(S)-2-Aza­niumyl-2-methyl-3-phenyl­propano­ate monohydrate

Fujii, I.

doi:10.1107/S2414314616015169

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 1| Part 10| October 2016| x161516

https://doi.org/10.1107/S2414314616015169

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(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate

Isao Fujii ^a ^*

^aSchool of Science, Tokai University, 4-1-1 Kitakaname, Hiratuka, Kanagawa 259-1292, Japan
^*Correspondence e-mail: fujii@wing.ncc.u-tokai.ac.jp

Edited by S. Bernès, Benemérita Universidad Autónoma de Puebla, México (Received 25 August 2016; accepted 26 September 2016; online 7 October 2016)

The title compound, C₁₀H₁₃NO₂·H₂O, crystallizes in a zwitterionic form as a monohydrate, involving the propylbenzene group with a trans conformation. It is a non-natural amino acid, and has attracted attention as an inhibitor of phenylalanine hydroxylase. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming C(5) chains along the c-axis direction. Two chains are linked by another N—H⋯O hydrogen bond, forming an R₃³(11) ring motif. Further O—H⋯O hydrogen bonds link these motifs via the water molecules, to form a three-dimensional framework.

Keywords: crystal structure; phenylalanine hydroxylase inhibitor; zwitterion; hydrogen bonding; three-dimensional framework.

CCDC reference: 1506760

Structure description

Solid-phase synthesis is now the accepted method to synthesize peptides, in which protected natural or non-natural amino acids are widely used; for example, 2-methylphenylalanine (MePhe), a non-natural amino acid. At first, it attracted attention as a substrate analogue and an inhibitor of phenylalanine hydroxylase (EC 1.14.16.1: phenylalanine 4-monooxygenase), related to phenylketonuria (PKU), a genetic disorder (Greengard et al., 1976 ; Binek et al., 1981 ). Despite the biological and pharmaceutical interest, only a few crystal structures for 2-methyl-substituted phenylalanine derivatives have been reported, for example (R)-α-MePheOMe·HCl·H₂O (QABCAX; Crisma et al., 1997 ), (RS)-α-MeTyr (DMTYRS; Gaudestad et al., 1976 ) or (S)-α-MeDOPA·1.5H₂O (COSGUM; Neuman et al., 1984 ).

In the title compound (Fig. 1, CAS No. 23239–35-2 for the non-hydrated molecule), the molecule has a conformation like a cross, in which the propylbenzene group has a trans conformation [torsion angle C10—C2—C3—C4: τ = 167.9 (2)°]. A similar conformation is found in other 2-methyl-substituted amino acids, for example, isoVal monohydrate, CISNUP [τ = 177.0 (3)°; Butcher et al., 2013 ] and DMTYRS [τ = −176.58 (1)°], while the cis conformation is observed in other cases, as in QABCAX. This slightly distorted conformation is also comparable to that found in the crystal structures of phenylalanine derivatives, for example in L-Phe monohydrate (GOFWOP; Williams et al., 2013 ).

Figure 1
A view of the molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level. The dashed line indicates the intermolecular O—H⋯O hydrogen bond (see Table 1

, entry 3).

In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming C(5) chains along the c-axis direction (Table 1, entry 1). Two chains are linked by another N—H⋯O hydrogen bond, forming R₃³(11) rings, approximately parallel to the bc plane (Fig. 2). Further O—H⋯O and N—H⋯O hydrogen bonds link the layers of R rings via the water molecules, forming a three-dimensional framework (Table 1 and Fig. 3).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1C⋯O2ⁱ	0.93 (3)	1.83 (3)	2.7642 (18)	175 (3)
N1—H1B⋯O1ⁱⁱ	0.91 (2)	1.99 (2)	2.8581 (18)	160.6 (19)
O3—H11A⋯O2	0.87 (2)	2.06 (2)	2.897 (2)	160 (3)
O3—H11B⋯O1ⁱⁱⁱ	0.91 (2)	1.92 (2)	2.825 (2)	178 (4)
N1—H1A⋯O3^iv	0.96 (3)	2.40 (3)	3.050 (2)	124.9 (18)
Symmetry codes: (i) x, y, z+1; (ii) $[-x+{\script{3\over 2}}, -y, z+{\script{1\over 2}}]$ ; (iii) x-1, y, z; (iv) x+1, y, z+1.

Figure 2
A view of the crystal packing of the title compound. Dashed lines indicate the N—H⋯O and O—H⋯O hydrogen bonds (see Table 1

Figure 3
A view along the c axis of the crystal packing of the title compound. Dashed lines indicate the O—H⋯O and N—H⋯O hydrogen bonds (see Table 1

The methyl groups are surrounded by the hydrophilic planes and are arranged in a columnar structure (Fig. 3), similar to that of 2-MeAsp (NUPVUR; Fujii, 2015 ). The hydrophilic layers present a honeycomb arrangement, and are well separated from the hydrophobic layers along the b-axis direction (Fig. 3).

Synthesis and crystallization

The title compound was purchased from Nagase–Sangyo Co. Ltd. The absolute configuration could not be established by anomalous-dispersion effects. The S enantiomer has been chosen by referring to the sign of the known polarity in the synthetic procedure (Yamada et al., 1969 ). Rod-like colourless crystals of the title compound were obtained by vapour-phase diffusion of an aqueous ethanol–chloroform solvent mixture at room temperature.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₀H₁₃NO₂·H₂O
M_r	197.23
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	297
a, b, c (Å)	6.1146 (9), 28.3272 (10), 5.9614 (8)
V (Å³)	1032.6 (2)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	0.77
Crystal size (mm)	0.4 × 0.2 × 0.2

Data collection
Diffractometer	Enraf–Nonius CAD-4-turbo
Absorption correction	ψ scan (North et al., 1968 )
T_min, T_max	0.750, 0.860
No. of measured, independent and observed [I > 2σ(I)] reflections	1490, 1448, 1384
R_int	0.071
(sin θ/λ)_max (Å⁻¹)	0.623

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.029, 0.082, 1.08
No. of reflections	1448
No. of parameters	149
No. of restraints	2
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.16, −0.18
Computer programs: CAD-4 Software (Enraf–Nonius, 1994 ), XCAD4 (Harms & Wocadlo, 1995 ), SHELXS97 (Sheldrick, 2008 ), SHELXL2014 (Sheldrick, 2015 ), ORTEP-3 for Windows and WinGX (Farrugia, 2012 ), Mercury (Macrae et al., 2008 ) and publCIF (Westrip, 2010 ).

Structural data

CCDC reference: 1506760

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2414314616015169/bh4013sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314616015169/bh4013Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314616015169/bh4013Isup3.cml

checkCIF report

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius, 1994); cell refinement: CAD-4 Software (Enraf–Nonius, 1994); data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: WinGX (Farrugia, 2012) and publCIF (Westrip, 2010).

(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate top

Crystal data top

C₁₀H₁₃NO₂·H₂O	F(000) = 424
M_r = 197.23	D_x = 1.269 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Cu Kα radiation, λ = 1.54184 Å
Hall symbol: P 2ac 2ab	Cell parameters from 25 reflections
a = 6.1146 (9) Å	θ = 28–35°
b = 28.3272 (10) Å	µ = 0.77 mm⁻¹
c = 5.9614 (8) Å	T = 297 K
V = 1032.6 (2) Å³	Rod, colorless
Z = 4	0.4 × 0.2 × 0.2 mm

Data collection top

Enraf–Nonius CAD-4-turbo diffractometer	1384 reflections with I > 2σ(I)
Radiation source: Enraf–Nonius FR590	R_int = 0.071
Graphite monochromator	θ_max = 73.9°, θ_min = 3.1°
non–profiled ω/2θ scans	h = −1→7
Absorption correction: ψ scan (North et al., 1968)	k = 0→35
T_min = 0.750, T_max = 0.860	l = −7→0
1490 measured reflections	3 standard reflections every 60 min
1448 independent reflections	intensity decay: 1%

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F² > 2σ(F²)] = 0.029	w = 1/[σ²(F_o²) + (0.0485P)² + 0.1286P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.082	(Δ/σ)_max < 0.001
S = 1.08	Δρ_max = 0.16 e Å⁻³
1448 reflections	Δρ_min = −0.18 e Å⁻³
149 parameters	Extinction correction: SHELXL2014 (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
2 restraints	Extinction coefficient: 0.0047 (9)
0 constraints

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C10	0.2812 (3)	0.03959 (6)	0.5984 (3)	0.0381 (4)
H10A	0.3235	0.0072	0.5798	0.057*
H10B	0.1725	0.0476	0.4886	0.057*
H10C	0.222	0.0441	0.7461	0.057*
N1	0.6435 (2)	0.05862 (5)	0.7456 (2)	0.0301 (3)
O3	0.0250 (3)	0.09096 (7)	0.0372 (3)	0.0624 (4)
C1	0.5807 (3)	0.06044 (5)	0.3360 (2)	0.0280 (3)
C2	0.4804 (3)	0.07123 (5)	0.5680 (2)	0.0271 (3)
C3	0.4175 (3)	0.12352 (5)	0.5933 (3)	0.0343 (4)
H3A	0.3305	0.1327	0.4644	0.041*
H3B	0.3261	0.1269	0.7254	0.041*
C4	0.6074 (3)	0.15712 (5)	0.6137 (3)	0.0380 (4)
C5	0.7560 (4)	0.16373 (6)	0.4415 (4)	0.0473 (5)
H5	0.7382	0.1473	0.3077	0.057*
C6	0.9312 (4)	0.19445 (7)	0.4654 (5)	0.0618 (6)
H6	1.0315	0.1979	0.3494	0.074*
C7	0.9564 (5)	0.21965 (8)	0.6600 (5)	0.0756 (8)
H7	1.0724	0.2407	0.6755	0.091*
C8	0.8094 (6)	0.21368 (8)	0.8318 (5)	0.0786 (8)
H8	0.8264	0.2307	0.9639	0.094*
C9	0.6365 (4)	0.18263 (7)	0.8105 (4)	0.0565 (6)
H9	0.5389	0.1788	0.9287	0.068*
O1	0.75798 (19)	0.03832 (4)	0.3320 (2)	0.0377 (3)
O2	0.4743 (2)	0.07410 (5)	0.16925 (18)	0.0402 (3)
H1A	0.778 (4)	0.0757 (8)	0.733 (4)	0.054 (6)*
H1B	0.683 (4)	0.0279 (8)	0.739 (3)	0.043 (5)*
H1C	0.579 (5)	0.0644 (7)	0.885 (4)	0.055 (6)*
H11A	0.158 (4)	0.0929 (12)	0.091 (6)	0.111 (12)*
H11B	−0.058 (6)	0.0735 (11)	0.131 (6)	0.124 (14)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C10	0.0367 (8)	0.0508 (8)	0.0267 (7)	−0.0065 (8)	0.0027 (7)	−0.0004 (7)
N1	0.0343 (7)	0.0354 (7)	0.0207 (6)	0.0039 (6)	−0.0012 (6)	0.0007 (5)
O3	0.0504 (9)	0.0922 (12)	0.0447 (8)	0.0064 (9)	0.0081 (8)	0.0098 (8)
C1	0.0313 (7)	0.0329 (7)	0.0199 (6)	−0.0011 (6)	0.0032 (7)	−0.0014 (5)
C2	0.0288 (8)	0.0352 (7)	0.0173 (6)	0.0033 (6)	0.0005 (6)	0.0003 (5)
C3	0.0356 (8)	0.0386 (7)	0.0286 (7)	0.0082 (7)	0.0030 (7)	−0.0002 (6)
C4	0.0464 (9)	0.0305 (7)	0.0371 (8)	0.0069 (7)	−0.0009 (8)	0.0029 (6)
C5	0.0531 (11)	0.0382 (8)	0.0507 (10)	0.0007 (8)	0.0072 (11)	0.0034 (8)
C6	0.0539 (12)	0.0495 (10)	0.0819 (16)	−0.0035 (10)	0.0101 (14)	0.0158 (10)
C7	0.0731 (16)	0.0520 (11)	0.102 (2)	−0.0188 (12)	−0.0224 (19)	0.0098 (13)
C8	0.108 (2)	0.0584 (12)	0.0692 (15)	−0.0206 (15)	−0.0236 (19)	−0.0094 (12)
C9	0.0775 (15)	0.0477 (9)	0.0443 (10)	−0.0044 (11)	−0.0012 (13)	−0.0067 (8)
O1	0.0375 (6)	0.0449 (6)	0.0306 (5)	0.0102 (5)	0.0062 (6)	−0.0029 (5)
O2	0.0383 (7)	0.0628 (7)	0.0194 (5)	0.0065 (6)	0.0007 (5)	0.0011 (5)

Geometric parameters (Å, º) top

C10—C2	1.523 (2)	C3—C4	1.506 (3)
C10—H10A	0.96	C3—H3A	0.97
C10—H10B	0.96	C3—H3B	0.97
C10—H10C	0.96	C4—C5	1.383 (3)
N1—C2	1.4983 (19)	C4—C9	1.389 (2)
N1—H1A	0.96 (3)	C5—C6	1.388 (3)
N1—H1B	0.91 (2)	C5—H5	0.93
N1—H1C	0.93 (3)	C6—C7	1.371 (4)
O3—H11A	0.87 (2)	C6—H6	0.93
O3—H11B	0.91 (2)	C7—C8	1.373 (4)
C1—O2	1.2497 (19)	C7—H7	0.93
C1—O1	1.252 (2)	C8—C9	1.381 (4)
C1—C2	1.5435 (19)	C8—H8	0.93
C2—C3	1.538 (2)	C9—H9	0.93

C2—C10—H10A	109.5	C4—C3—H3A	108.5
C2—C10—H10B	109.5	C2—C3—H3A	108.5
H10A—C10—H10B	109.5	C4—C3—H3B	108.5
C2—C10—H10C	109.5	C2—C3—H3B	108.5
H10A—C10—H10C	109.5	H3A—C3—H3B	107.5
H10B—C10—H10C	109.5	C5—C4—C9	118.15 (19)
C2—N1—H1A	113.3 (14)	C5—C4—C3	122.14 (15)
C2—N1—H1B	112.2 (14)	C9—C4—C3	119.71 (17)
H1A—N1—H1B	104.6 (19)	C4—C5—C6	121.1 (2)
C2—N1—H1C	107.7 (16)	C4—C5—H5	119.5
H1A—N1—H1C	110 (2)	C6—C5—H5	119.5
H1B—N1—H1C	108.8 (19)	C7—C6—C5	120.0 (2)
H11A—O3—H11B	109 (3)	C7—C6—H6	120
O2—C1—O1	126.21 (14)	C5—C6—H6	120
O2—C1—C2	116.37 (13)	C6—C7—C8	119.5 (2)
O1—C1—C2	117.41 (13)	C6—C7—H7	120.2
N1—C2—C10	107.93 (12)	C8—C7—H7	120.2
N1—C2—C3	109.06 (12)	C7—C8—C9	120.7 (2)
C10—C2—C3	110.82 (14)	C7—C8—H8	119.6
N1—C2—C1	108.74 (12)	C9—C8—H8	119.6
C10—C2—C1	107.95 (12)	C8—C9—C4	120.5 (2)
C3—C2—C1	112.22 (12)	C8—C9—H9	119.8
C4—C3—C2	115.10 (14)	C4—C9—H9	119.8

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1C···O2ⁱ	0.93 (3)	1.83 (3)	2.7642 (18)	175 (3)
N1—H1B···O1ⁱⁱ	0.91 (2)	1.99 (2)	2.8581 (18)	160.6 (19)
O3—H11A···O2	0.87 (2)	2.06 (2)	2.897 (2)	160 (3)
O3—H11B···O1ⁱⁱⁱ	0.91 (2)	1.92 (2)	2.825 (2)	178 (4)
C10—H10C···O3ⁱ	0.96	2.5	3.378 (2)	153
N1—H1A···O3^iv	0.96 (3)	2.40 (3)	3.050 (2)	124.9 (18)

Symmetry codes: (i) x, y, z+1; (ii) −x+3/2, −y, z+1/2; (iii) x−1, y, z; (iv) x+1, y, z+1.

Acknowledgements

The author thanks Tokai University for a research grant, which partially supported this work.

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