Development of Efficient Synthetic Method for Unnatural Amino Acids and Peptides and Its Application

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In order to establish the synthetic method for unnatural amino acids and peptides containing such amino acids by employing pyridoxal derivatives, we studied α-alkylation and β-replacement reaction of Ser derivatives and the following results were obtained.1) Asymmetric α-alkylation of amino esters were successfully achieved by employing pyridoxal derivatives having a chiral ionophore side chain at C-3 and/or a chiral ansa-structure, giving rise to optically active α, α-dialkyl amino esters. The stereoselectivity of the reaction was found to depend on the kind of metal ion : the chiral environment is specifically constructed by coordination of the metal ion with the ionophore side chain. On application of this reaction to peptides, stereoselective and N-terminal selective α-alkylation of peptides was accomplished, being a novel method for the synthesis of unnatural peptides by direct modification.2) Pyridoxal derivatives having an ethoxyethoxy group at C-3 and an imidazole side chain at C-5 was found to catalyze β-replacement reaction of Ser O-carbonate with thiols to give various S-substituted Cys derivatives in the presence of LiィイD1+ィエD1. Peptides having Ser O-carbonate at the N-terminal position were also successfully converted to the peptides having S-substituted Cys at the N-terminal position by the same reaction. The β-replacement reaction with a carbon nucleophile such as nitroacetate also took place in the presence of LiィイD1+ィエD1 and ZnィイD12+ィエD1 by using pyridoxal derivatives having a methylthio group at C-2.We are studying the application of these reactions to solid-phase reactions, which would be of great use and versatile particularly on application to construction of peptides library.