N-tert-But­oxy­carbonyl-α-(2-fluoro­benzyl)-l-proline

P Rajalakshmi; N Srinivasan; R V Krishnakumar; Ibrahim Abdul Razak; Mohd Mustaqim Rosli

doi:10.1107/S1600536813019788

. 2013 Jul 24;69(Pt 8):o1297. doi: 10.1107/S1600536813019788

N-tert-Butoxycarbonyl-α-(2-fluorobenzyl)-l-proline

P Rajalakshmi ^a, N Srinivasan ^a,^*, R V Krishnakumar ^a, Ibrahim Abdul Razak ^b, Mohd Mustaqim Rosli ^b

PMCID: PMC3793788 PMID: 24109375

Abstract

In the title compound, C₁₇H₂₂FNO₄, the pyrrolidine ring adopts an envelope conformation with the disordered components of the methylene C atom, with site occupancies of 0.896 (7) and 0.104 (7), being the flap on either side of the mean plane involving the other atoms of the ring. The carboxylic acid group forms dihedral angles of 72.06 (11) and 45.44 (5)° with the N-tert-butoxycarbonyl group and the 2-fluorobenzyl group, respectively. In the crystal, two-dimensional layers of molecules parallel to (001) are built through an R ₄ ⁴(23) motif generated via O—H⋯O, C—H⋯O and C—H⋯F interactions, and an R ₂ ²(11) motif generated by C—H⋯O and C—H⋯F interactions.

Related literature

For general background, see: Taylor et al. (1998 ▶); Jeng et al. (2002 ▶); Anderson et al. (2004 ▶); Ryder et al. (2000 ▶). For biological activity of the title compound, see: Tamazyan et al. (2004 ▶). For graph-set notation of hydrogen bonding, see: Bernstein et al. (1995 ▶). For puckering parameters, see: Cremer & Pople (1975 ▶). graphic file with name e-69-o1297-scheme1.jpg

Experimental

Crystal data

C₁₇H₂₂FNO₄
M _r = 323.36
Orthorhombic,
a = 10.4777 (1) Å
b = 12.4283 (2) Å
c = 13.1550 (2) Å
V = 1713.04 (4) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 100 K
0.54 × 0.34 × 0.24 mm

Data collection

Bruker Kappa APEXII diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2008 ▶) T _min = 0.962, T _max = 0.977
14001 measured reflections
3426 independent reflections
2712 reflections with I > 2σ(I)
R _int = 0.031
Standard reflections: 0

Refinement

R[F ² > 2σ(F ²)] = 0.050
wR(F ²) = 0.114
S = 1.06
3426 reflections
225 parameters
8 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.37 e Å⁻³
Δρ_min = −0.32 e Å⁻³

Data collection: APEX2 (Bruker, 2009 ▶); cell refinement: SAINT (Bruker, 2009 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLUTON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536813019788/gk2586sup1.cif

e-69-o1297-sup1.cif^{(29.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813019788/gk2586Isup2.hkl

e-69-o1297-Isup2.hkl^{(164.6KB, 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
C15—H15A⋯F1ⁱ	0.95	2.59	3.378 (3)	141
C16—H16A⋯O1ⁱ	0.95	2.60	3.541 (3)	173
O1—H1⋯O3ⁱⁱ	0.89 (3)	1.73 (3)	2.611 (2)	173 (3)

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

Acknowledgments

The authors thank Dr Mutharasu Devarajan, Associate Professor, and the staff of the X-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, for their help in the data collection.

supplementary crystallographic information

Comment

Modified amino acids are known to enhance the chemical, physical and biological properties of proteins (Anderson et al., 2004). Also, due to their structural diversity and functional versatility, they are widely used as chiral building blocks and molecular scaffolds in pharmaceutics (Taylor et al., 1998; Ryder et al., 2000; Jeng et al., 2002). N-Butoxycarbonyl-(S)-α-benzyl proline, a closely related analogue of the title compound N-tert-butoxycarbonyl-α-(2-fluorobenzyl)-L-proline, is a potential non-nucleoside reverse transcriptase inhibitor in anti-human-immunodeficiency virus type-1 (Tamazyan et al., 2004).

The present paper describes the crystal structure of the title compound (Fig. 1), which crystallizes in the orthorhombic space group P2₁2₁2₁. It is a modified amino acid with the N-terminus protected by a tert-butyloxycarbonyl (Boc) group and the C^α (C2) H atom replaced by a 2-fluorobenzyl group. In the pyrrolidine ring, the C4 atom of the ring displays positional disorder with site-occupation factors of 0.896 (7) and 0.104 (7). The pyrrolidine ring (N1/C2/C3/C4A/C5) adopts the envelope conformation with the C4A atom deviating from the plane defined the remaining ring atoms by 0.5677 (4) Å. Puckering parameters calculated for this ring are of Q = 0.369 (3) Å, φ = 285.7 (3)° (Cremer & Pople, 1975). The dihedral angles between the mean plane of the carboxylic acid group, N-Boc and 2-methyl-2-fluorobenzene are 72.06 (11)° and 45.44 (5)°, respectively.

The molecules are linked by a combination of O—H···O, C—H···O and C—H···F hydrogen bonds. The carboxylic O1 acts as a donor to the carbonyl O3 at (-x + 1, y - 1/2, -z + 3/2) forming chains parallel to the b axis through C(7) motifs (Bernstein et al., 1995). These 2₁ screw-generated parallel chains are interconnected through C15—H15A···F1 (-x, y + 1/2, -z + 3/2) and C16—H16A···O1 (-x, y + 1/2, -z + 3/2) hydrogen bonds leading to a layer parallel to the ab plane. The characteristic building units of this layer are an R⁴₄(23) ring generated by all the hydrogen-bonds and an R²₂(11) generated exclusively by C—H···O and C—H···F hydrogen bonds (Fig. 2).

Experimental

A mixture of 2-(2-fluorobenzyl)-L-proline (1.0 mmol) and tetramethylammonium hydroxide pentahydrate (1.2 mmol) in acetonitrile (10 ml) was stirred for 30 min. After 30 min, Boc₂O (2.0 mmol) was added and stirred continuously for 2 d. The acetonitrile was removed in vacuo and residue was partitioned between ether (20 ml) and water (10 ml). The aqueous layer was washed with ether (10 ml) and acidified with 10% aqueous citric acid to pH 3–4. The aqueous layer was extracted with ethyl acetate (3 × 10 ml) and combined organic extracts were washed with brine solution (1 × 10 ml), dried over Na₂SO₄, and concentrated to yield N-tert-butoxycarbonyl-α-(2-fluorobenzyl)-L-proline (m.p. 430-433 K) as a white solid. Crystals were grown from ethanolic solution by slow evaporation at room temperature.