The thesis is devoted to the development of general synthetic approaches to the functionalized bicyclo[1.1.1]pentane derivatives, which can be used as building blocks for the needs of medical chemistry and tools for studying the structure of peptides.
A method for the synthesis of new enantiomerically pure amino acids with a bicyclo[1.1.1]pentane core - (bicyclo[1.1.1]pent-1-yl)glycine and (3-fluorobicyclo [1.1.1]pent-1-yl)glycine was developed. It is based on the use of an asymmetric Strecker reaction using phenylglycinol as a chiral inducer. The target amino acids were converted to Fmoc derivatives, which are compatible with solid-phase peptide synthesis. New amino acid (3-fluorobicyclo[1.1.1]pent-1-yl)glycine was introduced into the model peptide PGLa by solid-phase peptide synthesis instead of alanine residues. The spectra of circular dichroism confirmed that the new monofluorinated label does not change the structure of this peptide. There was also only a slight loss of antimicrobial activity of the synthetic analogue of PGLa compared to the natural compound. The intramolecular 19F-19F distance was measured using the centerband only detection of exchange (CODEX) NMR experiment. Imidazole-1-sulfonilazide hydrochloride was used as the diazo transfer reagent to obtaining bicyclo[1.1.1]pentylazides from bicyclo[1.1.1]pentylamines. Bicyclo[1.1.1]pentylazides with various substituents in the 3rd position (H-, F-, F3C-, Ph-, MeO2C-, BocHN-, CbzHN-) were obtained with a yield of 61-84%. Volatile azides (H-, F-, F3C-) were introduced into the [3+2]cycloaddition reaction with propiolic acid methyl ester under the catalysis of Cu(OAc)2•H2O at room temperature. Thus, methyl 1,2,3-triazole-4-carboxylates with bicyclo[1.1.1]pentyl substituents in the 1st position were obtained with a yield of 59-82%.
Seyferth–Gilbert reaction involving dimethyl-1-diazo-2-oxopropylphosphonate, known as Ohira-Bestman reagent, was used, for the first time, in the synthesis of functionalised (Ph-, F3C-, MeO2C-, BocHN-) bicyclo[1.1.1]pentylalkynes. The yield of bicyclo[1.1.1]pentylalkynes were 43-88% for two steps, based on corresponding alcohols. Alkynes with protected carboxylic and amino groups (MeO2C-, BocHN-) were introduced into the Cu(OAc)2•H2O [3+2]cycloaddition reaction with benzylazide CH2Cl2 solution at room temperature. Corresponding 1-benzyl-4-(bicyclo[1.1.1]pentyl)-1,2,3-triazoles were obtained with yields of 99% and 83%. Methods for the synthesis of Sulfur-containing bicyclo[1.1.1]pentane derivatives, such as sulfinates, sulfonamides and sulfonyl fluorides, with protected amino and carboxyl groups (t-BuO2C-, BocHN-) in the 3rd position were developed. N-hydroxypyridin-2-thione esters, known as Barton esters, were obtained from the corresponding bicyclo[1.1.1]pentancarboxylic acids. Irradiation of the solutions of these esters with an 500 W incandescent lamp in the presence of 2,2'-dipyridyldisulfide led to decarboxylation with the formation of bicyclo[1.1.1]pentyl (2-pyridyl)sulfides. These compounds were oxidized to bicyclo[1.1.1]pentyl (2-pyridyl)sulfones using 3-chloroperoxybenzoic acid. Reaction of the obtained sulfones with EtSNa gave 3-substituted sodium bicyclo[1.1.1]pentylsulfinates. The obtained sulfinates were transformed into bicyclo[1.1.1]pentylsulfonamides (69-70%) upon treatment with hydroxylamine-O-sulfonic acid in water. Bicyclo[1.1.1]pentyl sulfonylfluorides were obtained in a 71-78% yield from the bicyclo[1.1.1]pentylsulfinates via electrophilic fluorination employing (PhSO2)2NF in CH3CN. To obtain parent bicyclo[1.1.1]pent-1-yl sulfinate, sulfonamide and sulfonyl fluoride, benzylthiol was added to [1.1.1]propellane (80%). The obtained bicyclo[1.1.1]pentyl (benzyl)sulfide was oxidized with 3-chloroperoxybenzoic acid to sulfone in 93% yield. Treatment of the sulfone with benzyl bromide in the presence of excess KOt-Bu at 40 ° C in THF led to the formation of potassium bicyclo[1.1.1]pent-1-yl sulfinate, which was successfully transformed into sulfonamide (74%) and sulfonyl fluoride (69%) in the conditions employed for substituted analogs. A method for the synthesis of non-functionalized di-Boc-protected bicyclo[1.1.1]pentyl hydrazines (77-85%) is proposed, which consists in halogen-lithium exchange of bicyclo[1.1.1]pentyl iodides with t-BuLi at -78 ° C, followed by reaction with di-tert-butyl azodicarboxylate. A new general approach to the synthesis of α,α,α-trisubstituted alkylhydrazines was developed. The method is based on the conversion of α,α,α-trisubstituted carboxylic acids into Barton esters and subsequent irradiation of their CHCl3 solutions with an incandescent lamp in the presence of di-tert-butyl azodicarboxylate. The reaction proceeds in good yields (63-87%) for most substrates. In the case of moderate or low stability of intermediate tertiary radical, the reaction proceed in significantly reduced yield (15-38%).
