Heterochiral N‐formyl methionyl peptides

Abstract

Crystal and molecular structures for the heterochiral sequence N‐formyl‐l‐methionine‐d‐phenylalanine, 1, and its tertiary butyl ester, 2, are reported. The solid‐state peptide conformation is compared to that observed in solution by n.m.r. techniques. For N‐f‐Met‐d‐Phe, 1, the crystal was orthorhombic, space group P21 2121 with a cell of dimensions a = 5.061(3), b = 16.575(5) and c = 19.656(6) Å at ambient temperature of 293K; V = 1649(2)Å3, Z = 4, Dm= 1.31(2)gcm−3, Dx= 1.307gcm−3, μ(Mokx) = 2.047cm−1. For N‐f‐Met‐d‐Phe‐OtBu. 2, the crystal was monoclinic, space group P21 with a cell of dimensions a = 9.963(2), b = 11.147(2), c = 19.166(3)Å. β= 102.31(1) at 273K; V = 2080(2) Å3 Z = 4, Dm= 1.22(2)gcm−3, Dx= 1.215gcm−3μ(MoKx) = 1.714cm−1. The structures were solved from diffractometer data and refined to conventional final R = 0.046, Rw= 0.053 for F‐Met‐d‐Phe (1301 observations. I ≥ 3σ(I)) and to R = 0.056, Rw= 0.064 for the t‐butylester (2411 observations. I ≥ 3σ(I)). The l‐d acid, 1, crystallizes in an extended β‐sheet conformation with trans‐planar peptide bond; the principal torsion angle values are φ1=– 141.2(4).Ψ1= 149.6(4)3, φ2= 157.4(4)°. The methionine side chain adopts a common coiled conformation with x11= ‐ 58.0(5).x21= 175.1(4), x31= 76.5(5). The Phe side chain adopts the statistically least favored g orientation in contrast to the most populated rotamer in solution. The crystal structure is composed of parallel β‐sheets held together by four weak intermolecular contacts including two C‐H O contacts from the alpha carbons to the formyl and peptide carbonyl oxygens. Sheet layers are joined in a head‐to‐tail fashion through a very short (2.569(4) Å) contact between the carboxyl OH and the formyl oxygen and may be further stabilized by a C‐H—O interaction between the formyl proton and the carboxyl OH. Two crystallographically independent molecules are observed in the crystal structure of N‐f‐l‐Met‐d‐Phe‐OtBu, 2. These are distinct conformational isomers differing principally at both the N and C termini. Particularly noteworthy is the synplanar orientation of the ester C = O with respect to the peptide nitrogen in molecule A. which contrasts to the antiplanar orientation in molecule B. Additionally, the formyl group is coiled more towards the C‐terminus in molecule B. Principal torsion angles are φ1(A) = ‐ 120.6(5), Ψ1(A) = 102.0(6)°, φ2(A) = 128.1(6), φ1(B) = ‐ 94.6(5), Ψ1(B) = 91.9(6)°. 121.7(6)°. The peptide bond is trans‐planar in both molecules. Side chain dispositions are essentially identical in both structures. The Met side chain adopts the zig‐zag trans‐planar conformation while the Phe residue adopts an orientation near + 60° in agreement with rotamer populations observed by solution n.m.r. Typical peptide intermolecular H‐bonding is observed in the ester crystal structure; both the peptide and formyl groups participate in the proposed H‐bonding scheme.