(S)-N-[(4-{(S)-1-[2-(4-Methoxybenzamido)-2-methylpropanoyl]pyrrolidine-2-carboxamido}-3,4,5,6-tetrahydro-2H-pyran-4-yl)carbonyl]proline dimethyl sulfoxide monosolvate (4-MeBz-Aib-Pro-Thp-Pro-OH)

The asymmetric unit of the title compound, C28H38N4O8·C2H6OS, contains one tetrapeptide and one disordered dimethyl sulfoxide (DMSO) molecule. The central five-membered ring (Pro2) of the peptide molecule has a disordered envelope conformation [occupancy ratio 0.879 (2):0.121 (2)] with the envelope flap atom, the central C atom of the three ring methylene groups, lying on alternate sides of the mean ring plane. The terminal five-membered ring (Pro4) also adopts an envelope conformation with the C atom of the methylene group closest to the carboxylic acid function as the envelope flap, and the six-membered tetrahydropyrane ring shows a chair conformation. The tetrapeptide exists in a helical conformation, stabilized by an intramolecular hydrogen bond between the amide N—H group of the heterocyclic α-amino acid Thp and the amide O atom of the 4-methoxybenzoyl group. This interaction has a graph set motif of S(10) and serves to maintain a fairly rigid β-turn structure. In the crystal, the terminal hydroxy group forms a hydrogen bond with the amide O atom of Thp of a neighbouring molecule, and the amide N—H group at the opposite end of the molecule forms a hydrogen bond with the amide O atom of Thp of another neighbouring molecule. The combination of both intermolecular interactions links the molecules into an extended three-dimensional framework.

The asymmetric unit of the title compound, C 28 H 38 N 4 O 8 Á-C 2 H 6 OS, contains one tetrapeptide and one disordered dimethyl sulfoxide (DMSO) molecule. The central fivemembered ring (Pro 2 ) of the peptide molecule has a disordered envelope conformation [occupancy ratio 0.879 (2): 0.121 (2)] with the envelope flap atom, the central C atom of the three ring methylene groups, lying on alternate sides of the mean ring plane. The terminal five-membered ring (Pro 4 ) also adopts an envelope conformation with the C atom of the methylene group closest to the carboxylic acid function as the envelope flap, and the six-membered tetrahydropyrane ring shows a chair conformation. The tetrapeptide exists in a helical conformation, stabilized by an intramolecular hydrogen bond between the amide N-H group of the heterocyclic -amino acid Thp and the amide O atom of the 4methoxybenzoyl group. This interaction has a graph set motif of S(10) and serves to maintain a fairly rigid -turn structure. In the crystal, the terminal hydroxy group forms a hydrogen bond with the amide O atom of Thp of a neighbouring molecule, and the amide N-H group at the opposite end of the molecule forms a hydrogen bond with the amide O atom of Thp of another neighbouring molecule. The combination of both intermolecular interactions links the molecules into an extended three-dimensional framework.

Experimental
Crystal data
The crystals of the title compound are enantiomerically pure and the expected absolute configuration, S at C2 and C8 of the two proline residues, has been confirmed by the diffraction experiment. The asymmetric unit contains one molecule of the peptide plus one molecule of DMSO. The S atom of the DMSO molecule is disordered over two sites (details in the Experimental section). The peptide molecule exists in a β-turn conformation stabilized by an intramolecular hydrogen bond between N6-H of the heterocyclic amino acid Thp and the O atom of the amide C=O group of the 4-methoxybenzoyl group ( Fig. 1; Table 1). This interaction has a graph set motif (Bernstein et al., 1995) of S(10). The central fivemembered ring of Pro2 is disordered in that the ring has an envelope conformation in which atom C23 as the envelope flap is located on alternate sides of the mean ring plane with the major conformation found in 72.0 (10)% of the molecules. The other 5-membered ring (Pro4) also has an envelope conformation with atom C14 as the envelope flap.
The six-membered tetrahydropyrane ring (Thp) exists in a chair conformation. All four amide groups are quite planar.
Classical intermolecular hydrogen bonds of the O-H···O and N-H···O type link the molecules into a threedimensional framework (Fig. 2). This network is built from two substructures. In the first substructure, the carboxylic

Experimental
The title compound was prepared in analogy to earlier described procedures (Suter et al., 2000;Stoykova et al., 2012) by treatment of (S)-N-[N-(4-methoxyphenyl)-2-methylalanyl]proline (4-MeOBz-Aib-Pro-OH; Stoykova et al., 2012) with two mol-equivalents of methyl (S)-N-(1-aza-6-oxaspiro[2.5]oct-1-en-2-yl)prolinate (Suter et al., 2000) in dry THF at room temperature for 48 h. After removing the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, CH 2 Cl 2 /MeOH; gradient 110:1 to 20:1). Saponification of the resulting tetrapeptide ester was achieved by treatment with 4 mol-equivalents of LiOH.H 2 O in THF/MeOH/H 2 O 3:1:1 at room temperature for 25 h. After completion of the reaction, 1M HCl was added until pH 1 was reached, and the organic solvent was evaporated. The residue was extracted with CH 2 Cl 2 , the combined organic phase was dried over MgSO 4 , and the solvent evaporated to give the title compound in 74% yield (over two steps). Colourless crystals suitable for an X-ray crystal structure analysis were grown from DMSO at ca 278 K.

Refinement
The structure contains one molecule of DMSO per peptide molecule. The S atom of the DMSO molecule is disordered over two sites with the major orientation having a site occupation factor of 0.879 (2). One C atom of the central fivemembered ring of the peptide molecule is also disordered over two sites with the major conformation having a site occupation factor of 0.720 (10). Similarity restraints with a tolerance of 0.01 Å were applied to the chemically equivalent bond lengths involving all disordered atoms, while neighbouring disordered atoms were restrained to have similar atomic displacement parameters. Seven low angle reflections were omitted on account of obscuration by the beam stop.
The amide and carboxylic acid H atoms were placed in the positions found in a difference Fourier map and were then refined isotropically. All other H atoms were placed in geometrically optimized positions and constrained to ride on their parent atoms with C-H = 0.95 (aromatic), 0.98 (methyl), 0.99 (methylene) or 1.00 (methine) Å and with U iso (H) = 1.5U eq (C) for the methyl groups and 1.2U eq (C) otherwise.

Figure 1
The molecular structure of the title compound showing the atom-labelling scheme and the intramolecular hydrogen bond  where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.003 Δρ max = 0.28 e Å −3 Δρ min = −0.33 e Å −3 Extinction correction: SHELXL97 (Sheldrick, 2008), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0096 (11) Absolute structure: Flack & Bernardinelli (1999, 2000, 4115 Friedel pairs Refinement. The structure contains one molecule of DMSO per peptide molecule. The S atom of the DMSO molecule is disordered over two sites with the major orientation having a site occupation factor of 0.879 (2). One C atom of the central five-membered ring of the peptide molecule is also disordered over two sites with the major conformation having a site occupation factor of 0.720 (10). Similarity restraints with a tolerance of 0.01 Å were applied to the chemically equivalent bond lengths involving all disordered atoms, while neighbouring disordered atoms were restrained to have similar atomic displacement parameters. Seven low angle reflections were omitted on account of obscuration by the beam stop.