THE PREFERRED SOLID-STATE CONFORMATION OF (ALPHA-ME)TRP PEPTIDES

The two Z-L-Ala-DL-(alpha Me)Trp-NH2 diastereomeric dipeptides were sy nthesized from (Z-L-Ala)(2)O and H-DL-(alpha Me)Trp-NH2. The latter ra cemate, prepared by phase-transfer catalyzed alkylation of the N-alpha -benzylidene derivative of alanine amide followed by acidic hydrolysis of the resulting Schiff base, was characterized by X-ray diffraction. The molecular and crystal structure of Z-L-Ala-L-(alpha Me)Trp-NH2, s eparated From its diastereomer by silica-gel column chromatography, wa s determined by X-ray diffraction analysis, Both independent molecules in the asymmetric unit of the dipeptide adopt a type-II beta-bend con formation. However, only the more regularly folded conformation of mol ecule B is stabilized by a 1<--4 C=O...H-N intramolecular H bond. The present results indicate that: (i) the C-alpha-methylated (alpha Me)Tr p residue is a strong beta-bend and helix former, and (ii) the relatio nship between (alpha Me)Trp chirality and helix screw sense tends to b e opposite to that of protein amino acids, The implications for the us e of the (alpha Me)Trp residue in designing conformationally restricte d analogs of bioactive peptides are briefly discussed. (C) Munksgaard 1995.