Shevchuk M. Organoboron and organosilicon methodologies in the synthesis of highly functionalized aminophosphonates

For the first time aminophosphonates and aminobisphosphonates were studied in the Petasis boronic acid Mannich reaction in detail. A series of aminophosphonates (primary and secondary aminophosphonates, alkyl- and aryl-aminophosphonates, alpha- and beta-amino-phosphonates, fluorinated phosphonates, aminobisphosphonates), carbonyl compounds (glyoxylic acid and alpha-ketoacids) and boronic acids (alkenyl-, aryl- and hetaryl-boronic acids) were evaluated. The influence of solvent and temperature on the reaction times, product yields and diastereomer ratios was studied. Diastereomer configurations of alpha-amino-phosphonate derived products were established by comparing theoretically predicted and experimental NMR shifts and confirmed by X-ray structural analysis. Free phosphonic acids were obtained employing transsilylation-methanolysis protocol. Hence, a convenient straightforward route towards highly functionalized C-substituted N-phosphonomethylglycine derivatives was developed. For the first time tetrakis(trimethylsilyl) ethenylidenebisphosphonate was studied as a Michael acceptor. Different aliphatic, aromatic and heterocyclic amines reacted to produce Michael adducts which could be further converted into the corresponding 2-amino-ethylidene-1,1-bisphosphonic acid in one pot. Several functionalized aminobisphosphonic acids were obtained, e.g. products bearing amidate, phosphonate and boronic acid groups. Notably, reaction could be successfully carried out in the presence of one free hydroxyl group. 2-Polyfluoroalkylaminoethylidene-1,1-bisphosphonic acids which are not readily available via conventional routes were synthesized utilizing this new bisphosphonate building block. Potassium fluoride mediated desilylation of intermediate tetrasilyl adducts resulted in correspondent tetrapotassium 2-aminoethylide-1,1-bisphosphonates. Tetrapotassium salts of bisphosphosphonic acids bearing pinacol boronate ester or amino acid tert-bytyl ester residues were prepared in this way. Hence, tetrakis(trimethylsilyl) ethenylidenebisphosphonate is a valuable reagent for the synthesis of functionalized 2-amino-ethylidene-1,1-bisphosphonic acids and their salts compatible with acid- and base-sensitive functional groups. Synthesized N-phosphonomethylglycine derivatives are moderate protein tyrosine phosphatase inhibitors and can be further used in the design and optimization of more potent inhibitors. Synthesized 2-aminoethylidene-1,1-bisphosphonic acids were found to be potent antimicrobial agents. Several compounds possess Norfloxacin-comparable degree of activity against Staphylococcus aureus.