Crystal structure of a tripeptide biphenyl hybrid C50H56N6O10·0.5H2O

The synthesis of the peptide biphenyl hybrid compound dimethyl 2,2′-[((2S,2′S)-2,2′-{[(2S,2′S)-1,1′-([1,1′-biphenyl]-2,2′-dicarbonyl)bis(pyrrolidine-1,2-diyl-2-carbonyl)]bis(azanediyl)}bis(3-phenylpropanoyl))bis(azanediyl)](2S,2′S)-dipropionate) is described. The crystal structure of this compound has a highly ordered supramolecular structure with extensive intermolecular hydrogen bonding.


Chemical context
Peptides are combined linear chains of amino acids and are essential for all biological processes. Consequently, they are of great interest in the biomedical field, and research into the use of peptides and modified peptides as therapeutics is increasing rapidly. At present there are over 100 approved peptide-based therapeutics on the market, with the majority being smaller than 20 amino acids (Bruno et al., 2013). However, these peptides have some drawbacks: their poor absorption after oral ingestion, low diffusion in tissue organs, and low metabolic stability towards protease enzymes as well as undesired side-effects of flexible peptides due to interaction with several receptors.
To overcome these disadvantages, researchers are aiming at the development of new treatment methods based on peptides and proteins, by introducing both structural and functional specific modifications and maintaining the features responsible for biological activity. The synthesis, structure, and properties of peptide-biphenyl hybrids I and II (Fig. 1), which Structure of peptide-biphenyl hybrids I and II. are derivatives of 1,1-biphenyl with amino acids or peptide chains at the positions C2 and C2 0 (Mann et al., 2002;Montero, Mann et al., 2004) have been studied intensively to overcome the disadvantages mentioned above.
Biphenyl is a typical drug-like scaffold, which is present in 2.1% of reference drug molecules (Bemis et al., 1996). Based on the important role of the biphenyl unit and peptides in biological activity, we report here the synthesis and crystallographic study of a peptide-2,2 0 -biphenyl hybrid with the tripeptide Pro-Phe-Ala (Fig. 2).

Synthesis and crystallization
To a round-bottom flask was added amine HN-prolinephenylalanine-alanine-COOMe (1 eq.), Et 3 N (2 eq.) and anhydrous CH 2 Cl 2 (50mL). To this solution was added a solution of (1,1 0 -biphenyl)-2,2 0 -dicarbonyl dichloride in CH 2 Cl 2 at 273 K under an N 2 atmosphere. After completion of the reaction, the mixture was washed with 1N HCl solution, water and a solution of brine, respectively. The organic phase was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude product was then purified by flash chromatography (AcOEt/hexane 3:2) to give a yellow solid (63% yield). The compound was recrystallized by slow evaporation in methanol to give crystals suitable for X-ray diffraction. Partial crystal packing of the title compound with dashed lines representing the hydrogen bonds (see also Table 1).  Computer programs: APEX2 and SAINT (Bruker, 2013), olex2.solve (Bourhis et al., 2015), SHELXL (Sheldrick, 2015) and OLEX2 (Dolomanov et al., 2009).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All H atoms were positioned geometrically and treated as riding on their parent atoms with N-H = 0.88 Å and U iso (H) = 1.2U eq (N), C aromatic -H = 0.95 Å and U iso (H) = 1.2U eq (C), C proline, methylen -H = 0.99 Å and U iso (H) = 1.2 U eq (C), C methyl -H = 0.98 Å and U iso (H) = 1.5 U eq (C), O water -H = 0.87 Å and U iso (H) = 1.52U eq (O). A rotating group model (AFIX 137) was applied to the methyl groups at C1, C4, C48, C50. The solvent water molecule is disordered and was refined with a site occupation factor fixed to 0.5. The ring of one of the proline residues shows two conformations with refined occupancy factors for atom C17 converging to 0.746 (11) and 0.254 (11).  (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: olex2.solve (Bourhis et al., 2015); program(s) used to refine structure: SHELXL (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009). Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.