Kozyrev Y. Synthesis of spiro- and cage N,O,S-containing heterocyclic systems

The dissertation is devoted to the study of the synthesis of new cyclobutane spiroheterocycles, including 5,8-dioxaspiro[3.5]nonane, 1-oxaspiro[3.3]heptane and 1-azaspiro[3.3]heptane motifs, followed by modification of functional groups to create a library of derivatives that can be used for the design of new drugs. The work also presents the development of methods for the synthesis of bicyclic cage systems that include pyrrolidine, piperidine, and morpholine fragments. A separate part of the work is devoted to sulfur-containing azaheterocyclic systems. The topic of the PhD thesis is relevant in view of the constant need for new unique building blocks for drug design. It has been established that the Johnson-Corey-Chaykovsky reaction is a convenient approach for the preparation of 1-oxaspiro[3.3]heptane system. It was found that 1-oxaspiro[2.3]hexanes react much faster and in higher yields than the corresponding cyclobutanones. A new method for the synthesis of 9-oxa-3-azabicyclo[3.3.1]nonane was developed based on commercially available (R)-2-((benzyloxy)methyl)oxirane, (R)-epichlorohydrin and benzylamine. Optimization of the key step of (4-benzyl-6-((benzyloxy)methyl)morpholin-2-yl)methanol production led to the discovery of a one-pot synthesis of the target substance. The strategy involves the stepwise addition of (R)-2-((benzyloxy)methyl)oxirane, (R)-epichlorohydrin and sodium methylate to benzylamine, followed by the catalytic hydrogenation of both benzyl groups and the conversion of hydrophilic morpholine-2,6-diylmethanol into hydrophobic tert-butyl 2,6-bis(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate. Further cyclization to the corresponding malonic diesters, decarboxylation and alkaline hydrolysis lead to 3-(tert-butoxycarbonyl)-9-oxa-3-azabicyclo[3.3.1]nonan-7-carboxylic acid. A series of compounds based on 2-azabicyclo[2.2.1]heptane was prepared in order to synthesize new piperidine derivatives with a bicyclic cage. The method is based on the intramolecular cyclization of a 4-oxocyclopentane-1,2-dicarboxylic acid derivative and benzylamine. A new method for the synthesis of unsaturated 3,4-dihydro-2H-thiopyran-1,1-dioxides has been developed that can be used as building blocks in the synthesis of pharmaceuticals. To date, among the compounds that include the dihydro-2H-thiopyran-1,1-dioxide fragment are well-known drugs as the antiglaucoma agent Dorzolamide and the diuretic Metikran. The developed methods for the synthesis of the above-mentioned types of compounds based on the use of commercially available starting compounds, the use of original synthetic techniques for the design of heterocyclic motifs and have been tested on a multigram scale of 10-100 g and above. Chapter 1 includes a literature review on the advanced methods for the synthesis of cyclobutane-containing heterocycles for drug design, as well as oxetanes, azetidines, sulfones, and morpholines. These heterocycles are the focus of this thesis. The qualitative study and analysis of printed sources allows us to clearly define the direction of the experimental synthetic part of further work. As a result, the author focuses his attention on the idea that the derivatives of these heterocyclic systems are interesting for the creation of new highly effective and low-toxic biologically active substances for further biological research. Chapter 2 describes the synthesis of three types of spirocycles containing a cyclobutane fragment, namely new substituted 1-oxaspiro[3.3]heptanes, 1-azaspiro[3.3]heptanes, and 5,8-dioxaspiro[3.5]nonanes. Chapter 3 is a sequential exposition of materials and methods of synthesis of 6-azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.1]heptane and 9-oxa-3-azabicyclo[3.3.1]nonane derivatives. In this section, the author describes new routes for the synthesis of these important building blocks. Chapter 4 presents an algorithm for finding optimal ways to solve problems related to the synthesis of unsaturated 3,4-dihydro-2H-thiopyran-1,1-dioxides. The proposed method extends the possibilities of synthetic approaches to similar functionalized cyclic sulfones. This chapter also presents spiro- and condensed pyrrolidine-containing derivatives of these sulfones. Section 5 describes the experimental part of the study, which includes the methods of synthesis of new compounds and their NMR characteristics, mass spectroscopy data, and other physical and chemical properties.