Conformational effects of C,‐dipropargylglycine as a constrained residue

Abstract

A useful synthon to approach artificial phenylalanyl peptides in a [2 + 2 + 2] cycloaddition reaction, Cα,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 αR or αL conformation, participating in a type I β-turn or an αL-αR-type fold, in which Leu2 assumes the αR 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 Dprg1 and D-Val2 assuming the αL conformation stereochemically favored for a D-chiral residue, with 4 → 1 type hydrogen bond linking L-Leu3 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 C5-type conformation for this residue, and solvent sequestered nature of L-Leu3 NH, suggesting possibility of a β-turn due to Dprg assuming a folded conformation. © 2001 John Wiley & Sons, Inc. Biopolymers 59: 330–338, 2001