Conformational effects of C α,α ‐dipropargylglycine as a constrained residue

A useful synthon to approach artificial phenylalanyl peptides in a [2 + 2 + 2] cycloaddition reaction, C α,α ‐dipropargylglycine (Dprg) is examined for its conformational preferences as a constrained residue. Crystal structure analysis and preliminary NMR results establish possible preference of the residue for folded (α) rather than extended (β) region of the ϕ,ψ conformational space. Boc–Dprg– L ‐Leu–OMe ( 1 ) displays two molecular conformations within the same crystallographic asymmetric unit, with Dprg in the α R or α L conformation, participating in a type I β‐turn or an α L ‐α R ‐type fold, in which Leu 2 assumes the α R conformation stereochemically favored for an L ‐chiral residue. Boc–Dprg– D ‐Val‐ L ‐Leu–OMe ( 2 ) displays a type I′ β‐turn conformation in crystal, with both Dprg 1 and D ‐Val 2 assuming the α L conformation stereochemically favored for a D ‐chiral residue, with 4 → 1 type hydrogen bond linking L ‐Leu 3 NH with Boc CO. NMR analysis using temperature variation, solvent titration, and a spin probe study suggests a fully solvent‐exposed nature of Dprg NH, ruling out a fully extended C 5 ‐type conformation for this residue, and solvent sequestered nature of L ‐Leu 3 NH, suggesting possibility of a β‐turn due to Dprg assuming a folded conformation. © 2001 John Wiley & Sons, Inc. Biopolymers 59: 330–338, 2001