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Mimetics of tripeptides adopting inverse and classical g-turn conformations have been designed and synthesized by an enantioselective approach and then incorporated in an analogue of the hormone vasopressin. In the mimetics one of the amide bonds of the g-turn has been exchanged for a Y[CH 2 O] isostere and the hydrogen bond between residues i and i2 of the turn has been replaced by a methylene bridge to give a six-membered, morpholin-3-one ring. The turn mimetics were assembled from three types of building blocks: azido epoxides, a-bromo acids and b-amino alcohols. Of these, the stereochemistry of the azido epoxide determines whether a classical or an inverse g-turn is mimicked. The key azido epoxide building blocks were prepared in six steps and approximately 40 % overall yield, whereas the a-bromo acids and b-amino alcohols were either commercially available or readily prepared from amino acids. The buildingblock approach allowed substantial variation of the side chains of the mimetics, together with complete stereocontrol, as well as use of uniform conditions for preparation of both classical and inverse g-turn mimetics. Conformational studies based on ab initio calculations and 1 H NMR spectroscopy revealed that the minimum-energy conformations of the mimetics closely resembled inverse or classical g-turns.

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A beta-turn mimetic in which the four amino acids of a beta-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular CO(i)-HN(i)(+3) hydrogen bond that is often found in beta-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a beta-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a beta-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on (1)H NMR data showed that the beta-turn mimetic was flexible, but that it resembled a type-II beta-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.