Conformation and crystal structures of 1-aminocyclohexaneacetic acid (β3,3Ac6c) in N-protected derivatives1

The gauche conformation of backbone torsion angles (ϕ, θ) for β3,-Ac6c-OH is observed in the N-protected derivatives of 1-aminocyclohexaneacetic acid.


Chemical context
-Amino acids are homologues of -amino acids, which are constituents of several bioactive natural and synthetic products. -Amino acids have been used as building blocks in peptidomimetic drug design (Cheng et al. 2001). The introduction of -amino acids into pharmacologically active peptide sequences has shown improved biological activity and metabolic stability (Yamazaki et al., 1991;Huang et al., 1993). The backbone conformation of a -amino acid is defined by the torsional angles ', and (Banerjee & Balaram, 1997), as shown in Fig. 1. The monosubstitution at theand -carbon atoms plays an important role in the folding of oligomers of -amino acids (Seebach et al., 2009).
In order to investigate the effect of protecting groups and disubstitution on the conformation of -amino acids, N- ISSN 1600-5368 protected derivatives of 1-aminocyclohexaneacetic acid ( 3,3 Ac 6 c), i.e. Valeroyl-3,3 -Ac 6 c-OH (I), Fmoc-3,3 -Ac 6 c-OH (II) and Pyr-3,3 -Ac 6 c-OH (III) were synthesized. The crystal structures of the three compounds were determined and are reported herein, together with their comparative conformational features.

Figure 2
ORTEP view of the molecular conformation with the atom-labelling scheme. for Valeroyl-3,3 -Ac 6 c-OH (I), (b) Fmoc-3,3 -Ac 6 c-OH (II) and (c) Pyr-3,3 -Ac 6 c-OH (III    motif which is extended into a ribbon structure along the caxis direction through a second but non-centrosymmetric cyclic carboxylic acid R 2 2 (8) O2-HÁ Á ÁO i hydrogen-bond motif (Fig. 4a). In (II), the intermolecular dimeric association is through the centrosymmetric R 2 2 (8) carboxylic acid hydrogenbonding motif. Structure extension is through N1-HÁ Á ÁO1 0 (carboxyl) hydrogen bonds (Table 2), generating a twodimensional layered structure lying parallel to (010) (Fig. 4c). Also present in the structure areinteractions between the Fmoc groups with an intercentroid distance of 3.786 (2) Å . Fig. 4c shows the aromatic rings of Fmoc groups stacked in a face-to-face and edge-to-face manner, together with interplane distances that are within the range for stabilizinginteractions (Burley & Petsko, 1985;Sengupta et al., 2005) and have been reported to induce self-assembly in peptides (Wang & Chau, 2011). In the case of (I) and (II), the molecular packing in the crystals leads to the formation of alternating hydrophobic and hydrophilic layers. In the crystals of (III), in which no dimer substructure formation is present, the molecules are linked by an intermolecular carboxylic acid O2-HÁ Á ÁN2 i hydrogen bond (Table 3) with a pyrazine N-atom acceptor, leading to the formation of a zigzag ribbon structure extending along the c-axis direction.

Synthesis and crystallization
Preparation of Valeroyl-3,3 Ac 6 c-OH (I): 3,3 Ac 6 c-OH (5 mmol, 785 mg) was dissolved in 5 ml of a 2M NaOH solution and a solution of 5 mmol of valeric anhydride (931 mg) dissolved in 1,4-dioxane was added, after which the mixture was stirred for 4 h at room temperature. On completion of the reaction, the 1,4-dioxane was evaporated and the product was extracted with diethyl ether (3 Â 5 ml). The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3 Â 10ml) and the combined organic layer was washed with brine solution. The organic layer was passed over anhydrous Na 2 SO 4 and evaporated to give Valeroyl-3 Ac 6 c-OH (yield: 1.1 g, 85.2%). Single crystals were grown by slow evaporation from a solution in methanol/water. Preparation of Fmoc-3,3 Ac 6 c-OH (II): 3,3 Ac 6 c-OH (10 mmol, 1.57 g) was dissolved in 1M Na 2 CO 3 solution and Fmoc-OSu (10 mmol, 3.37 g) dissolved in CH 3 CN was added.  Table 1 Hydrogen-bond geometry (Å , ) for (I). Symmetry codes: (i) Àx; y þ 1 2 ; Àz þ 1 2 ; (ii) Àx; Ày; Àz.    The reaction mixture was stirred at room temperature for 6 h. After completion of the reaction, the CH 3 CN was evaporated and the residue was extracted with diethyl ether (3 Â 10 ml). The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3 Â 15 ml). The combined organic layer was washed with brine solution. The ethyl acetate layer was passed over anhydrous Na 2 SO 4 and evaporated. The residue was purified by crystallization in ethyl acetate/n-hexane, affording Fmoc-3,3 Ac 6 c-OH (yield: 3.0 g, 79%). Single crystals were obtained by slow evaporation from an ethyl acetate/ n-hexane solution. Preparation of Pyr-3,3 Ac 6 c-OH (III): Pyrazine carboxylic acid (3 mmol, 372 mg) was dissolved in dry CH 2 Cl 2 and then 200 ml of N-methylmorpholine was added, followed by 3,3 Ac 6 c-OMe. HCl (3 mmol, 622.5 mg) and EDCI. HCl (3 mmol,576 mg) at 273 K. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, water was added and the reaction mixture was extracted with CH 2 Cl 2 (3 Â 5ml). The combined organic layer was washed with 2M HCl (2 Â 5ml), Na 2 CO 3 (2 Â 5ml) and brine solution (2 Â 5ml). The organic layer was passed over anhydrous Na 2 SO 4 and evaporated to give Pyr-3,3 Ac 6 c-OMe (Yield: 600 mg, 72.2%). Pyr-3,3 Ac 6 c-OMe (2 mmol, 554 mg) was dissolved in 2 ml of methanol and 1 ml of 2M NaOH, and the reaction mixture was stirred at room temperature for 4 h. Methanol was evaporated and the residue was extracted with diethyl ether (2 Â 5ml). The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3 Â 5ml). The combined organic layer was washed with brine solution (1 Â 5ml). The ethyl acetate layer was passed over anhydrous Na 2 SO 4 and evaporated to give Pyr-3,3 Ac 6 c-OH (yield: 370 mg, 70.3%). Single crystals were grown from an ethanol/ water solution.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 4. For derivative (I), H atoms for N1 and O2 were located in a difference Fourier map and both their coordinates and U iso values were refined. The remaining H atoms were positioned geometrically and were treated as riding on their parent C atoms, with C-H distances of 0.96-0.98 Å and with U iso (H) = 1.2U eq (C) or 1.5U eq (methyl C). For derivatives (II) and (III), all hydrogen atoms were located from a difference Fourier map and both their coordinates and U iso values were refined. In (II), the carboxyl O-H distance was constrained to 0.84 Å . Although not of consequence with the achiral molecule of (III), which crystallized in the non-  SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: PLATON (Spek, 2009).  Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.