Peptides constrained by an aliphatic linkage between two C(alpha) sites: design, synthesis, and unexpected conformational properties of an i,(i + 4)-linked peptide.
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 Schöllkopf 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.
Alexander McNamara
L M
LM
Department of Chemistry, University College London, Christoper Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, U.K.
Andrews
M J
MJ
Mitzel
F
F
Siligardi
G
G
Tabor
A B
AB
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D010452:Peptide Biosynthesis; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary
D000596:Amino Acids; D010456:Peptides, Cyclic