organic compounds
(S)-2-Azaniumyl-2-methyl-3-phenylpropanoate monohydrate
aSchool of Science, Tokai University, 4-1-1 Kitakaname, Hiratuka, Kanagawa 259-1292, Japan
*Correspondence e-mail: fujii@wing.ncc.u-tokai.ac.jp
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 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 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 (GreengardIn 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).
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).
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 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.
could not be established by anomalous-dispersion effects. TheRefinement
Crystal data, data collection and structure .
details are summarized in Table 2
|
Structural data
CCDC reference: 1506760
https://doi.org/10.1107/S2414314616015169/bh4013sup1.cif
contains datablocks I, global. DOI: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
Data collection: CAD-4 Software (Enraf–Nonius, 1994); cell
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).C10H13NO2·H2O | F(000) = 424 |
Mr = 197.23 | Dx = 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 |
Enraf–Nonius CAD-4-turbo diffractometer | 1384 reflections with I > 2σ(I) |
Radiation source: Enraf–Nonius FR590 | Rint = 0.071 |
Graphite monochromator | θmax = 73.9°, θmin = 3.1° |
non–profiled ω/2θ scans | h = −1→7 |
Absorption correction: ψ scan (North et al., 1968) | k = 0→35 |
Tmin = 0.750, Tmax = 0.860 | l = −7→0 |
1490 measured reflections | 3 standard reflections every 60 min |
1448 independent reflections | intensity decay: 1% |
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(Fo2) + (0.0485P)2 + 0.1286P] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.082 | (Δ/σ)max < 0.001 |
S = 1.08 | Δρmax = 0.16 e Å−3 |
1448 reflections | Δρmin = −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 |
x | y | z | Uiso*/Ueq | ||
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)* |
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) |
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 |
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···O3iv | 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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