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Information × Registration Number 0212U001474, 0109U001355 , R & D reports Title Development of new methods of glycosaminide synthesis and new approaches to the synthesis of bacterial cell wall glycopeptides popup.stage_title Head Chirva Vasily Yakovlevich, Registration Date 07-02-2012 Organization National Taurida V. Vernadsky University popup.description2 The subject of the research is the development of effective synthetic scheme for the preparation of glycopeptides, which are structurally analogous to disaccharide-peptide fragment of bacterial cell wall and GMDP drug, based on the new cost-effective approach to the synthesis of partially protected muramic acid derivatives and on the new approach to the formation of beta-(1->4)-glycosaminide bond; the search of new high-effective glycosyl donor and glycosyl acceptor reagents, optimal glycosylation conditions. The goal of the research is the synthesis of oligosaccharide and disaccharide-peptide fragments of bacterial peptidoglycan and their analogs by using newly developed synthetic scheme; the synthesis and study of reactivity of new glycosyl donors derived from 2-amino-2-deoxy sugars; the study of the conditions of glycosyl acceptor activation by means of phase transfer catalysis. The objects of the research are the conditions of direct selective 4,6-O-benzylidenation of starting N-acetyl-D-glucosamine; factors influencing stereoselectivity of 1-O-benzylation of N-acetyl-D-glucosamine derivatives under the conditions of anomeric alkylation method; factors influencing the target product yield and stereoselectivity of OH-group glycosylation at C-4 of glucopyranose ring of N-acetyl-D-glucosamine derivatives using 2-(2,2,2-trichloroethoxy)-(3,4,6-tri-О-acetyl-1,2-dideoxy-alpha-D-glucopyrano)-[2,1-d]-2-oxazoline; the conditions of effective N-deblocking of previously synthesized disaccharide derivative, which is essential for the preparation of bacterial cell wall glycopeptides and their analogs; the reactions of glycoside synthesis in a number of 2-amino-2-deoxy sugars; О-, and N-glycosides of N-acetyl glucosamine, glucosaminyloxysuccinimide. The problems to be solved in the course of the research are the following: low cost-efficiency of the synthesis of key N-acetyl-D-glucosamine derivatives used for preparation of oligosaccharides, bacterial cell wall glycopeptides, and their analogs; low effectiveness and poor stereoselectivity of glycosylation of 4-OH group in N-acetyl-D-glucosamine derivatives; insufficient stereo- and regioselectivity of glycosylation of glycosyl acceptors activated under the conditions of basic catalysis. Synthetic operations are carried out using standard and newly developed methods of organic synthesis, including methods of carbohydrate and peptide chemistry. The structure of synthesized and isolated compounds is determined by NMR spectroscopy and other spectral and chemico-analytical methods. Biological activity of isolated and synthesized species is determined by standard biochemical methods. As a result of the work, there was proposed a new way of synthesis of protected muramic acid derivatives based on our proprietary method of direct 4,6-О-benzylidenation of N-acetyl-D-glucosamine, and on the stereoselective procedure of 1,2-trans-1-O-benzylation of partially protected N-acetyl-D-glucosamine derivatives. The high effectiveness of this method is achieved due to the synthesis of the target compound by short synthetic route without use of protecting groups. There was studied a dependence of stereoselectivity of anomeric alkylation of D-glucosamine derivatives on the nature of alkali metal cation in the intermediate anomeric alcoholate; there was determined that while cation is changed from lithium to potassium, the stereoselectivity of 1-O-benzylation changes from predominant formation of 1,2-trans-glycosidated N-acetyl-D-glucosamine derivatives to predominant formation of 1,2-cis-glycosidated derivatives, with additional increase of 1,2-cis-selectivity upon potassium ion complexation by 18-crown-6. The obtained results were explained by means of Hammond's postulate and Curtin - Hammett principle. There was proposed a new synthetic scheme for obtaining of oligosaccharide derivatives with beta-(1->4)-glycosaminide bond and their analogs, including bacterial cell wall glycopeptides. The high effectiveness of the developed scheme is achieved due to enhanced reactivity of proposed glycosylating agent - 2-(2,2,2-trichloroethoxy)-(3,4,6-tri-О-acetyl-1,2-dideoxy-alpha-D-glucopyrano)-[2,1-d]-2-oxazoline, its 1,2-trans-stereoselectivity, as well due to the possibility of carrying out the glycoside synthesis in very mild conditions - at room temperature and in a neutral medium. There was carried out the synthesis of new muramyl dipeptide glycosides with acyclic aglycones that have different configurations at the glycosidic center. Such compounds as beta-cyclohexylmethyl, beta-cyclohexylethyl-MDP showed high protective effect against intraperitoneal infection of mice by S. aureus. It was established that alpha-anomers of N-acetylglucosamine are formed with comparable yields by the interaction of alpha-D-glucosaminyl chloride with cyclic alcohols in the presence of mercury (II) iodide at heating or by use of activating system ZnCl2 / quaternary ammonium salts at room temperature. For the first time, it was established that carrying out the reaction of the alcohol with alpha-D-glucosaminyl chloride in "zinc chloride - co-promoter" system at boiling predominantly leads to beta-glycosides. Product Description popup.authors Астраханцева Ганна Олександівна Зайцев Георгій Павлович Земляков Сергій Олександрович Какаян Олена Серкисівна Пєртєль Сергій Степанович Цикалова Вікторія Миколаївна Чупахіна Тетяна Олександрівна Щербакова Валентина Анатоліївна popup.nrat_date 2020-04-02 Close