The thesis is devoted to the development of synthetic approaches to bicyclic sultams with a bridgehead Nitrogen atom (Paquette’s sultams) and studying of their structural features.
Bicyclic saturated sultams represent a promising class of sp3-rich three-dimensional scaffolds of outmost importance to organic and medicinal chemistry. In the literature review, 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 -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. The
literature data show that there is much space for further synthetic studies on saturated bicyclic sultams aimed at the preparation of novel chemotypes (especially in the field of bridged and spirocyclic derivatives). Moreover, the wide application of these derivatives not only in drug discovery but also in other areas can be envisaged.
As a result of this research work, a series of aliphatic sulfonyl fluorides (12 examples) bearing secondary amino group – useful building blocks for protective group-free synthesis – was synthesized. Among them are the derivatives of azetidine, pyrrolidine, piperidine, morpholine, and azepane heterocyclic systems. The obtained compounds were stable enough for the purification and storage under ambient conditions. These sulfonyl fluorides were used in PG-free synthesis under common reaction conditions. Synthetic procedures were consistent with the principles of atom economy and "ideal synthesis" preventing loss of the material at the protection and deprotection steps.
Aliphatic sulfonyl chlorides often decompose during storage and exhibit thermal liability. On the other hand, sulfonyl fluorides are remarkably stable under mild acidic and basic conditions and less reactive toward nucleophilic substitution, including hydrolysis, compared to sulfonyl chlorides. A library of saturated heterocyclic sulfonyl fluorides was synthesized. Since it was needed to reduce the nucleophilicity and basicity of the amino function, the synthesis was started from corresponding cyclic N-Boc protected alcohols. Mesylation was carried out smoothly under standard reaction conditions on all substrates, yielding desired products in 90–95% purity, which were immediately used in the next step without purification. Nucleophilic substitution of the mesylate has been performed in DMF at 95 °C using 1.4 equiv of potassium thioacetate, and the crude product was obtained with a purity of 85–90%. Under such conditions, the reaction was fruitful even when more than 100 g of the starting mesylate was used in a one run. Chlorination occurred in rather harsh reaction conditions for Boc-amines, as it produces a large amount of hydrochloric acid. However, using a two-phase system dichloromethane/water (1:1) and controlling the reaction temperature in the range of 0–5 °C allowed to obtain the corresponding sulfonyl chlorides in yields from moderate to good. It is worth noting that all sulfonyl chlorides were thermolabile and the yields dropped sharply if the
methylene solution was concentrated under reduced pressure at temperature over 40 °C. Conversion to sulfonyl fluorides was performed under standard reaction conditions using potassium fluoride and a 3% solution of 18-crown-6 in acetonitrile. N-Boc cleavage step using 4 M hydrochloric acid in dioxane gave hydrochlorides of the corresponding amine sulfonyl fluorides that crystallized from the reaction mixture in pure form.
Some sulfonyl fluorides
