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Acta Crystallogr Sect E Struct Rep Online. 2008 December 1; 64(Pt 12): o2447.
Published online 2008 November 26. doi:  10.1107/S1600536808039056
PMCID: PMC2960037

(S)-2-[(2R,3S)-2-Ammonio-3-hydr­oxy-3-(4-nitro­phen­yl)propanamido]-4-methyl­penta­noate monohydrate

Abstract

The structure of the title compound, C15H21N3O6·H2O, is of inter­est with respect to assumed anti­cancer activity. The title mol­ecules are linked through inter­molecular O—H(...)O hydrogen-bonded chains along the a axis. These chains are connected by inter­molecular N—H(...)O hydrogen bonds through the crystallographic screw axis along [010], forming layers, which are stabilized by other N—H(...)O bonds with water O atoms as acceptors and O—H(...)O bonds with water H atoms as donors. The H atoms of the protonated amino cation are also involved in inter­molecular N—H(...)O bonding inter­actions.

Related literature

For various medicinal agents similar to the title compound, see: Shinagawa et al. (1987 [triangle]); Shin & Pyo (1984 [triangle]). For anti-cancer and anti-inflammatory biological properties, see: Aozuka et al. (2004 [triangle]). For amino­peptidase N (APN/CD13) inhibitors, see: Xu & Li (2005 [triangle]). For the synthesis of the starting material, see: Testa et al. (2004 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-o2447-scheme1.jpg

Experimental

Crystal data

  • C15H21N3O6·H2O
  • M r = 357.36
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-o2447-efi1.jpg
  • a = 8.9787 (7) Å
  • b = 6.7850 (5) Å
  • c = 14.7148 (11) Å
  • β = 95.362 (5)°
  • V = 892.51 (12) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.11 mm−1
  • T = 296 (2) K
  • 0.50 × 0.20 × 0.15 mm

Data collection

  • Bruker APEXII CCD area-detector diffractometer
  • Absorption correction: multi-scan (SADABS; Bruker, 2005 [triangle]) T min = 0.949, T max = 0.984
  • 8245 measured reflections
  • 2254 independent reflections
  • 1853 reflections with I > 2σ(I)
  • R int = 0.028

Refinement

  • R[F 2 > 2σ(F 2)] = 0.041
  • wR(F 2) = 0.104
  • S = 1.04
  • 2254 reflections
  • 243 parameters
  • 1 restraint
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.19 e Å−3
  • Δρmin = −0.16 e Å−3

Data collection: APEX2 (Bruker, 2005 [triangle]); cell refinement: APEX2 and SAINT (Bruker, 2005 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: WinGX (Farrugia, 1999 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808039056/si2128sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808039056/si2128Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

Financial support from the National Natural Foundation Research (grant Nos. 30701053, 30772654, 36072541) is gratefully acknowledged.

supplementary crystallographic information

Comment

The 2-amino-1-hydroxy carboxylic acids and 1-amino-2-hydroxy carboxylic acids are important precursor and scaffold of various medicinal agents (Shinagawa et al., 1987). It was reported that many of their derivatives exhibit anti-cancer and anti-inflammatory properties (Aozuka et al., 2004). Our lab has been engaged in developing 1-amino-2-hydroxy carboxylic acids derivatives as Aminopeptidase N (APN/CD13) inhibitors (Xu & Li, 2005). One of the aims of the projects is to use different amino acid coupled with 1-amino-2-hydroxy carboxylic acids scaffold, the resulting target derivatives are hope to have antitumor activities. Both the title compound (Fig. 1) and the reported chloramphenicol base have the amino-hydroxy-nitrophenyl scaffold in their structures (Shin & Pyo, 1984). In the molecule, the bond length of C8–N2 is 1.489 (3) Å, which is slightly longer than that of the C8–N2 (1.473 (7) Å) in the chloramphenicol base. This is probably due to the electrostatic attractions between the carboxyl anion and the protonated amino cation. The title molecules are linked through intermolecular O—H···O hydrogen bonded chains along the a axis (Table 1, Fig. 2). These chains are connected by intermolecular N—H···O hydrogen bonds through the crystallographic screw axis along the [0 1 0] direction to form layers which are stabilized by other N—H···O bonds with water oxygen atoms as acceptors and O—H···O bonds with water hydrogen atoms as donors.The H atoms of the protonated amino cation were also involved in intermolecular N—H···O bonding interactions.

Experimental

The starting material, (2R,3S)-2-(tert-butoxycarbonylamino) -3-hydroxy-3-(4-nitrophenyl) propanoic acid, prepared according to the literature (Testa et al., 2004), was coupled with L-leucine methyl ester by using dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt). Finally, the title compound was yielded by hydrolyzing in NaOH and then deprotecting Boc group with hydrochloride. Crystals appropriate for data collection were obtained by slow evaporation of the solid in methanol at room temperature. Yield 40%, m.p. 481 K.

Refinement

All H atoms were positioned geometrically using a riding model with C—H = 0.92–1.02 Å, N—H = 0.86 and O—H = 0.82 Å. Their isotropic displacement parameters were set to 1.2 times (1.5 times for CH3 groups) the equivalent displacement parameter of their parent atoms. In addition, the three H atoms at N2 were located from a difference Fourier map and refined isotropically, with N–H distances in the range 0.88 (3)–0.92 (3) Å with Uiso(H) = 1.3–1.75 times Ueq(N2).

In the absence of significant anomalous dispersion effects, 1625 Friedel pairs were averaged.

Figures

Fig. 1.
A view of the title molecules, showing 30% probability displacement ellipsoids and the numbering scheme of non-hydrogen atoms.
Fig. 2.
A view of the unit cell of the title compound, showing intermolecular hydrogen bonds as dashed lines.

Crystal data

C15H21N3O6·H2OF000 = 380
Mr = 357.36Dx = 1.330 Mg m3
Monoclinic, P21Melting point = 556.2–558.6 K
Hall symbol: P 2ybMo Kα radiation λ = 0.71073 Å
a = 8.9787 (7) ÅCell parameters from 2639 reflections
b = 6.7850 (5) Åθ = 2.8–24.2º
c = 14.7148 (11) ŵ = 0.11 mm1
β = 95.362 (5)ºT = 296 (2) K
V = 892.51 (12) Å3Prism, colourless
Z = 20.50 × 0.20 × 0.15 mm

Data collection

Bruker APEXII CCD area-detector diffractometer2254 independent reflections
Radiation source: fine-focus sealed tube1853 reflections with I > 2σ(I)
Monochromator: graphiteRint = 0.028
T = 296(2) Kθmax = 27.6º
[var phi] and ω scansθmin = 2.3º
Absorption correction: multi-scan(SADABS; Bruker, 2005)h = −11→11
Tmin = 0.949, Tmax = 0.984k = −8→8
8245 measured reflectionsl = −19→18

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.041H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.105  w = 1/[σ2(Fo2) + (0.059P)2 + 0.0778P] where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max < 0.001
2254 reflectionsΔρmax = 0.19 e Å3
243 parametersΔρmin = −0.16 e Å3
1 restraintExtinction correction: none
Primary atom site location: structure-invariant direct methods

Special details

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 F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

xyzUiso*/Ueq
C10.1171 (3)1.0193 (5)0.8450 (2)0.0593 (8)
C20.1386 (3)1.1114 (5)0.7646 (2)0.0576 (8)
H20.16201.24490.76370.069*
C30.1250 (3)1.0037 (4)0.68503 (19)0.0466 (6)
H100.13881.06470.62980.056*
C40.0906 (2)0.8025 (4)0.68693 (16)0.0350 (5)
C50.0699 (3)0.7141 (5)0.76921 (18)0.0487 (7)
H50.04660.58060.77080.058*
C60.0834 (3)0.8219 (6)0.8498 (2)0.0627 (9)
H60.07000.76240.90530.075*
C70.0792 (2)0.6835 (4)0.59945 (16)0.0320 (5)
H70.05860.54570.61370.038*
C80.2268 (2)0.6944 (3)0.55531 (14)0.0303 (5)
H80.25700.83260.55090.036*
C90.3482 (2)0.5812 (4)0.61333 (15)0.0313 (5)
C100.7060 (2)0.5166 (4)0.64655 (17)0.0386 (6)
C110.5895 (2)0.6028 (4)0.70569 (15)0.0368 (5)
H110.55330.49840.74410.044*
C120.6643 (3)0.7644 (5)0.76667 (18)0.0469 (6)
H12A0.74400.70470.80640.056*
H12B0.71000.85830.72800.056*
C130.5625 (4)0.8776 (7)0.8260 (2)0.0707 (10)
H130.47900.93170.78600.085*
C140.6501 (6)1.0509 (8)0.8721 (3)0.1067 (16)
H14A0.72691.00110.91590.160*
H14B0.58321.13310.90250.160*
H14C0.69501.12660.82680.160*
C150.4992 (5)0.7477 (10)0.8948 (3)0.1045 (17)
H15A0.57920.69440.93530.157*
H15B0.44420.64200.86400.157*
H15C0.43370.82320.92920.157*
N10.1333 (4)1.1348 (8)0.9301 (3)0.0933 (13)
N20.2080 (2)0.6066 (3)0.46217 (14)0.0345 (4)
N30.46309 (18)0.6869 (3)0.64893 (13)0.0346 (4)
H3A0.46340.81150.63810.042*
O10.1562 (6)1.3125 (7)0.9239 (3)0.1463 (17)
O20.1267 (4)1.0520 (8)1.0013 (2)0.1297 (16)
O3−0.03561 (16)0.7538 (3)0.53411 (11)0.0371 (4)
H4−0.11470.69880.54200.056*
O40.33299 (19)0.4031 (3)0.62517 (14)0.0482 (5)
O50.71194 (18)0.5906 (3)0.56790 (12)0.0471 (5)
O60.7901 (2)0.3852 (3)0.67915 (14)0.0548 (5)
O70.50705 (17)0.5833 (3)0.42343 (12)0.0410 (4)
H7W0.54210.58860.48400.086 (12)*
H8W0.53270.67920.38730.071 (10)*
H2B0.154 (3)0.500 (5)0.4578 (19)0.045 (8)*
H2C0.162 (4)0.702 (5)0.416 (2)0.055 (8)*
H2A0.305 (4)0.564 (5)0.448 (2)0.060 (9)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0459 (16)0.076 (2)0.0564 (18)0.0056 (15)0.0037 (13)−0.0238 (17)
C20.0583 (18)0.0473 (16)0.0666 (19)0.0060 (14)0.0025 (14)−0.0134 (16)
C30.0478 (15)0.0390 (14)0.0530 (16)0.0044 (12)0.0046 (12)−0.0038 (13)
C40.0207 (10)0.0405 (13)0.0438 (13)0.0056 (9)0.0035 (9)−0.0001 (11)
C50.0405 (14)0.0568 (18)0.0502 (15)−0.0030 (12)0.0117 (11)0.0034 (14)
C60.0536 (17)0.092 (3)0.0436 (16)−0.0035 (18)0.0122 (13)0.0009 (17)
C70.0198 (9)0.0319 (10)0.0443 (12)0.0009 (9)0.0030 (8)0.0040 (10)
C80.0212 (10)0.0278 (10)0.0420 (12)−0.0012 (8)0.0041 (8)−0.0011 (10)
C90.0234 (10)0.0322 (12)0.0389 (11)0.0043 (9)0.0063 (8)−0.0008 (10)
C100.0236 (10)0.0444 (14)0.0469 (14)−0.0012 (10)−0.0007 (9)−0.0097 (11)
C110.0246 (10)0.0462 (14)0.0394 (12)0.0048 (10)0.0019 (8)0.0056 (11)
C120.0376 (13)0.0602 (16)0.0419 (13)0.0076 (12)−0.0014 (10)−0.0077 (13)
C130.0663 (19)0.099 (3)0.0454 (16)0.034 (2)−0.0050 (14)−0.0190 (18)
C140.143 (4)0.097 (3)0.079 (3)0.024 (3)−0.001 (3)−0.040 (3)
C150.084 (3)0.170 (5)0.064 (2)0.017 (3)0.0297 (19)−0.009 (3)
N10.085 (2)0.126 (4)0.069 (2)0.004 (2)0.0054 (17)−0.041 (2)
N20.0247 (10)0.0361 (11)0.0433 (11)−0.0023 (9)0.0057 (8)−0.0012 (10)
N30.0223 (9)0.0356 (10)0.0458 (11)−0.0005 (8)0.0027 (7)0.0025 (9)
O10.222 (5)0.107 (3)0.105 (3)0.002 (3)−0.009 (3)−0.062 (3)
O20.155 (3)0.180 (4)0.0575 (16)−0.041 (3)0.0267 (18)−0.043 (2)
O30.0214 (7)0.0398 (9)0.0495 (9)0.0015 (7)0.0012 (6)0.0023 (8)
O40.0373 (9)0.0318 (9)0.0742 (12)0.0033 (8)−0.0014 (8)0.0039 (9)
O50.0272 (8)0.0707 (13)0.0439 (10)0.0003 (9)0.0073 (7)−0.0007 (10)
O60.0444 (10)0.0550 (12)0.0641 (12)0.0190 (10)0.0003 (9)−0.0045 (10)
O70.0323 (8)0.0407 (9)0.0507 (10)−0.0021 (8)0.0070 (7)0.0013 (9)

Geometric parameters (Å, °)

C1—C21.368 (5)C11—C121.532 (4)
C1—C61.376 (5)C11—H110.9800
C1—N11.473 (4)C12—C131.528 (4)
C2—C31.376 (4)C12—H12A0.9700
C2—H20.9300C12—H12B0.9700
C3—C41.401 (4)C13—C151.494 (6)
C3—H100.9300C13—C141.537 (6)
C4—C51.379 (3)C13—H130.9800
C4—C71.515 (3)C14—H14A0.9600
C5—C61.388 (4)C14—H14B0.9600
C5—H50.9300C14—H14C0.9600
C6—H60.9300C15—H15A0.9600
C7—O31.424 (3)C15—H15B0.9600
C7—C81.531 (3)C15—H15C0.9600
C7—H70.9800N1—O21.195 (6)
C8—N21.489 (3)N1—O11.228 (7)
C8—C91.528 (3)N2—H2B0.87 (3)
C8—H80.9800N2—H2C0.99 (3)
C9—O41.231 (3)N2—H2A0.95 (3)
C9—N31.323 (3)N3—H3A0.8600
C10—O61.236 (3)O3—H40.8200
C10—O51.267 (3)O7—H7W0.9174
C10—C111.538 (3)O7—H8W0.8845
C11—N31.461 (3)
C2—C1—C6122.5 (3)C12—C11—H11109.3
C2—C1—N1118.8 (4)C10—C11—H11109.3
C6—C1—N1118.6 (4)C13—C12—C11116.2 (2)
C1—C2—C3119.0 (3)C13—C12—H12A108.2
C1—C2—H2120.5C11—C12—H12A108.2
C3—C2—H2120.5C13—C12—H12B108.2
C2—C3—C4120.2 (3)C11—C12—H12B108.2
C2—C3—H10119.9H12A—C12—H12B107.4
C4—C3—H10119.9C15—C13—C12112.1 (4)
C5—C4—C3119.3 (3)C15—C13—C14111.3 (3)
C5—C4—C7120.7 (2)C12—C13—C14109.2 (3)
C3—C4—C7120.0 (2)C15—C13—H13108.1
C4—C5—C6120.8 (3)C12—C13—H13108.1
C4—C5—H5119.6C14—C13—H13108.1
C6—C5—H5119.6C13—C14—H14A109.5
C1—C6—C5118.1 (3)C13—C14—H14B109.5
C1—C6—H6120.9H14A—C14—H14B109.5
C5—C6—H6120.9C13—C14—H14C109.5
O3—C7—C4112.48 (18)H14A—C14—H14C109.5
O3—C7—C8107.33 (17)H14B—C14—H14C109.5
C4—C7—C8110.03 (18)C13—C15—H15A109.5
O3—C7—H7109.0C13—C15—H15B109.5
C4—C7—H7109.0H15A—C15—H15B109.5
C8—C7—H7109.0C13—C15—H15C109.5
N2—C8—C9109.07 (18)H15A—C15—H15C109.5
N2—C8—C7110.07 (17)H15B—C15—H15C109.5
C9—C8—C7109.85 (18)O2—N1—O1123.3 (4)
N2—C8—H8109.3O2—N1—C1119.1 (5)
C9—C8—H8109.3O1—N1—C1117.6 (4)
C7—C8—H8109.3C8—N2—H2B114.5 (19)
O4—C9—N3124.7 (2)C8—N2—H2C111.6 (18)
O4—C9—C8119.3 (2)H2B—N2—H2C107 (3)
N3—C9—C8116.0 (2)C8—N2—H2A107.1 (19)
O6—C10—O5124.3 (2)H2B—N2—H2A104 (3)
O6—C10—C11118.5 (2)H2C—N2—H2A112 (3)
O5—C10—C11117.1 (2)C9—N3—C11123.3 (2)
N3—C11—C12109.3 (2)C9—N3—H3A118.3
N3—C11—C10111.00 (19)C11—N3—H3A118.3
C12—C11—C10108.64 (19)C7—O3—H4109.5
N3—C11—H11109.3H7W—O7—H8W118.1
C6—C1—C2—C30.5 (5)C7—C8—C9—O461.9 (3)
N1—C1—C2—C3179.3 (3)N2—C8—C9—N3122.4 (2)
C1—C2—C3—C4−0.3 (4)C7—C8—C9—N3−116.9 (2)
C2—C3—C4—C50.2 (4)O6—C10—C11—N3−155.5 (2)
C2—C3—C4—C7−178.6 (2)O5—C10—C11—N326.6 (3)
C3—C4—C5—C6−0.2 (4)O6—C10—C11—C1284.4 (3)
C7—C4—C5—C6178.6 (2)O5—C10—C11—C12−93.6 (3)
C2—C1—C6—C5−0.5 (5)N3—C11—C12—C1354.7 (3)
N1—C1—C6—C5−179.3 (3)C10—C11—C12—C13175.9 (3)
C4—C5—C6—C10.4 (4)C11—C12—C13—C1564.0 (4)
C5—C4—C7—O3119.8 (2)C11—C12—C13—C14−172.3 (3)
C3—C4—C7—O3−61.3 (3)C2—C1—N1—O2−174.0 (4)
C5—C4—C7—C8−120.6 (2)C6—C1—N1—O24.9 (5)
C3—C4—C7—C858.2 (3)C2—C1—N1—O14.6 (6)
O3—C7—C8—N2−47.8 (2)C6—C1—N1—O1−176.5 (4)
C4—C7—C8—N2−170.52 (19)O4—C9—N3—C111.5 (3)
O3—C7—C8—C9−167.95 (18)C8—C9—N3—C11−179.66 (19)
C4—C7—C8—C969.4 (2)C12—C11—N3—C9−156.1 (2)
N2—C8—C9—O4−58.8 (3)C10—C11—N3—C984.1 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O7—H7W···O50.921.872.679 (2)146
O7—H8W···O4i0.881.962.734 (3)146
N2—H2B···O3ii0.87 (3)1.99 (3)2.854 (3)172 (3)
O3—H4···O5iii0.821.792.612 (2)175
N3—H3A···O7i0.862.082.914 (3)163
N2—H2C···O6i0.99 (3)1.96 (3)2.811 (3)143 (3)
N2—H2A···O70.95 (3)1.89 (3)2.801 (2)158 (3)

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: SI2128).

References

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  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Shin, W. & Pyo, M. (1984). Bull. Korean Chem. Soc.5, 158–162.
  • Shinagawa, S., Kanamaru, T., Harada, S., Asai, M. & Ookazaki, H. (1987). J. Med. Chem.30, 1458–1463. [PubMed]
  • Testa, M. L., Ciriminna, R., Hajji, C., Garcia, E. Z., Ciclosi, M., Arques, J. S. & Pagliaroa, M. (2004). Adv. Synth. Catal.346, 655–660.
  • Xu, W. F. & Li, Q. B. (2005). Curr. Med. Chem. Anti-Cancer Agents, 5, 281–301. [PubMed]

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