Ethyl 4-{1-[(2,4-dinitro­phen­yl)hydrazono]eth­yl}-5-(2-naphthyl­methoxy­meth­yl)isoxazole-3-carboxyl­ate

Natale, N.R.; Szabon-Watola, M.I.; Twamley, B.; Bridges, R.J.; Patel, S.; Rajale, T.

doi:10.1107/S1600536808041901

organic compounds

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ISSN: 2056-9890

Volume 65| Part 1| January 2009| Pages o144-o145

doi:10.1107/S1600536808041901

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Ethyl 4-{1-[(2,4-dinitrophenyl)hydrazono]ethyl}-5-(2-naphthylmethoxymethyl)isoxazole-3-carboxylate

Nicholas R. Natale,^a ^* Monica I. Szabon-Watola,^b Brendan Twamley,^b Richard J. Bridges,^a Sarjubhai Patel ^a and Trideep Rajale ^a ‡

^aCenter For Structural and Functional Neuroscience, Department of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA, and ^bDepartment of Chemistry, University of Idaho, Moscow, ID 83844-2343, USA
^*Correspondence e-mail: nicholas.natale@umontana.edu

(Received 24 November 2008; accepted 9 December 2008; online 17 December 2008)

The title compound, C₂₆H₂₃N₅O₈, was prepared and its structure investigated to further develop a working hypothesis for the essential binding pharmacophore for ligands of the System Xc- transporter [Patel et al. (2004 ). Neuropharmacology, 46, 273–284]. The hydrazone group displays an E geometry and the isoxazole double bond and C=N group of the hydrazone are in an s-cis relationship. The secondary amino NH group forms an intramolecular N—H⋯O hydrogen bond to a ring nitro group. There is a dihedral angle of 44.27 (5)° between the isoxazole plane and the hydrazone group plane.

Related literature

For a related structure, see: Burkhart et al. (1999 , 2001 ). For general background, see: Davis et al. (1993 ); Honore & Lauridsen (1980 ); Krogsgaard-Larsen, Honore, Hansen, Curtis & Lodge (1980 ); Natale et al. (2006 ); Patel et al. (2004, 2006 ); Stables & Kupferberg (2008 ); Twamley et al. (2007 ); Zhou & Natale (1998 ).

Experimental

Crystal data

C₂₆H₂₃N₅O₈
M_r = 533.49
Triclinic, $[P \overline 1]$
a = 7.0839 (6) Å
b = 12.176 (1) Å
c = 14.184 (2) Å
α = 90.581 (1)°
β = 95.925 (2)°
γ = 99.251 (2)°
V = 1200.7 (2) Å³
Z = 2
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 90 (2) K
0.47 × 0.33 × 0.30 mm

Data collection

Bruker SMART APEX diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2007 ) T_min = 0.949, T_max = 0.971
18560 measured reflections
4357 independent reflections
4009 reflections with I > 2σ(I)
R_int = 0.023

Refinement

R[F² > 2σ(F²)] = 0.035
wR(F²) = 0.092
S = 1.02
4357 reflections
354 parameters
H-atom parameters constrained
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.23 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N28—H28A⋯O37	0.88	1.96	2.6028 (14)	128

Data collection: SMART (Bruker, 2007); cell refinement: SAINT-Plus (Bruker, 2007); data reduction: SAINT-Plus; program(s) used to solve structure: XS in SHELXTL (Sheldrick, 2008 ); program(s) used to refine structure: XL in SHELXTL; molecular graphics: XP in SHELXTL; software used to prepare material for publication: publCIF (Westrip, 2009 ).

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808041901/hg2449sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536808041901/hg2449Isup2.hkl

checkCIF report

Comment top

In the course of our continuing studies on the synthesis and structure activity relationships of analogs of AMPA (II) (see Figure 2; Krogsgaard-Larsen et al., 1980; Honore, & Lauridsen, 1980) for glutamate receptors and transporters (Natale et al., 2006), we have found that a simple isoxazole hydrazone (IIIb) (Burkhart et al., 1999) exhibited significant binding at the System Xc- transporter (SXc-) (Patel et al., 2004), and that this correlated with anticonvulsant activity in vivo (Stables & Kupferberg, 2008). Since the three dimensional structure of the SXc- is unsolved at this writing we have developed a preliminary pharmacophore model for ligand binding which indicates that lipophilic groups appear to be tolerated (Patel et al., 2006), which is also promising from the perspective of increasing the likelihood of delivering such ligands past the blood brain barrier. Therefore we carried out the synthesis of (Ia) and also examined its structure, see Figure 1. We had previously examined the structure of (IIIa), (see Figure 2) and found it adopted an s-trans-E geometry at the juncture between the isoxazole and the hydrazone double bond, respectively (Burkhart et al., 1999). The naphthyloxy analog (Ia) adopts a similar E-geometry at the C=N double bond, but an s-cis conformation at the C-4 bond between the isoxazole and the hydrazone. The observation that (Ib) exhibits no significant glutamate inhibition at SystemXc- represents a negative control in the Structure Activity Relationship. This raises interesting questions as to the relationship between conformation and geometry vis-a-vis biological effect, and this will be the subject of forthcoming manuscripts.

Related literature top

For related literature, see: Burkhart et al. (1999, 2001); Davis et al. (1993); Honore & Lauridsen (1980); Krogsgaard-Larsen, Honore, Hansen, Curtis & Lodge (1980); Natale et al. (2006); Patel et al. (2004, 2006); Stables & Kupferberg (2008); Twamley et al. (2007); Zhou & Natale (1998). It would be much more useful to readers if the "Related literature" section had some kind of simple sub-division, so that, instead of just "For related literature, see···" it said, for example, "For general background, see···. For related structures, see···.? etc. Please revise this section as indicated.

Experimental top

The title compound (Ia) was prepared from ethyl 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)isoxazole-3-carboxylate (Zhou & Natale, 1998) via lateral metalation (Burkhart et al., 2001), and electrophilic quenching using the Davis oxaziridine (Davis et al., 1993), to the corresponding 5-methyl alcohol. This alcohol can also be prepared by bromination followed by nucleophilic substitution by water (Twamley et al., 2007). The title compound was obtained from the 5-methyl alcohol by Williamson ether synthesis, deprotection and hydrazone formation (Burkhart et al., 1999).

4-{1-[(2,4-Dinitro-phenyl)-hydrazono]-ethyl}-5-(naphthalen-2-ylmethoxymethyl)-\ isoxazole-3-carboxylic acid ethyl ester (Ia)

To a stirred solution of ethyl 5-(naphthalen-2-yl-methoxymethyl)-4-acetyl-isoxazole-3-carboxylate (0.650 g, 1.93 mmol), in 10 ml of THF, a solution of 12 ml (1.0 eq.) of reagent 2,4-DNP was added and the reaction mixture was monitored by TLC (ether/hexane as a mobile phase). During reaction the reddish precipitate formed which was separated and purified by column chromatography. The fast moving, major isomer was examined by crystallography. Yield 57% The major isomer, yellow crystals, m.p.= 105–107 °C, ¹H NMR (deuteriochloroform): δ 1.45 (t, 3H, J=7.1 Hz), 2.34 (s, 3H), 4.48 (q, 2H, J=7.1 Hz), 4.77 (s, 2H), 4.83 (s, 2H), 7.42 (m, 3H), 7.56 (d, 1H, J=9.5 Hz), 7.80 (m, 4H), 8.03 (dd, 1H, J=2.4, 9.5 Hz), 9.00 (d, 1H, J=2.6 Hz), 9.99 (brs, 1H, NH). ¹³C NMR (500 MHz) δ 14.1, 17.3, 60.6, 62.7, 73.1, 116.0, 118.3, 123.2, 125.4, 126.3, 126.4, 127.0, 127.5, 127.6, 128.4, 129.8, 132.9, 133.0, 134.1, 138.6, 143.8, 144.2, 154.1, 159.8, 168.8. The minor isomer, ¹H NMR (deuteriochloroform):δ 1.40 (t, 3H, J=7.1 Hz), 2.43 (s, 3H), 4.46 (q, 2H, J=7.1 Hz), 4.80 (s, 2H), 4.93 (s, 2H), 7.22 (d, 1H, J=9.5 Hz), 7.42 (m, 3H), 7.80 (m, 4H), 8.03 (dd, 1H, J=2.4, 9.5 Hz), 8.65 (d, 1H, J=2.6 Hz), 10.75 (brs, 1H, NH).

Computing details top

Data collection: SMART (Bruker, 2007); cell refinement: SAINT-Plus (Bruker, 2007); data reduction: SAINT-Plus (Bruker, 2007); program(s) used to solve structure: XS in SHELXTL (Sheldrick, 2008); program(s) used to refine structure: XL in SHELXTL (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: publCIF (Westrip, 2009).

Figures top

	Fig. 1. Molecular Structure of (Ia), showing 30% probablility displacement ellipsoids.
	Fig. 2. Structure of the title Compound (Ia), corresponding carboxylic acid (Ib), the neurotransmitter AMPA (II), and previously reported simple analog (III).

Ethyl 4-{1-[(2,4-dinitrophenyl)hydrazono]ethyl}- 5-(2-naphthylmethoxymethyl)isoxazole-3-carboxylate top

Crystal data top

C₂₆H₂₃N₅O₈	Z = 2
M_r = 533.49	F(000) = 556
Triclinic, P1	D_x = 1.476 Mg m⁻³
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.0839 (6) Å	Cell parameters from 6135 reflections
b = 12.176 (1) Å	θ = 2.3–30.1°
c = 14.184 (2) Å	µ = 0.11 mm⁻¹
α = 90.581 (1)°	T = 90 K
β = 95.925 (2)°	Needle, yellow
γ = 99.251 (2)°	0.47 × 0.33 × 0.30 mm
V = 1200.7 (2) Å³

Data collection top

Bruker SMART APEX diffractometer	4357 independent reflections
Radiation source: normal-focus sealed tube	4009 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.023
Detector resolution: 8.3 pixels mm^-1	θ_max = 25.3°, θ_min = 2.2°
ω scans	h = −8→8
Absorption correction: multi-scan (SADABS; Bruker, 2007)	k = −14→14
T_min = 0.949, T_max = 0.971	l = −17→17
18560 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.035	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.092	H-atom parameters constrained
S = 1.02	w = 1/[σ²(F_o²) + (0.0462P)² + 0.5022P] where P = (F_o² + 2F_c²)/3
4357 reflections	(Δ/σ)_max < 0.001
354 parameters	Δρ_max = 0.28 e Å⁻³
0 restraints	Δρ_min = −0.23 e Å⁻³

Crystal data top

C₂₆H₂₃N₅O₈	γ = 99.251 (2)°
M_r = 533.49	V = 1200.7 (2) Å³
Triclinic, P1	Z = 2
a = 7.0839 (6) Å	Mo Kα radiation
b = 12.176 (1) Å	µ = 0.11 mm⁻¹
c = 14.184 (2) Å	T = 90 K
α = 90.581 (1)°	0.47 × 0.33 × 0.30 mm
β = 95.925 (2)°

Data collection top

Bruker SMART APEX diffractometer	4357 independent reflections
Absorption correction: multi-scan (SADABS; Bruker, 2007)	4009 reflections with I > 2σ(I)
T_min = 0.949, T_max = 0.971	R_int = 0.023
18560 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.035	0 restraints
wR(F²) = 0.092	H-atom parameters constrained
S = 1.02	Δρ_max = 0.28 e Å⁻³
4357 reflections	Δρ_min = −0.23 e Å⁻³
354 parameters

Special details top

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) top

	x	y	z	U_iso*/U_eq
C1	0.86385 (19)	0.87869 (12)	0.65591 (10)	0.0225 (3)
H1A	0.8404	0.9531	0.6498	0.027*
C2	0.9219 (2)	0.84176 (12)	0.74301 (10)	0.0243 (3)
H2A	0.9396	0.8910	0.7967	0.029*
C3	0.95619 (18)	0.73084 (12)	0.75441 (10)	0.0223 (3)
C4	1.0160 (2)	0.68877 (14)	0.84368 (10)	0.0279 (3)
H4A	1.0362	0.7363	0.8985	0.034*
C5	1.0451 (2)	0.58036 (14)	0.85179 (11)	0.0300 (4)
H5A	1.0835	0.5532	0.9121	0.036*
C6	1.01822 (19)	0.50944 (13)	0.77116 (11)	0.0272 (3)
H6A	1.0391	0.4346	0.7772	0.033*
C7	0.96224 (19)	0.54760 (12)	0.68412 (10)	0.0230 (3)
H7A	0.9457	0.4990	0.6301	0.028*
C8	0.92856 (18)	0.65841 (11)	0.67329 (10)	0.0199 (3)
C9	0.86964 (18)	0.69966 (11)	0.58372 (9)	0.0186 (3)
H9A	0.8517	0.6517	0.5292	0.022*
C10	0.83807 (18)	0.80712 (11)	0.57424 (9)	0.0187 (3)
C12	0.78057 (19)	0.85335 (11)	0.47991 (9)	0.0199 (3)
H12A	0.6616	0.8857	0.4827	0.024*
H12B	0.8835	0.9130	0.4636	0.024*
O13	0.74889 (14)	0.76632 (8)	0.40973 (7)	0.0234 (2)
C14	0.7541 (2)	0.80387 (11)	0.31558 (9)	0.0210 (3)
H14A	0.8040	0.7487	0.2772	0.025*
H14B	0.8446	0.8749	0.3162	0.025*
C15	0.56224 (19)	0.82104 (11)	0.26945 (9)	0.0183 (3)
O16	0.50754 (14)	0.92145 (7)	0.28170 (7)	0.0218 (2)
N17	0.32990 (17)	0.92234 (9)	0.22939 (8)	0.0214 (3)
C18	0.28435 (19)	0.82377 (11)	0.18738 (9)	0.0178 (3)
C19	0.09928 (19)	0.79318 (11)	0.12615 (9)	0.0183 (3)
O20	0.04690 (14)	0.70128 (8)	0.09134 (7)	0.0255 (2)
O21	0.00088 (13)	0.87728 (8)	0.11528 (7)	0.0221 (2)
C22	−0.1807 (2)	0.85128 (12)	0.05412 (10)	0.0248 (3)
H22A	−0.2644	0.7876	0.0792	0.030*
H22B	−0.1561	0.8310	−0.0107	0.030*
C23	−0.2763 (2)	0.95228 (13)	0.05216 (11)	0.0303 (3)
H23A	−0.3983	0.9371	0.0112	0.045*
H23B	−0.1922	1.0148	0.0274	0.045*
H23C	−0.3012	0.9712	0.1166	0.045*
C24	0.42658 (18)	0.75465 (11)	0.21070 (9)	0.0166 (3)
C25	0.43276 (18)	0.63811 (11)	0.18367 (9)	0.0163 (3)
C26	0.4029 (2)	0.59917 (11)	0.08182 (9)	0.0211 (3)
H26A	0.2937	0.5381	0.0727	0.032*
H26B	0.5190	0.5731	0.0647	0.032*
H26C	0.3763	0.6609	0.0414	0.032*
N27	0.47840 (15)	0.57795 (9)	0.25405 (8)	0.0166 (2)
N28	0.49202 (15)	0.47000 (9)	0.23163 (8)	0.0169 (2)
H28A	0.4652	0.4444	0.1727	0.020*
C29	0.54745 (17)	0.40296 (10)	0.30165 (9)	0.0159 (3)
C30	0.56433 (18)	0.29033 (10)	0.28470 (9)	0.0165 (3)
C31	0.62357 (18)	0.22374 (11)	0.35731 (10)	0.0179 (3)
H31A	0.6335	0.1482	0.3449	0.022*
C32	0.66733 (18)	0.26928 (11)	0.44716 (9)	0.0184 (3)
C33	0.65367 (18)	0.37992 (11)	0.46714 (9)	0.0186 (3)
H33A	0.6844	0.4096	0.5301	0.022*
C34	0.59579 (18)	0.44555 (11)	0.39560 (9)	0.0180 (3)
H34A	0.5880	0.5211	0.4093	0.022*
N35	0.52605 (15)	0.23912 (9)	0.19029 (8)	0.0186 (2)
O36	0.56216 (15)	0.14538 (8)	0.17852 (7)	0.0263 (2)
O37	0.45844 (14)	0.29207 (8)	0.12397 (7)	0.0222 (2)
N38	0.73724 (16)	0.20206 (10)	0.52367 (8)	0.0215 (3)
O39	0.79957 (15)	0.24887 (9)	0.60029 (7)	0.0288 (2)
O40	0.73174 (15)	0.10215 (8)	0.50788 (8)	0.0292 (2)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0195 (7)	0.0215 (7)	0.0262 (7)	0.0015 (5)	0.0036 (6)	−0.0018 (6)
C2	0.0201 (7)	0.0306 (8)	0.0208 (7)	0.0002 (6)	0.0033 (5)	−0.0071 (6)
C3	0.0130 (6)	0.0332 (8)	0.0198 (7)	−0.0001 (6)	0.0033 (5)	0.0021 (6)
C4	0.0183 (7)	0.0457 (9)	0.0186 (7)	0.0014 (6)	0.0022 (5)	0.0002 (6)
C5	0.0185 (7)	0.0494 (10)	0.0221 (7)	0.0044 (6)	0.0019 (6)	0.0141 (7)
C6	0.0163 (7)	0.0330 (8)	0.0320 (8)	0.0026 (6)	0.0029 (6)	0.0116 (6)
C7	0.0156 (6)	0.0273 (7)	0.0248 (7)	0.0000 (5)	0.0016 (5)	0.0037 (6)
C8	0.0116 (6)	0.0263 (7)	0.0208 (7)	−0.0010 (5)	0.0031 (5)	0.0029 (5)
C9	0.0140 (6)	0.0234 (7)	0.0176 (7)	0.0002 (5)	0.0014 (5)	−0.0011 (5)
C10	0.0130 (6)	0.0222 (7)	0.0202 (7)	0.0005 (5)	0.0025 (5)	0.0010 (5)
C12	0.0189 (6)	0.0181 (7)	0.0223 (7)	0.0024 (5)	0.0014 (5)	−0.0008 (5)
O13	0.0318 (5)	0.0187 (5)	0.0175 (5)	0.0021 (4)	−0.0043 (4)	0.0013 (4)
C14	0.0244 (7)	0.0205 (7)	0.0175 (7)	0.0031 (5)	−0.0002 (5)	0.0025 (5)
C15	0.0250 (7)	0.0154 (6)	0.0149 (6)	0.0035 (5)	0.0036 (5)	0.0027 (5)
O16	0.0270 (5)	0.0169 (5)	0.0208 (5)	0.0048 (4)	−0.0026 (4)	−0.0004 (4)
N17	0.0248 (6)	0.0205 (6)	0.0196 (6)	0.0067 (5)	−0.0001 (5)	0.0032 (5)
C18	0.0223 (7)	0.0170 (6)	0.0150 (6)	0.0048 (5)	0.0041 (5)	0.0037 (5)
C19	0.0217 (7)	0.0186 (7)	0.0164 (6)	0.0064 (5)	0.0058 (5)	0.0046 (5)
O20	0.0271 (5)	0.0202 (5)	0.0287 (6)	0.0057 (4)	−0.0028 (4)	−0.0007 (4)
O21	0.0218 (5)	0.0216 (5)	0.0240 (5)	0.0083 (4)	−0.0007 (4)	0.0012 (4)
C22	0.0199 (7)	0.0309 (8)	0.0244 (7)	0.0089 (6)	−0.0012 (6)	−0.0018 (6)
C23	0.0261 (8)	0.0322 (8)	0.0344 (8)	0.0122 (6)	−0.0006 (6)	0.0043 (7)
C24	0.0199 (6)	0.0172 (6)	0.0137 (6)	0.0043 (5)	0.0035 (5)	0.0038 (5)
C25	0.0141 (6)	0.0173 (6)	0.0180 (6)	0.0035 (5)	0.0018 (5)	0.0013 (5)
C26	0.0260 (7)	0.0192 (7)	0.0187 (7)	0.0058 (5)	0.0020 (5)	0.0011 (5)
N27	0.0159 (5)	0.0141 (5)	0.0204 (6)	0.0037 (4)	0.0018 (4)	0.0004 (4)
N28	0.0208 (6)	0.0149 (5)	0.0151 (5)	0.0043 (4)	0.0008 (4)	−0.0001 (4)
C29	0.0118 (6)	0.0169 (6)	0.0192 (6)	0.0019 (5)	0.0035 (5)	0.0019 (5)
C30	0.0139 (6)	0.0165 (6)	0.0188 (7)	0.0008 (5)	0.0031 (5)	0.0003 (5)
C31	0.0145 (6)	0.0158 (6)	0.0243 (7)	0.0027 (5)	0.0052 (5)	0.0027 (5)
C32	0.0138 (6)	0.0218 (7)	0.0203 (7)	0.0033 (5)	0.0037 (5)	0.0065 (5)
C33	0.0164 (6)	0.0225 (7)	0.0170 (7)	0.0034 (5)	0.0022 (5)	0.0003 (5)
C34	0.0177 (6)	0.0165 (6)	0.0204 (7)	0.0036 (5)	0.0032 (5)	−0.0004 (5)
N35	0.0179 (6)	0.0166 (6)	0.0212 (6)	0.0014 (4)	0.0036 (4)	−0.0005 (4)
O36	0.0373 (6)	0.0150 (5)	0.0275 (5)	0.0073 (4)	0.0038 (4)	−0.0032 (4)
O37	0.0275 (5)	0.0214 (5)	0.0176 (5)	0.0058 (4)	−0.0010 (4)	0.0007 (4)
N38	0.0183 (6)	0.0251 (6)	0.0230 (6)	0.0066 (5)	0.0058 (5)	0.0078 (5)
O39	0.0328 (6)	0.0356 (6)	0.0190 (5)	0.0098 (5)	−0.0001 (4)	0.0051 (4)
O40	0.0360 (6)	0.0203 (5)	0.0333 (6)	0.0095 (4)	0.0040 (5)	0.0093 (4)

Geometric parameters (Å, º) top

C1—C2	1.365 (2)	C19—O21	1.3300 (16)
C1—C10	1.4210 (19)	O21—C22	1.4628 (16)
C1—H1A	0.9500	C22—C23	1.496 (2)
C2—C3	1.418 (2)	C22—H22A	0.9900
C2—H2A	0.9500	C22—H22B	0.9900
C3—C4	1.420 (2)	C23—H23A	0.9800
C3—C8	1.420 (2)	C23—H23B	0.9800
C4—C5	1.373 (2)	C23—H23C	0.9800
C4—H4A	0.9500	C24—C25	1.4749 (18)
C5—C6	1.404 (2)	C25—N27	1.2893 (17)
C5—H5A	0.9500	C25—C26	1.4991 (18)
C6—C7	1.366 (2)	C26—H26A	0.9800
C6—H6A	0.9500	C26—H26B	0.9800
C7—C8	1.415 (2)	C26—H26C	0.9800
C7—H7A	0.9500	N27—N28	1.3700 (15)
C8—C9	1.4182 (19)	N28—C29	1.3587 (17)
C9—C10	1.3682 (19)	N28—H28A	0.8800
C9—H9A	0.9500	C29—C34	1.4130 (19)
C10—C12	1.4998 (18)	C29—C30	1.4160 (18)
C12—O13	1.4214 (16)	C30—C31	1.3898 (18)
C12—H12A	0.9900	C30—N35	1.4524 (17)
C12—H12B	0.9900	C31—C32	1.3699 (19)
O13—C14	1.4181 (16)	C31—H31A	0.9500
C14—C15	1.4930 (19)	C32—C33	1.3945 (19)
C14—H14A	0.9900	C32—N38	1.4596 (17)
C14—H14B	0.9900	C33—C34	1.3684 (18)
C15—O16	1.3554 (16)	C33—H33A	0.9500
C15—C24	1.3575 (19)	C34—H34A	0.9500
O16—N17	1.3950 (15)	N35—O36	1.2227 (14)
N17—C18	1.3120 (17)	N35—O37	1.2443 (14)
C18—C24	1.4291 (18)	N38—O39	1.2282 (15)
C18—C19	1.4876 (19)	N38—O40	1.2284 (15)
C19—O20	1.2047 (16)

C2—C1—C10	120.75 (13)	C19—O21—C22	114.54 (11)
C2—C1—H1A	119.6	O21—C22—C23	107.90 (12)
C10—C1—H1A	119.6	O21—C22—H22A	110.1
C1—C2—C3	120.89 (13)	C23—C22—H22A	110.1
C1—C2—H2A	119.6	O21—C22—H22B	110.1
C3—C2—H2A	119.6	C23—C22—H22B	110.1
C2—C3—C4	122.80 (13)	H22A—C22—H22B	108.4
C2—C3—C8	118.70 (13)	C22—C23—H23A	109.5
C4—C3—C8	118.50 (13)	C22—C23—H23B	109.5
C5—C4—C3	120.92 (14)	H23A—C23—H23B	109.5
C5—C4—H4A	119.5	C22—C23—H23C	109.5
C3—C4—H4A	119.5	H23A—C23—H23C	109.5
C4—C5—C6	120.20 (14)	H23B—C23—H23C	109.5
C4—C5—H5A	119.9	C15—C24—C18	103.34 (11)
C6—C5—H5A	119.9	C15—C24—C25	125.47 (12)
C7—C6—C5	120.32 (14)	C18—C24—C25	131.16 (12)
C7—C6—H6A	119.8	N27—C25—C24	113.88 (11)
C5—C6—H6A	119.8	N27—C25—C26	124.68 (12)
C6—C7—C8	121.02 (14)	C24—C25—C26	121.28 (11)
C6—C7—H7A	119.5	C25—C26—H26A	109.5
C8—C7—H7A	119.5	C25—C26—H26B	109.5
C7—C8—C9	121.98 (13)	H26A—C26—H26B	109.5
C7—C8—C3	119.02 (13)	C25—C26—H26C	109.5
C9—C8—C3	118.99 (13)	H26A—C26—H26C	109.5
C10—C9—C8	121.36 (12)	H26B—C26—H26C	109.5
C10—C9—H9A	119.3	C25—N27—N28	115.76 (11)
C8—C9—H9A	119.3	C29—N28—N27	119.06 (11)
C9—C10—C1	119.31 (12)	C29—N28—H28A	120.5
C9—C10—C12	122.27 (12)	N27—N28—H28A	120.5
C1—C10—C12	118.41 (12)	N28—C29—C34	120.13 (11)
O13—C12—C10	109.06 (10)	N28—C29—C30	122.70 (12)
O13—C12—H12A	109.9	C34—C29—C30	117.16 (12)
C10—C12—H12A	109.9	C31—C30—C29	121.66 (12)
O13—C12—H12B	109.9	C31—C30—N35	116.43 (11)
C10—C12—H12B	109.9	C29—C30—N35	121.90 (11)
H12A—C12—H12B	108.3	C32—C31—C30	118.64 (12)
C14—O13—C12	114.09 (10)	C32—C31—H31A	120.7
O13—C14—C15	113.35 (11)	C30—C31—H31A	120.7
O13—C14—H14A	108.9	C31—C32—C33	121.72 (12)
C15—C14—H14A	108.9	C31—C32—N38	119.48 (12)
O13—C14—H14B	108.9	C33—C32—N38	118.76 (12)
C15—C14—H14B	108.9	C34—C33—C32	119.63 (12)
H14A—C14—H14B	107.7	C34—C33—H33A	120.2
O16—C15—C24	109.91 (11)	C32—C33—H33A	120.2
O16—C15—C14	118.15 (11)	C33—C34—C29	121.19 (12)
C24—C15—C14	131.86 (12)	C33—C34—H34A	119.4
C15—O16—N17	109.21 (10)	C29—C34—H34A	119.4
C18—N17—O16	105.26 (10)	O36—N35—O37	122.13 (11)
N17—C18—C24	112.27 (12)	O36—N35—C30	118.81 (11)
N17—C18—C19	120.58 (12)	O37—N35—C30	119.06 (10)
C24—C18—C19	127.11 (12)	O39—N38—O40	123.59 (11)
O20—C19—O21	124.76 (12)	O39—N38—C32	118.01 (11)
O20—C19—C18	122.48 (12)	O40—N38—C32	118.39 (11)
O21—C19—C18	112.76 (11)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N28—H28A···O37	0.88	1.96	2.6028 (14)	128

Experimental details

Crystal data
Chemical formula	C₂₆H₂₃N₅O₈
M_r	533.49
Crystal system, space group	Triclinic, P1
Temperature (K)	90
a, b, c (Å)	7.0839 (6), 12.176 (1), 14.184 (2)
α, β, γ (°)	90.581 (1), 95.925 (2), 99.251 (2)
V (Å³)	1200.7 (2)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.11
Crystal size (mm)	0.47 × 0.33 × 0.30

Data collection
Diffractometer	Bruker SMART APEX diffractometer
Absorption correction	Multi-scan (SADABS; Bruker, 2007)
T_min, T_max	0.949, 0.971
No. of measured, independent and observed [I > 2σ(I)] reflections	18560, 4357, 4009
R_int	0.023
(sin θ/λ)_max (Å⁻¹)	0.600

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.092, 1.02
No. of reflections	4357
No. of parameters	354
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.28, −0.23

Computer programs: SMART (Bruker, 2007), SAINT-Plus (Bruker, 2007), XS in SHELXTL (Sheldrick, 2008), XL in SHELXTL (Sheldrick, 2008), XP in SHELXTL (Sheldrick, 2008), publCIF (Westrip, 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N28—H28A···O37	0.88	1.96	2.6028 (14)	128

Footnotes

‡Formerly at Department Of Chemistry, University of Idaho, 83844-2343, USA.

Acknowledgements

The authors thank NIH for grants NS038444(NN), NINDS NS30570 (RJB), P20RR015583 (RJB, SP, NN), and the Malcolm and Carol Renfrew Scholarship (MIS, TR). The Bruker SMART APEX diffraction facility was established at the University of Idaho with the assistance of the NSF–EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver, WA, USA.

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