Efficient and Stereoselective Chiral Synthesis of Isosteric Peptides Directed toward Development of Drugs

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In recent years, increasing interest has been shown in the backbone modification of amide bonds in biologically active peptides. The major purpose in this area deals with stabilizing a given peptides toward enzymatic degradation by in vitro proteases or imparting enzyme inhibitory activity to the synthesized peptide mimic. The peptide bond in polypeptides and proteins generally assumes the trans amide bond configuration, since its cis counterpart induces unfavorable steric interactions.The(E)CH=CH bonding in peptide mimic closely resembles three-dimentional structure(bond length, bond angle, and rigidity)of the parent amide. Thus replacement of an amide bond by a(E)CH=CH bond should not signiflcantly alter the overall conformation of a peptide molecule, and hence, its biological activity, provided that the replaced amide bond is not directly involved in either the secondary or tertiary structure of the peptide or the mechanism whereby the biological response is elicited.Because it has … More been reported that alpha-carbon stereochemistry was one of the essential factors for enzyme inhibition, the synthesis of(E)-alkene dipeptide isosteres would be highly valuable. We have disclosed following points during our study on the synthesis of(E)-. dipeptide isosteres.1)Both the(E)- and(Z)-alpha, beta -unsaturated esters afford the alpha-alkylated(E)-beta, gamma -unsaturated esters in very high chemical and optical yields by treatment with alkylcyanocopper-trifluoroborane reagents under very mild conditions. The presence of a HNBoc group at the delta-position does not erert any influence on the course of the anti-S_N2' reaction.2)A simple synthsis of psi[(E)CH=CH]Gly dipeptide'Nisosteres via reduction of delta-aminated-gamma-mesyloxy-alpha, beta-unsaturated esters with alkenylcopper reagents has been developed. Reaction times of 5 - 30 min at - 78 ﾟC were sufficient for conversion of the mesylates into the isosteres.3)The absolute configuration at the alpha-alkylated carbon center in delta-oxygenated or delta-aminated beta, gamma-unsaturated esters can be determined by circular dichroism measurement with confidence. Whereas(2S)-compounds show a positive n ->PI* Cotton effect around 220 nm, (2R)-'@series of compounds exhibit a negative n ->PI* Cotton effect near 220 nm.4)The synthesized dipeptide isosteres were coupled with natural(S)-amino acids to yield a new type of peptides. Evaluation of biological activities is in progress. Less