Design of peptides: synthesis, crystal structure, molecular conformation, and conformational calculations of N-Boc-L-Phe-Dehydro-Ala-OCH₃

Abstract

It is noteworthy that the dehydro-Ala residue adopts an extended conformation that is different than those observed in dehydro-Phe, dehydro-Leu, and dehydro-Abu.The peptide N-Boc-L-Phe-dehydro-Ala-OCH₃(C₁₈H₂₄N₂O₅) was synthesized by the usual workup procedure and finally by converting N-Boc-L-Phe-L-Ser-OCH₃ to N-Boc-L-Phe-dehydro-Ala-OCH₃. It was crystallized from its solution in a methanol-water mixture at room temperature. The crystals belong to the monoclinic space group P2₁ with a = 9.577(1) Å, b = 5.195 (3) Å, c = 19.563 (3) Å, β = 94.67 (5)°, V = 970.1(6) ų, Z = 2, d_m = 1.201(5) Mg m^-3, d_c = 1.197 (5) Mg m^-3. The structure was determined using direct method procedures. It was refined by a full-matrix least-squares procedure to an R value of 0.048 for 1370 observed reflections. The C₂^α-C₂^β distance is 1.327 (8) Å, while the bond angles N2-C₂^α-C₂ and C₁-N2-C₂^αare 109.8 (5)° and 127.8 (5)°, respectively. The backbone adopts a nonspecific conformation with dehydro-Ala in a fully extended conformation with the following torsion angles: θ^l = 175.2 (4)°, ω,₀ = 170.2 (4)°, Φ₁ = 135.8 (5)°, Ψ₁ = -22.6(6)°, ω₁ = 168.5 (5)°, Ψ₂,= -170.3(5)°, Ψ₂^T =-178.6(5)°, θ^T = 178.4(7)°. The rigid planar and trans conformation of dehydro-Ala forces Phe to adopt a strained conformation. The Boc group has a trans-trans conformation. The side-chain torsion angles of the Phe residue are χ₁ = 63.3(6)°, χ₁^2,1 =-92.1(6)°, χ₁^2,2 = 89.5 (6)°. The observed conformation is stabilized by three nonlinear intramolecular C-H---O type of interactions. The crystal structure is stabilized by an intermolecular hydrogen bond N1-H1---O₂ of distance 2.938(7) Å along the b axis while the van der Waals forces are the stabilizing interactions in the ac plane. The low-energy conformation found by calculations corresponds to the solid state conformation established by the crystal structure analysis.