Design and synthesis of chiral cyclic a,a-disubstituted alpha-amino acids and its peptides

摘要

The alpha-and 3_(10)-helices are important components of secondary structures in proteins,and play a crucial role in some biological processes.Oligopeptides composed of proteinogenic L-alpha-amino acids,such as alanine,valine,and leucine form a right-handed(P)alpha-helical structure because of the asymmetric center of the alpha-carbon atom.On the other hand,oligopeptides of chiral alpha-methylated alpha,alpha-disubstituted alpha-amino acids form a right-handed,or a left-handed 3_(10)-helical structure depending on the chiral quaternary carbon.In the case of L-threonine and L-isoleucine there is an additional asymmetric center on the side-chain(Fig.1).However,so far it has not been clear how the side-chain chiral center affects the secondary structure of their peptides.Here we developed two practical routes to synthesize optically active cyclic alpha,alpha-disubstituted amino acids,in which the alpha-carbon atom is not a chiral center but the asymmetric centers exist on the side-chain.One is a route starting from dimethyl L-(+)-tartrate,and another is a chemoenzymatic strategy.