H–d-Phe–d-Pro–Gly methyl ester hydro­chloride monohydrate

Mitsunobu Doi; Yuko Ichimiya; Akiko Asano

doi:10.1107/S160053680800528X

. 2008 Mar 12;64(Pt 4):o704. doi: 10.1107/S160053680800528X

H–d-Phe–d-Pro–Gly methyl ester hydrochloride monohydrate

Mitsunobu Doi ^a,^*, Yuko Ichimiya ^a, Akiko Asano ^a

PMCID: PMC2961031 PMID: 21202095

Abstract

The conformation of the title tripeptide methyl ester hydrochloride monohydrate, 1-[2-(methoxycarbonylmethylaminocarbonyl)pyrrolidin-1-ylcarbonyl]-2-phenylethanaminium chloride monohydrate, C₁₇H₂₄N₃O₄ ⁺·Cl⁻·H₂O, is extended, but the structure cannot be classified as any typical secondary structure. Interactions through water molecules and chloride ions were formed, in addition to peptide–peptide hydrogen bonds, stabilizing the molecular packing. In comparison with the previous β-turn structure of the Phe–d-Pro–Gly analogue [Doi, Ichimiya & Asano (2007 ▶). Acta Cryst. E63, o4691], it was suggested that the difference between the chiralities of Phe and Pro residues of the title compound is important to induce the β-turn structure.

Related literature

For related literature, see: Cremer & Pople (1975 ▶); Doi, Fujita et al. (2001 ▶); Doi, Ichimiya et al. (2007 ▶); Espinosa & Gellman (2000 ▶); Llamas-Saiz et al. (2007 ▶); Tamaki et al. (1985 ▶); Yamada et al. (2002 ▶).

Experimental

Crystal data

C₁₇H₂₄N₃O₄ ⁺·Cl⁻·H₂O
M _r = 387.86
Orthorhombic,
a = 7.3707 (5) Å
b = 9.6667 (7) Å
c = 27.099 (2) Å
V = 1930.8 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.23 mm⁻¹
T = 90 (2) K
0.40 × 0.35 × 0.35 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.874, T _max = 0.923
23047 measured reflections
4553 independent reflections
4540 reflections with I > 2σ(I)
R _int = 0.019

Refinement

R[F ² > 2σ(F ²)] = 0.032
wR(F ²) = 0.087
S = 0.85
4553 reflections
237 parameters
H-atom parameters constrained
Δρ_max = 0.46 e Å⁻³
Δρ_min = −0.21 e Å⁻³
Absolute structure: Flack (1983 ▶), 1920 Friedel pairs
Flack parameter: 0.03 (4)

Data collection: SMART (Bruker, 1998 ▶); cell refinement: SAINT-Plus (Bruker, 1998 ▶);; data reduction: SAINT-Plus; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2003 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053680800528X/pv2069sup1.cif

e-64-0o704-sup1.cif^{(22.9KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680800528X/pv2069Isup2.hkl

e-64-0o704-Isup2.hkl^{(223.1KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N10—H10A⋯O1	0.91	1.96	2.845 (2)	166
N10—H10C⋯Cl	0.91	2.31	3.112 (1)	147
N10—H10B⋯O18ⁱ	0.91	1.94	2.755 (1)	148
O1—H2⋯Clⁱⁱ	0.77	2.43	3.201 (1)	177
N30—H30⋯Clⁱⁱⁱ	0.88	2.43	3.299 (1)	171
O1—H1⋯Cl^iv	0.82	2.33	3.139 (1)	165

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

supplementary crystallographic information

Comment

The β-turn structures were formed at D-Pro residue in a Gramicidin S and its analogue (Doi et al., 2001; Yamada et al., 2002; Llamas-Saiz, et al., 2007), and a motif including D-Pro promoted β-hairpin in the protein GB1 analogue (Espinosa & Gellman, 2000). A tripeptide motif of Boc–Phe–D-Pro–Gly–OMe (Boc = t-butyloxycarbonyl; OMe = methylester) was designed from these peptides, and the β-turn structure was elucidated (Doi et al., 2007). Moreover, the CD spectra of Gramicidin S analogues suggested that the chiral combination of Phe and Pro residues contributes to the β-turn formation (Tamaki et al., 1985). Title peptide (I) was designed to highlight the chirality of the Phe residue in this tripeptide β-turn motif.

The molecular structure of (I) is shown in Fig. 1. The peptide is a chloride salt and its N-terminal (N10 atom) is protonated. The peptide molecule is somewhat extended, but the structure is not classified to any typical secondary structures from torsion angles. The Pro residue shows a ring puckering with amplitude of Q2 = 0.361 (2) Å and phase of φ2 = 293.1 (2) ° (Cremer & Pople, 1975), which is slightly different from those of the β-turn structure of Boc–Phe–D-Pro–Gly–OMe (Doi et al., 2007).

A peptide-peptide hydrogen bond is formed between N10 and O18 atoms. This interaction makes the molecular arrangement propagated along the b axis, but no sheet structure is created (Fig. 2). Molecular packing is stabilized by the interactions with chloride ion (Cl) and water molecule (O1).

CD spectra of (I) showed no clear proof of special structures existed in acetonitril solution (data not shown), and the structure of (I) was somewhat extended. In contrast to the β-turn structure of the diastereomeric tripeptide (Boc–Phe–D-Pro–Gly–OMe), these results indicate that the chirality of Phe different from that of Pro is important for folding of this tripeptide motif.

Experimental

The title compound was synthesized by a conventional liquid-phase method and the protected peptide, Boc–D-Phe–D-Pro–Gly–OMe (Boc = t-Butyloxycarboxy; OMe = methylester), was obtained. Boc group was removed by using HCl/dioxane, and the hydrocloride salt was obtained. Crystals were grown from aqueous acetonitrile solutions by vapor diffusion method.