Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin

A β-turn mimetic in which the four amino acids of a β-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular COi − HNi+3 hydrogen bond that is often found in β-turns has been replaced by an ethylene bridge.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 β-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 β-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 1H NMR data showed that the β-turn mimetic was flexible, but that it resembled a type-II β-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.

Hedenström, MattiasUmeå universitet,Kemiska institutionen(Swepub:umu)mashem96 (författare)
Kreye, PaulUmeå universitet,Kemiska institutionen (författare)
Sethson, IngmarUmeå universitet,Kemiska institutionen(Swepub:umu)inrsen01 (författare)
Brickmann, KayAstraZeneca R&D Mölndal, Mölndal, Sweden (författare)
Kihlberg, JanUmeå universitet,Kemiska institutionen,AstraZeneca R&D Mölndal, Mölndal, Sweden(Swepub:umu)jaki0001 (författare)
Umeå universitetKemiska institutionen (creator_code:org_t)

Ingår i:Journal of Organic Chemistry: American Chemical Society (ACS)69:10, s. 3500-35080022-32631520-6904

Av författaren/redakt...: Blomberg, David; Hedenström, Matt ...; Kreye, Paul; Sethson, Ingmar; Brickmann, Kay; Kihlberg, Jan

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