultams represent a promising class of sp³‐rich three‐dimensional scaffolds of outmost importance to organic and medicinal chemistry. In this review with 99 references, synthesis, properties, and applications of these compounds are surveyed. The literature data are categorized according to the structural types (i.e. fused, bridged, and spirocyclic compounds), as well as homologous series (from β‐ to ε‐sultams). It is shown that most of the approaches are based on the construction of the sultam ring; these methods include intramolecular N‐sulfonylations, sulfonamide N‐alkylations, carbanion‐mediated sulfonamide intramolecular cyclizations (CSIC), ring‐closing metathesis, Michael additions, aza‐Prins reaction, as well as both intra‐ and intermolecular [2+2] and [3+2] cycloadditions and other transformations.

One‐pot intramolecular cyclization of novel sp³‐enriched cyanoalkylsulfonyl fluorides into spirocyclic β‐ or γ‐sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH₄, NiCl₂·6H₂O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48–84 %, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S‐nucleophilic substitution in β‐functionalized alkanenitriles or double alkylation of α‐alkylthioacetonitrile, followed by oxidative chlorination with Cl₂ and further reaction with KHF₂. The title mono‐ and bifunctional sultams are advanced sp³‐enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.