Peptides constrained by an aliphatic linkage between two C(alpha) sites: design, synthesis, and unexpected conformational properties of an i,(i + 4)-linked peptide. |
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Authors: | L M Alexander McNamara M J Andrews F Mitzel G Siligardi A B Tabor |
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Affiliation: | Department of Chemistry, University College London, Christoper Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, U.K. |
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Abstract: | A novel route for the synthesis of cyclic peptides constrained by an aliphatic bridge between two C(alpha)sites, using a triply orthogonal protecting group strategy, is described. The synthesis of the orthogonally protected bis-amino acid 1, via an enantioselective route utilizing the Sch?llkopf and Evans methodologies, is first described. This is then incorporated into a short, alanine-rich peptide 13, using a novel triply orthogonal protecting group strategy to couple first one, then the other, amino acid moiety in such a way that an aliphatic bridge is formed between the i and i + 4 positions. Unexpectedly, the resulting constrained peptide does not adopt a helical conformation: instead, it is shown by CD at low temperature to adopt a left-handed type II beta-turn conformation in aqueous media and a right-handed type I beta-turn conformation in TFE. |
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