Abstract
The β turn segment in designed peptide hairpins has been expanded by the insertion of β‐, γ‐ and δ‐amino acids at the i+2 position. The model octapeptides Boc‐Leu‐Phe‐Val‐^D^Pro‐Ac~6~c‐Leu‐Phe‐Val‐OMe (1), Boc‐Leu‐Phe‐Val‐^D^Pro‐β^3^‐Ac~6~c‐Leu‐Phe‐Val‐OMe (2), and Boc‐Leu‐Phe‐Val‐^D^Pro‐Gpn‐Leu‐Phe‐Val‐OMe (3) have been shown to adopt β hairpin conformations in methanol by the observation of key diagnostic nuclear Overhauser effects. Boc‐Leu‐Val‐Val‐^D^Pro‐δ‐Ava‐Leu‐Val‐Val‐OMe (4) adopts a β hairpin conformation in crystals; this is stabilized by three cross‐strand hydrogen bonds as demonstrated by X‐ray diffraction. The canonical C~10~ turn in an α–α segment is expanded to C~11~, C~12~, and C~13~ turns in α–β, α–γ, and α–δ segments, respectively. The crystal structures of Piv‐^L^Pro‐β^3^‐Ac~6~c‐NHMe (5) and Boc‐Ac~6~c‐Gpn‐Ac~6~c‐OMe (6) reveal intramolecularly hydrogen‐bonded C~11~ and C~12~ conformations, respectively. Computer modeling of octapeptide sequences that contain centrally positioned hybrid‐turn segments, by using turn parameters derived from the structures of peptides 5 and 6, establishes the stereochemical acceptability of the β hairpins in the cases of peptides 2 and 3. Accommodation of ω‐amino acids into the turn segments is achieved by the adoption of gauche conformations around the backbone CC bonds.