Crystal structure of (3R)-3-benzyl-4-[(tert-but­oxy­carbon­yl)amino]­butanoic acid

Karol Jędrzejczak; Małgorzata Szczesio; Monika Oracz; Stefan Jankowski; Marek L Główka

doi:10.1107/S1600536814019497

. 2014 Sep 3;70(Pt 10):o1081–o1082. doi: 10.1107/S1600536814019497

Crystal structure of (3R)-3-benzyl-4-[(tert-butoxycarbonyl)amino]butanoic acid

Karol Jędrzejczak ^a, Małgorzata Szczesio ^b, Monika Oracz ^b, Stefan Jankowski ^a, Marek L Główka ^b,^*

PMCID: PMC4257155 PMID: 25484683

Abstract

The characteristic feature of the title molecule, C₁₆H₂₃NO₄, is the syn configuration of the partially double amide C—N bond [C—N—C—O torsion angle = −14.8 (2)°]. The crystal packing is determined by intermolecular O—H⋯O and N—H⋯O hydrogen bonds, which link the molecules into a double-chain structure extending along [010].

Keywords: crystal structure, butanoic acid, monosubstituted γ-amino acids, hydrogen bonding

Related literature

The title enantiomeric compound was synthesized according to Loukas et al. (2003 ▶) and Felluga et al. (2008 ▶). For related structures, see: Pihko & Koskinen (1998 ▶); Jimeno et al. (2011 ▶). For solution conformation of oligomers based on monosubstituted γ-amino acids, see: Guo et al. (2012 ▶); Kang & Byun (2012 ▶). For amino acid analysis by HPLC after derivatization with Marfey’s reagent, see: Marfey (1984 ▶). graphic file with name e-70-o1081-scheme1.jpg

Experimental

Crystal data

C₁₆H₂₃NO₄
M _r = 293.35
Monoclinic,
a = 19.5872 (12) Å
b = 6.5263 (4) Å
c = 14.7598 (9) Å
β = 120.846 (2)°
V = 1619.89 (17) Å³
Z = 4
Cu Kα radiation
μ = 0.70 mm⁻¹
T = 100 K
0.4 × 0.04 × 0.04 mm

Data collection

Bruker SMART APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2003 ▶) T _min = 0.738, T _max = 0.973
8769 measured reflections
2880 independent reflections
2805 reflections with I > 2σ(I)
R _int = 0.036

Refinement

R[F ² > 2σ(F ²)] = 0.029
wR(F ²) = 0.073
S = 1.06
2880 reflections
197 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.16 e Å⁻³
Δρ_min = −0.18 e Å⁻³
Absolute structure: Flack (1983 ▶), 1138 Friedel pairs
Absolute structure parameter: 0.05 (15)

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT-Plus (Bruker, 2008 ▶); 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, 2009 ▶) and Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: PLATON.

Supplementary Material

Crystal structure: contains datablock(s) I, New_Global_Publ_Block. DOI: 10.1107/S1600536814019497/gk2614sup1.cif

e-70-o1081-sup1.cif^{(24.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814019497/gk2614Isup2.hkl

e-70-o1081-Isup2.hkl^{(141.4KB, hkl)}

Click here for additional data file.^{(5.9KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814019497/gk2614Isup3.cml

Click here for additional data file.^{(1.2MB, tif)}

. DOI: 10.1107/S1600536814019497/gk2614fig1.tif

The molecular structure with displacement ellipsoids drawn at the 50% probability level.

Click here for additional data file.^{(1.5MB, tif)}

. DOI: 10.1107/S1600536814019497/gk2614fig2.tif

Packing of the title compound viewed along the [101] direction.

CCDC reference: 938020

Additional supporting information: crystallographic information; 3D view; checkCIF report

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O6ⁱ	0.82	1.83	2.6368 (15)	170
N5—H5⋯O2ⁱⁱ	0.846 (18)	2.131 (18)	2.8856 (16)	148.2 (15)

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

supplementary crystallographic information

S1. Comment

γ-Amino acids are important components of α,γ-peptide hybrids, which are resistant towards enzymatic degradation and, as a result, display useful biological activity, including antibiotic, antiviral and anticancer properties. The acids are also important elements of foldamers. In comparison with the α-amino acids, they show significant flexibility due to the two additional single bonds between the carboxylic and amine functions. Still, their oligomers form well defined conformations in solutions, in particular helical ones in the case of monosubstituted γ-amino acids (Guo et al., 2012, Kang et al., 2012). Thus, the structures and common conformations of γ-amino acids and their derivatives are of interest. The molecular structure is shown in Figure 1. The crystal packing is determined by intermolecular N5—H···O2 and O1—H···O6 hydrogen bonds, which organize the molecules into infinite double chains parallel to the [010] direction (Fig.2). The geometrical parameters of the hydrogen bonds are listed in Table 1.

S2. Experimental

(3R)-4-((tert-Butoxycarbonyl)amino-)-3-benzyl-butanoic acid was obtained from racemic (±)-3-aminomethyl-4-phenylbutanoic acid hydrochloride, which was synthesized following earlier published procedure (Felluga et al., 2008), with some modifications. Ethyl (±)-3-nitromethyl-4-phenylbutanoate was hydrolyzed and then hydrogenated using 10% Pd/C to get acid, which was transformed into Boc-derivative and purified by crystallization from ethyl acetate/hexane.

Enantiomeric resolution of racemic (±)-3-aminomethyl-4-phenylbutanoic acid (1 g) was achieved by crystallization from ethyl acetate (110 mL) in the presence of (S)-(-)-methylbenzylamine (0.41 g). The solution was left for 24 h at +5°C for crystallization, which was repeated four times to obtain (3S)-4-((tert-butoxycarbonyl)amino-)-3-benzyl-butanoic acid (0.151 g) with ee = 97.4 %. (R)-(+)-Methylbenzylamine (0.17 g) was applied to the mother liquor after the first crystallization of (3S)-4-((tert-butoxycarbonyl)amino-)-3-benzyl-butanoic acid ammonium salt. Three subsequent crystallizations led to (3R)-(-)-4-((tert-butoxycarbonyl)amino-)-3-phenyl-pentanoic acid (0.196 g) with ee = 98.1 %. Acids were recovered from ethyl acetate solution using 1M NaHSO₄ solution.

The enantiomeric purity was determined according to the known procedure using N_α-(2,4-dinitro-5-fluorophenyl)-L-valinamide as derivating reagent (Marfey, 1984). Sample of enantiomer (5 mg) was dissolved in TFA – dichloromethane (1:1), the solution was shaken for 10 min, then solvents were removed by evaporation. The residue was dissolved in CH₂Cl₂ and the solvent was removed again. This procedure was repeated five times to remove TFA completely. The dry residue was dissolved in 0.2 M NaHCO₃ to obtain 0.05 M solutions (0.5 mL) of (3R)-4-amino–3-benzyl-butanoic acid. Mixture of 0.05 M aqueous solution of deprotected amino acid (25 µL), 0.2 N NaHCO₃ (50 µL), 1% solution of N_α-(2,4-dinitro-5-fluorophenyl)-L-valine amide in acetone (50 µL) and 75 µL of acetone was shaken for 1 minute and then placed in a water bath for 45 min at 45°C. Then mixture was shaken again for 30 sec, 0.1M HCl (170 µL) and acetone (75 µL) were added. A yellowish solution was analysed by HPLC (Vydac column C8 (4.6 x 25 cm), gradient 40 - 80, detection at 340 nm), diastereomeric derivative of (3R)-4-amino-3-benzyl-butanoic acid was detected at 12.67 min retention time.

Single crystals were obtained by recrystallization from acetonitrile at room temperatute.