ИСТИНА

Regulation of amino acid metabolism in the body using specific inhibitors is of significant therapeutic interest. In this regard, in the last twenty years, much attention has been paid to α-fluorine-containing α-amino acids. Among them, the most promising were α-fluoromethyl-substituted analogues, the biological activity of which is associated with selective irreversible inhibition of pyridoxalphosphate-dependent enzymes involved in the amination of α-keto acids, racemization, deamination, transamination, decarboxylation and other conversions of α-amino acids. Many representatives of α-fluoromethyl-substituted α-amino acids have a wide range of biological properties, including antiviral and antitumor activity. So, for example, α-difluoromethylornithine (eflornithine) has already found application in medical practice for the treatment of African sleeping sickness and some types of pneumonia (for example, caused by Pneumocystis carinii) - the most common infections associated with acquired immunodeficiency syndrome (AIDS). In addition, α-aminophosphonic acids, structural P-analogues of α-amino acids, have a wide spectrum of biological activity, exhibiting the properties of proteolytic enzyme inhibitors. Therefore, the development of effective methods for the synthesis of α-CF3-containing derivatives of ornithine and their phosphorus analogues is a very urgent task today. This work is devoted to the development of a new method for the synthesis of α-trifluoromethylornithine derivatives by hydroamination of the corresponding α-allenyl-containing derivatives of amino acids and subsequent hydrogenation of the resulting unsaturated products. The method involves [2,3]-sigmatropic rearrangement of α-trifluoromethyl-containing diazocarboxylates (phosnonates) with N-propargyldimethylamine by catalysis with divalent copper salts, which leads to the formation of the corresponding allenyl-containing derivatives. Subsequent Cu (I) -catalyzed addition of various nucleophiles to the terminal allen system selectively gives the desired derivatives of ornithine. To search for optimal conditions for obtaining unsaturated analogues of α-CF3-ornithine, as well as an active catalytic system, a series of model reactions was carried out. As nucleophiles, cyclic saturated amines as well as aromatic amines were selected. Next, the hydroamination products were reduced to saturated ornithine derivatives with hydrogen using palladium on coal. As a result of the study, effective catalytic methods for the synthesis of previously unknown derivatives of α-trifluoromethylornithine and its phosphorus analogues were developed. All syntheses are easily scaled, making it possible to obtain the corresponding products in quantities sufficient for their biological activity tests.