Андріашвілі Владислав АльбертовичТолмачов Андрій Олексійович2024-07-012024-07-012024Андріашвілі В. А. Хемо- та стереоселективний синтез сульфонамідів : дис. ... д-ра філософії : 102 : Хімія / наук. кер. А. О. Толмачов. Київ, 2024. 199 с.УДК 547.542+ 547.368.2https://ir.library.knu.ua/handle/15071834/2461The dissertation is devoted to the study of synthesis of functionalized sulfonamides, proceeded with preservation of the configuration of the starting compounds (for stereoselective syntheses) or with preservation of potentially active functional groups of the side chain (for chemoselective syntheses). Taking into account the long history of sulfonylamides and the fairly high number of methods for their synthesis, a literature study and comparison of sulfonyl chlorides and sulfonyl fluorides (as the main sources of the sulfonyl fragment) in the reactions of polyfunctional sulfur-containing substrates was conducted. It was shown that even considering the longer time since the beginning of the use of sulfonyl chlorides in organic synthesis, sulfonyl fluorides are much more desirable for chemoselective transformations. Moreover, this regularity is reproduced either for reactions with the preservation of an active sulfonyl group and for the reaction on the Sulfur atom with the preservation of potentially active side functional group. It is worth noting that for the chemoselective synthesis of sulfonamides (the most widespread type of modifications), more than 90% of the known literature sources consist of sulfonyl fluoride reactions. The main advantage of sulfonyl chlorides over sulfonyl fluorides for this reaction is demonstrated on the reactions of α,β-unsaturated sulfonyl halides exclusively – being an excellent Michael acceptor, (substituted) vinyl sulfonyl fluorides produce only the corresponding Michael addition products to a multiple bond or a double addition-substitution reaction in case of using of an excess nucleophile. One of the promising directions for the development of sulfonamide synthesis methodology is sulfinate transformations. In the work, the scope of application of the Paras method for the synthesis of sp3-enriched sulfinates, precursors of the corresponding sulfonamides, was tested and expanded. It was shown that the Mitsunobu reaction (the key step in the synthesis of the active intermediate) is not necessary for most of the objects, in particular those that were racemates or had no chiral centers at all. At the same time, the synthesis of optically active compounds required the Mitsunobu reaction, since the previously proposed method led to a significant loss of the optical purity of the target compounds. In addition, in order to optimize the procedure for the large-scale synthesis of the corresponding sulfinates, a safe alternative to peroxide oxidants was found: using NaIO4 as a stoichiometric oxidant in the presence of a catalytic amount of RuCl3·3H2O in the H2O – CH3CN – CCl4 system. Aforementioned sulfinates were tested in the reaction with hydroxylamine-Osulfonic acid, producing stereochemically pure sulfonamides. As a result, a number of regularities were established. In particular, the significant dependence of the reaction yield on the nature of the substituents on the Nitrogen atom in the hydroxylamine molecule. Thus, the reaction proceeded quickly and with high yields for primary aliphatic amines derivatives; the use of secondary or tertiary amine derivatives slightly slowed the process without significantly affecting the product yield, while N-hydroxy derivatives of pyrrolidine (a secondary cyclic amine) and aniline did not give the desired product under any conditions. It is worth noting that this approach showed a high tolerance for optical purity - for all products, ee values the corresponding alcohols was retained, and for 1,3-disubstituted cyclobutane derivatives, the corresponding values of the diastereomeric excess were observed. The chemoselectivity of the sulfonamide synthesis for a library of bifunctional sulfonyl chloride or sulfonyl fluoride-containing compounds was investigated. At the first step of the study, it was shown that the sulfonyl chloride group shows exceptional selectivity and reacts firstly during the competitive process of the aromatic nucleophilic substitution in the corresponding substrates. As a result, in parallel synthesis of aminosulfonylamides from selected series of sulfonyl chlorides and amines, 259 products were obtained in pure form from the theoretically possible 410 members of the library, which is equivalent to 63% success rate of the synthesis methodology. In addition, the possibility of stepwise amination of SNAr-reactive SO2Cl-containing substrates was studied. This approach was found to produce the corresponding sulfonamides with a greater than 69% success rate, mainly limited with SNAr-inactive substrates. At the same time, sulfonyl fluorides required more harsh conditions for the synthesis of the corresponding sulfonamides. In that case complete reversal of the selectivity order was found – for sulfonyl fluorides derivatives arylation step seems to be dominant, especially among the electron-deficient substrates (such as fluoropyridine, α-chloropyrimidine, α-chloropyrazine and αchlorothiazole). The possibility of stepwise amination was also tested – in this case, a 94% synthesis success rate was achieved on a library of 237 theoretical products with an average yield of 52%. Based on the previous results, the theoretical products of the double sequential amidation-arylation reaction of the investigated sulfonyl chlorides with commercially available amines were generated. As a result, a theoretical chemical space of 6.67 billion chemical compounds achievable by simple chemical synthesis (the so-called REAL database) was created. The analysis of the obtained database showed that from a medical chemical point of view represented compounds are mostly outside the Ro5 rule (about 68%), but 32% can be characterized as drug-like compounds (among which 110 million compounds corresponds to the "rule of four ", and 52 million – to the strictest Churcher’s rules). Comparison of the created space with known databases of known compounds (in particular, ChEMBL (v.33), PubChem, ZINC15 and the stock collection of compounds of Enamine) by calculating Tanimoto similarity coefficients and using tSNE approach showed the high uniqueness of the created set. At the same time, among the 115 compounds present in the ChEMBL database, a number of compounds with already confirmed biological activity were found, demonstrating the utility of this approach for creating new libraries in the early stages of drug development.Дисертаційна робота присвячена вивченню реакцій синтезу функціоналізованих сульфонамідів, що протікають зі збереженням конфігурації вихідних сполук (для стереоселективних синтезів) або зі збереженням потенційно активних функціональних груп бічного ланцюга (для хемоселективних синтезів). Враховуючи давню історію сульфонамідів та досить широке відоме навіть із загальної хімічної ерудиції коло методів для їх синтезу, було проведено літературне дослідження та порівняння сульфонілхлоридів та сульфонілфлуоридів (як основних джерел сульфонільного фрагменту) у реакціях поліфункціональних Сульфур-вмісних субстратів. Показано, що навіть враховуючи більший час з моменту початку використання сульфонілхлоридів в органічному синтезі, для хемоселективних реакцій набагато більш прийнятним є сульфонілфлуориди.uaorganosulfur compoundsnitrogen-containing heterocyclessp3- enriched compoundssulfinatesbuilding blocksoptical purityсульфурорганічні сполукинітрогеновмісні гетероциклиsp3 -збагачені сполукисульфінатибудівельні блокиоптична чистотаДисертація