Abstract
α,α-Disubstituted amino acids are α-amino acids in which the hydrogen atom at the α-position of the L-α-amino acid is replaced with an alkyl substituent. The introduction of an α-alkyl substituent changes the properties of amino acids, with the conformational freedom of the side chain in the amino acids and the secondary structure of their peptides being especially restricted. The author developed a synthetic route of optically active α-ethylated α,α-disubstituted amino acids using chiral cyclic 1,2-diol as a chiral auxiliary. It was found that the preferred secondary structure of peptides composed of chiral α-ethylated α,α-disubstituted amino acids is a fully extended C5-conformation, whereas that of peptides composed of chiral α-methylated α,α-disubstituted amino acids is a 310-helical structure. Also, a new chiral cyclic amino acid; (3S,4S)-1-amino-3,4-di(methoxy)cyclopentanecarboxylic acid {(S,S)-Ac5cdOM}, and a bicyclic amino acid; (1R,6R)-8-aminobicyclo[4.3.0]non-3-ene-8-carboxylic acid {(R,R)-Ab5,6=c}, in which the α-carbon atom is not the chiral center but chiral centers exist at the side-chain cycloalkane skeleton, were designed and synthesized. The (S,S)-Ac5cdOM hexa- and octapeptides preferentially formed left-handed (M) helices, in which the helical-screw direction is exclusively controlled by the side-chain chiral centers. Contrary to the left-handed helices of (S,S)-Ac5cdOM peptides, the (R,R)-Ab5,6=c hexapeptide formed both diastereomeric right-handed (P) and left-handed (M) helices, and the twelve chiral centers at the side chain showed no preference for helical-screw direction. Thus, the chiral environment at the side chain is important for the control of helical-screw direction. Furthermore, the author designed a new class of chiral cyclic α,α-disubstituted amino acids that have pendant chiral centers at the substituent of the δ-nitrogen atom. The synthetic route would provide various optically-active cyclic α,α-disubstituted amino acids bearing a pendant chiral moiety.
