Síntesis diastereoselectiva de compuestos fosforados análogos de L-carnitina

The L-carnitine is an essential nutrient, so endogenously synthesized by the amino acids lysine and methionine, or can be obtained from the diet, mainly meat, the main function of L-carnitine is to be the substrate of the enzyme carnitine palmitoiltransferase 1, which catalyzes the initial step in the transport of long-chain fatty acids into the mitochondrial matrix. In recent years the L-carnitine analogs or derivatives has attracted considerable attention from groups of researchers because of their biological and pharmacological applications. This study describes a new synthetic methodology that afford of (2R, 3S)-_-hydroxy-_-aminophosphonic acid 9 and mixtures of diastereomeric (3S)-_-hydroxy-_-aminophosphonic acids 9/10 phosphocarnitine analogs P +NMe3 OH O OH OH IP +NMe3 OH O OH OH I- (2R, 3S)-9 (2R, 3S)-9/(2S, 3S)-10 The synthetic route was designed to be scalable and thus obtain the quantities needed for subsequent evaluation of these compounds. A key intermediary for the route of synthesis was _-(N,N-dibenzyl)amino-?-hydroxyphosphonate 4 obtained from the diastereoselective reduction of _-(N,N-dibenzyl)amino?-ketophosphonate 3, which in turn the was obtained easily from _-aminoacid L-leucine 1. Subsequently, it ordered removal of protective groups and the methylation of the amino group. Finally, the hydrolysis of phosphonic esters provided of (2R, 3S)-_-hydroxy-?-aminophosphonic acid 9 (Scheme 1) P +NMe3 OH O OH OH I- 9 P(OMe)2 NBn2 OH O P(OMe)2 NBn2 O O OH NH2 O P(OMe)2 +NMe3 OH O I- 1 3 4 7 H - Scheme 1 The methodology developed allowed obtaining (2R,3S)-_-hydroxy-_- aminophosphonic acid 9 with a high diastereoselectivityd and good chemicals yield. The same methodology was developed for obtaining the diastereomeric mixture of (3S)-_-hydroxy-_-aminophosphonic acids 9/10