REDOX N-ALKYLATION OF TOSYL PROTECTED AMINO-ACID AND PEPTIDE ESTERS

Condensation of N(alpha)-tosylated amino acid and peptide esters with alcohols (MeOH, EtOH, (i)PrOH) in the presence of the triphenylphosphi ne-diethyl azodicarboxylate adduct produced excellent yields of the co rresponding N(alpha)-alkylated derivatives. Optically pure N(alpha)-al kylamino acids can only be obtained from methyl and benzyl esters usin g iodotrimethylsilane and hydrogenolysis, respectively, for the carbox y-deprotection and sodium in liquid ammonia for the amino-deprotection . That carboxy-deprotection of methyl esters by saponification is acco mpanied by racemization was established by high-performance liquid chr omatography studies. Alkylation rates and yields for the reactions exa mined were found to depend only on the relative positions of the tosyl amino and the carboxy functions. Removal of the carboxy group from the alpha-position resulted in longer reaction times and significant decr eases in the yield of the desired N-alkylated derivatives. Accordingly , tosyl-protected lysyl and ornithyl side-chains of fully protected am ino acids and peptides were selectively N-methylated in moderate yield s in the presence of other amino functions bearing the tert-butoxycarb onyl (Boc) group which is commonly used for protection in peptide synt hesis.