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We have synthesized a dideoxydidehydronucleoside derivative, 2(
S)-acetoxymethyl-4-[4-amino-2-oxopyrimidin-1(2
H)-yl]-2,5-dihydrofuran, C
11H
13N
3O
4, which is an analogue of the potently anti-HIV active compound, dideoxy-didehydrocytidine (d4C). The target compound crystallizes with two molecules in the asymmetric unit that differ primarily in the orientation of the C6'-acetyl group. One molecule has an extended conformation and the orientation of the acetyl group in the second molecule gives an unusual hooked-shaped conformation. The two conformers form
A-
B dimers
via N-H
N hydrogen bonds. The dimers link
via N-H
O hydrogen bonds to form chains parallel to the
b cell axis.
Supporting information
CCDC reference: 156223
To a solution of 2(S)-(hydroxymethyl)-4-[(3,4-dihydro-2-oxo-4-amino-1(2H)-pyrimidinyl]- 2,5-dihydrofuran (0.08 g, 0.38 mmol) in pyridine (10 ml), Ac2O was added and the reaction mixture was stirred at room temperature overnight. Saturated NaHCO3 solution (30 ml) was then added and the solution was extracted with CHCl3 (3 × 20 ml). The combined CHCl3 part was evaporated to dryness and the residual pyridine was co-evaporated with toluene. The gummy residue was purified on a silica gel column to give the acetyl derivative (0.09 g, 94%). Triethylamine (0.1 ml, 0.72 mmol) was added to a solution of the acetyl derivative (0.09 g, 0.35 mmol) in CH3CN (10 ml) containing TPSCl (0.22 g, 0.72 mmol) and DMAP (0.90 g, 0.72 mmol) at 273 K. The reaction mixture was stirred at room temperature for 3.5 h. Concentrated NH4OH solution (28% solution, 6 ml) was added and the solution was further stirred at room temperature for 2 h. The solvent was evaporated to dryness, the residue was purified on a silica-gel column and crystallized from methanol to give (II) (0.048 g, 54% for two steps): m.p. 384 K; 1H NMR (DMSO-d6): δ 7.56 (d, J = 7.5 Hz, 1H, H-6), 7.40 (bd, 2H, NH2), 6.05 (m, 1H, H-3'), 5.78 (d, J = 7.5 Hz, 1H, H-5), 4.98 (m, 1H, H-2'), 4.87 (m, 2H, H-5'), 4.06 (m, 2H, –CH2), 2.01 (s, 3H, acetyl –CH3); 13C NMR (DMSO-d6): δ 172.7 (ester CO), 167.6 (C-2), 157.0 (C-4), 145.1 (C-6), 141.4 (C-4'), 115.9 (C-3'), 97.1 (C-5), 84.3 (C-2') 74.1 (C-5') 67.1 (–CH2), 20.7 (–CH3); HRMS (FAB): (M+H)+ calcd for C11H14N3O4 252.0984, found 252.0979.
H atoms were refined as riding (N—H = 0.86 Å and C—H = 0.93–0.98 Å). 950 Friedel pair reflections were merged for the last four cycles of refinement.
Data collection: CAD-4 Operations Manual (Enraf-Nonius, 1977); cell refinement: CAD-4 Operations Manual; data reduction: MolEN (Fair, 1990); program(s) used to solve structure: SHELXTL (Sheldrick, 1995); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); software used to prepare material for publication: SHELXTL (Sheldrick, 1995).
Crystal data top
C11H13N3O4 | F(000) = 1056 |
Mr = 251.24 | Dx = 1.389 Mg m−3 |
Monoclinic, I2 | Mo Kα radiation, λ = 0.71073 Å |
a = 15.995 (2) Å | Cell parameters from 22 reflections |
b = 6.865 (1) Å | θ = 10.0–13.6° |
c = 21.934 (5) Å | µ = 0.11 mm−1 |
β = 94.16 (2)° | T = 213 K |
V = 2402.1 (7) Å3 | Prism, colourless |
Z = 8 | 0.33 × 0.22 × 0.18 mm |
Data collection top
Enraf-Nonius CAD4 diffractometer | Rint = 0.052 |
Radiation source: fine-focus sealed tube | θmax = 25.0°, θmin = 2.5° |
Graphite monochromator | h = −18→18 |
θ–2θ scans | k = −8→8 |
8222 measured reflections | l = −25→25 |
2283 independent reflections | 4 standard reflections every 120 min |
1774 reflections with I > 2σ(I) | intensity decay: <2% |
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) = 0.098 | H-atom parameters constrained |
S = 1.10 | w = 1/[σ2(Fo2) + (0.0514P)2 + 0.4716P] where P = (Fo2 + 2Fc2)/3 |
2283 reflections | (Δ/σ)max = 0.003 |
327 parameters | Δρmax = 0.19 e Å−3 |
1 restraint | Δρmin = −0.15 e Å−3 |
Crystal data top
C11H13N3O4 | V = 2402.1 (7) Å3 |
Mr = 251.24 | Z = 8 |
Monoclinic, I2 | Mo Kα radiation |
a = 15.995 (2) Å | µ = 0.11 mm−1 |
b = 6.865 (1) Å | T = 213 K |
c = 21.934 (5) Å | 0.33 × 0.22 × 0.18 mm |
β = 94.16 (2)° | |
Data collection top
Enraf-Nonius CAD4 diffractometer | Rint = 0.052 |
8222 measured reflections | 4 standard reflections every 120 min |
2283 independent reflections | intensity decay: <2% |
1774 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.035 | 1 restraint |
wR(F2) = 0.098 | H-atom parameters constrained |
S = 1.10 | Δρmax = 0.19 e Å−3 |
2283 reflections | Δρmin = −0.15 e Å−3 |
327 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 | Uiso*/Ueq | |
N1A | 0.62987 (16) | 0.6799 (4) | 0.32781 (12) | 0.0396 (6) | |
C2A | 0.6342 (2) | 0.6182 (5) | 0.26694 (14) | 0.0384 (8) | |
O2A | 0.62436 (16) | 0.4432 (3) | 0.25443 (11) | 0.0497 (6) | |
N3A | 0.64866 (17) | 0.7528 (4) | 0.22349 (12) | 0.0381 (6) | |
C4A | 0.66029 (18) | 0.9390 (5) | 0.23880 (15) | 0.0370 (7) | |
N4A | 0.66864 (17) | 1.0679 (4) | 0.19433 (12) | 0.0437 (7) | |
H4A1 | 0.6665 | 1.0301 | 0.1569 | 0.052* | |
H4A2 | 0.6762 | 1.1891 | 0.2031 | 0.052* | |
C5A | 0.6635 (2) | 1.0027 (5) | 0.30127 (15) | 0.0441 (8) | |
H5A | 0.6764 | 1.1308 | 0.3119 | 0.053* | |
C6A | 0.6473 (2) | 0.8713 (5) | 0.34311 (15) | 0.0435 (8) | |
H6A | 0.6477 | 0.9091 | 0.3838 | 0.052* | |
O1'A | 0.54676 (17) | 0.3059 (5) | 0.42688 (12) | 0.0733 (9) | |
C2'A | 0.6119 (2) | 0.3866 (6) | 0.46711 (16) | 0.0518 (9) | |
H2'A | 0.5881 | 0.4467 | 0.5024 | 0.062* | |
C3'A | 0.6518 (2) | 0.5394 (6) | 0.42967 (15) | 0.0504 (9) | |
H3'A | 0.6967 | 0.6179 | 0.4433 | 0.060* | |
C4'A | 0.61363 (19) | 0.5452 (5) | 0.37491 (14) | 0.0398 (7) | |
C5'A | 0.5427 (2) | 0.4036 (6) | 0.36962 (15) | 0.0486 (8) | |
H5'3 | 0.4896 | 0.4707 | 0.3622 | 0.058* | |
H5'4 | 0.5494 | 0.3123 | 0.3366 | 0.058* | |
C6'A | 0.6729 (2) | 0.2301 (6) | 0.48793 (19) | 0.0630 (10) | |
H6'3 | 0.7022 | 0.1852 | 0.4534 | 0.076* | |
H6'4 | 0.7141 | 0.2837 | 0.5179 | 0.076* | |
O6'A | 0.63128 (19) | 0.0661 (5) | 0.51458 (14) | 0.0757 (8) | |
C7'A | 0.6220 (3) | 0.0767 (10) | 0.5736 (3) | 0.0867 (16) | |
O7'A | 0.6488 (3) | 0.2085 (9) | 0.60597 (17) | 0.1191 (16) | |
C8'A | 0.5717 (4) | −0.0952 (10) | 0.5941 (3) | 0.127 (3) | |
H8'4 | 0.5969 | −0.2141 | 0.5814 | 0.191* | |
H8'5 | 0.5154 | −0.0868 | 0.5760 | 0.191* | |
H8'6 | 0.5710 | −0.0938 | 0.6378 | 0.191* | |
N1B | 0.88680 (17) | 0.4728 (4) | 0.53657 (12) | 0.0396 (6) | |
C2B | 0.8724 (2) | 0.5296 (5) | 0.47537 (15) | 0.0388 (7) | |
O2B | 0.86200 (17) | 0.7040 (3) | 0.46333 (11) | 0.0542 (6) | |
N3B | 0.87003 (17) | 0.3921 (4) | 0.43128 (12) | 0.0400 (6) | |
C4B | 0.8818 (2) | 0.2035 (5) | 0.44639 (14) | 0.0374 (7) | |
N4B | 0.87731 (19) | 0.0744 (5) | 0.40148 (13) | 0.0513 (7) | |
H4B1 | 0.8672 | 0.1122 | 0.3643 | 0.062* | |
H4B2 | 0.8845 | −0.0474 | 0.4095 | 0.062* | |
C5B | 0.8981 (2) | 0.1417 (5) | 0.50832 (15) | 0.0420 (8) | |
H5B | 0.9066 | 0.0112 | 0.5182 | 0.050* | |
C6B | 0.9005 (2) | 0.2802 (5) | 0.55164 (15) | 0.0434 (8) | |
H6B | 0.9116 | 0.2455 | 0.5924 | 0.052* | |
O1'B | 0.85489 (17) | 0.8726 (4) | 0.64398 (12) | 0.0639 (7) | |
C2'B | 0.9346 (2) | 0.7969 (6) | 0.66829 (17) | 0.0564 (10) | |
H2'B | 0.9762 | 0.9019 | 0.6702 | 0.068* | |
C3'B | 0.9572 (2) | 0.6497 (6) | 0.62247 (15) | 0.0509 (9) | |
H3'B | 1.0090 | 0.5888 | 0.6218 | 0.061* | |
C4'B | 0.8927 (2) | 0.6193 (5) | 0.58317 (14) | 0.0421 (8) | |
C5'B | 0.8203 (2) | 0.7440 (5) | 0.59756 (16) | 0.0527 (9) | |
H5'1 | 0.7987 | 0.8161 | 0.5618 | 0.063* | |
H5'2 | 0.7755 | 0.6660 | 0.6125 | 0.063* | |
C6'B | 0.9285 (3) | 0.7125 (7) | 0.73152 (17) | 0.0602 (10) | |
H6'1 | 0.9817 | 0.6544 | 0.7457 | 0.072* | |
H6'2 | 0.9158 | 0.8150 | 0.7598 | 0.072* | |
O6'B | 0.86357 (16) | 0.5669 (5) | 0.72953 (12) | 0.0590 (7) | |
C7'B | 0.8842 (3) | 0.3783 (8) | 0.7355 (2) | 0.0701 (12) | |
O7'B | 0.9543 (2) | 0.3234 (6) | 0.7413 (3) | 0.1290 (17) | |
C8'B | 0.8083 (3) | 0.2535 (8) | 0.7344 (3) | 0.0978 (17) | |
H8'1 | 0.7757 | 0.2714 | 0.6963 | 0.147* | |
H8'2 | 0.7754 | 0.2889 | 0.7676 | 0.147* | |
H8'3 | 0.8248 | 0.1194 | 0.7385 | 0.147* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
N1A | 0.0490 (15) | 0.0345 (16) | 0.0354 (14) | −0.0043 (12) | 0.0040 (11) | −0.0028 (12) |
C2A | 0.0431 (18) | 0.0357 (19) | 0.0363 (17) | 0.0042 (14) | 0.0023 (13) | −0.0052 (15) |
O2A | 0.0752 (17) | 0.0271 (13) | 0.0474 (14) | −0.0011 (11) | 0.0077 (12) | −0.0063 (11) |
N3A | 0.0467 (15) | 0.0321 (15) | 0.0358 (13) | 0.0009 (12) | 0.0043 (12) | −0.0016 (12) |
C4A | 0.0357 (17) | 0.0348 (18) | 0.0402 (18) | 0.0003 (14) | 0.0014 (14) | −0.0021 (14) |
N4A | 0.0597 (17) | 0.0323 (14) | 0.0387 (14) | −0.0030 (13) | 0.0015 (13) | 0.0020 (12) |
C5A | 0.061 (2) | 0.0297 (18) | 0.0419 (18) | −0.0038 (15) | 0.0039 (16) | −0.0035 (15) |
C6A | 0.059 (2) | 0.0329 (17) | 0.0385 (17) | −0.0039 (16) | 0.0045 (15) | −0.0102 (16) |
O1'A | 0.0702 (17) | 0.092 (2) | 0.0558 (16) | −0.0396 (16) | −0.0104 (13) | 0.0267 (15) |
C2'A | 0.053 (2) | 0.059 (2) | 0.0429 (19) | −0.0133 (18) | 0.0019 (16) | 0.0052 (19) |
C3'A | 0.0523 (19) | 0.052 (2) | 0.047 (2) | −0.0130 (18) | 0.0002 (16) | 0.0014 (18) |
C4'A | 0.0419 (17) | 0.0391 (18) | 0.0388 (17) | −0.0010 (15) | 0.0067 (14) | −0.0012 (15) |
C5'A | 0.0507 (19) | 0.053 (2) | 0.0418 (19) | −0.0118 (17) | 0.0005 (14) | 0.0005 (17) |
C6'A | 0.062 (2) | 0.065 (3) | 0.063 (2) | −0.007 (2) | 0.0097 (19) | 0.014 (2) |
O6'A | 0.085 (2) | 0.072 (2) | 0.0725 (19) | −0.0027 (17) | 0.0176 (16) | 0.0191 (17) |
C7'A | 0.072 (3) | 0.112 (5) | 0.077 (4) | 0.029 (3) | 0.012 (3) | 0.038 (3) |
O7'A | 0.111 (3) | 0.177 (5) | 0.068 (2) | 0.007 (3) | −0.004 (2) | 0.006 (3) |
C8'A | 0.120 (5) | 0.123 (5) | 0.147 (5) | 0.030 (4) | 0.063 (4) | 0.086 (5) |
N1B | 0.0546 (17) | 0.0308 (14) | 0.0333 (14) | 0.0027 (12) | 0.0026 (12) | −0.0006 (12) |
C2B | 0.0498 (19) | 0.0278 (18) | 0.0385 (17) | −0.0065 (15) | 0.0025 (14) | −0.0010 (15) |
O2B | 0.0885 (18) | 0.0292 (13) | 0.0450 (13) | −0.0015 (12) | 0.0061 (12) | 0.0018 (11) |
N3B | 0.0553 (16) | 0.0290 (14) | 0.0358 (14) | −0.0021 (12) | 0.0033 (12) | 0.0011 (13) |
C4B | 0.0483 (18) | 0.0276 (16) | 0.0369 (17) | −0.0031 (14) | 0.0066 (14) | −0.0011 (15) |
N4B | 0.083 (2) | 0.0312 (15) | 0.0391 (15) | 0.0010 (14) | 0.0031 (14) | −0.0021 (13) |
C5B | 0.055 (2) | 0.0299 (17) | 0.0407 (18) | 0.0033 (14) | 0.0023 (15) | 0.0028 (15) |
C6B | 0.0516 (19) | 0.041 (2) | 0.0378 (18) | 0.0023 (16) | 0.0061 (15) | 0.0061 (16) |
O1'B | 0.0845 (18) | 0.0507 (16) | 0.0560 (15) | 0.0122 (15) | 0.0016 (13) | −0.0187 (14) |
C2'B | 0.062 (2) | 0.054 (2) | 0.052 (2) | −0.012 (2) | 0.0017 (18) | −0.0180 (19) |
C3'B | 0.0478 (19) | 0.057 (2) | 0.049 (2) | −0.0045 (16) | 0.0067 (16) | −0.0121 (17) |
C4'B | 0.052 (2) | 0.0360 (18) | 0.0388 (18) | −0.0020 (15) | 0.0083 (15) | −0.0048 (15) |
C5'B | 0.059 (2) | 0.051 (2) | 0.0481 (19) | 0.0062 (18) | 0.0032 (16) | −0.0081 (18) |
C6'B | 0.063 (2) | 0.068 (3) | 0.049 (2) | −0.001 (2) | −0.0021 (18) | −0.021 (2) |
O6'B | 0.0542 (15) | 0.0656 (19) | 0.0578 (16) | 0.0017 (14) | 0.0080 (12) | −0.0085 (14) |
C7'B | 0.065 (3) | 0.070 (3) | 0.077 (3) | 0.007 (2) | 0.018 (2) | −0.005 (3) |
O7'B | 0.072 (2) | 0.091 (3) | 0.225 (5) | 0.022 (2) | 0.018 (3) | 0.006 (3) |
C8'B | 0.090 (3) | 0.072 (4) | 0.136 (5) | −0.014 (3) | 0.038 (3) | −0.020 (3) |
Geometric parameters (Å, º) top
N1A—C6A | 1.379 (4) | N1B—C6B | 1.376 (4) |
N1A—C2A | 1.407 (4) | N1B—C2B | 1.401 (4) |
N1A—C4'A | 1.425 (4) | N1B—C4'B | 1.432 (4) |
C2A—O2A | 1.239 (4) | C2B—O2B | 1.235 (4) |
C2A—N3A | 1.359 (4) | C2B—N3B | 1.350 (4) |
N3A—C4A | 1.331 (4) | N3B—C4B | 1.346 (4) |
C4A—N4A | 1.331 (4) | C4B—N4B | 1.323 (4) |
C4A—C5A | 1.435 (4) | C4B—C5B | 1.429 (4) |
N4A—H4A1 | 0.8600 | N4B—H4B1 | 0.8600 |
N4A—H4A2 | 0.8600 | N4B—H4B2 | 0.8600 |
C5A—C6A | 1.326 (5) | C5B—C6B | 1.343 (5) |
C5A—H5A | 0.9300 | C5B—H5B | 0.9300 |
C6A—H6A | 0.9300 | C6B—H6B | 0.9300 |
O1'A—C5'A | 1.421 (4) | O1'B—C5'B | 1.429 (4) |
O1'A—C2'A | 1.428 (4) | O1'B—C2'B | 1.442 (5) |
C2'A—C6'A | 1.499 (6) | C2'B—C3'B | 1.488 (5) |
C2'A—C3'A | 1.503 (5) | C2'B—C6'B | 1.513 (6) |
C2'A—H2'A | 0.9800 | C2'B—H2'B | 0.9800 |
C3'A—C4'A | 1.308 (5) | C3'B—C4'B | 1.312 (5) |
C3'A—H3'A | 0.9300 | C3'B—H3'B | 0.9300 |
C4'A—C5'A | 1.492 (5) | C4'B—C5'B | 1.492 (5) |
C5'A—H5'3 | 0.9700 | C5'B—H5'1 | 0.9700 |
C5'A—H5'4 | 0.9700 | C5'B—H5'2 | 0.9700 |
C6'A—O6'A | 1.452 (5) | C6'B—O6'B | 1.440 (5) |
C6'A—H6'3 | 0.9700 | C6'B—H6'1 | 0.9700 |
C6'A—H6'4 | 0.9700 | C6'B—H6'2 | 0.9700 |
O6'A—C7'A | 1.315 (6) | O6'B—C7'B | 1.340 (6) |
C7'A—O7'A | 1.210 (8) | C7'B—O7'B | 1.181 (5) |
C7'A—C8'A | 1.515 (8) | C7'B—C8'B | 1.484 (7) |
C8'A—H8'4 | 0.9600 | C8'B—H8'1 | 0.9600 |
C8'A—H8'5 | 0.9600 | C8'B—H8'2 | 0.9600 |
C8'A—H8'6 | 0.9600 | C8'B—H8'3 | 0.9600 |
| | | |
C6A—N1A—C2A | 119.7 (3) | C6B—N1B—C2B | 120.7 (3) |
C6A—N1A—C4'A | 119.1 (3) | C6B—N1B—C4'B | 120.1 (3) |
C2A—N1A—C4'A | 121.1 (3) | C2B—N1B—C4'B | 119.1 (3) |
O2A—C2A—N3A | 121.9 (3) | O2B—C2B—N3B | 121.9 (3) |
O2A—C2A—N1A | 119.2 (3) | O2B—C2B—N1B | 119.0 (3) |
N3A—C2A—N1A | 118.9 (3) | N3B—C2B—N1B | 119.0 (3) |
C4A—N3A—C2A | 120.2 (3) | C4B—N3B—C2B | 120.0 (3) |
N4A—C4A—N3A | 118.2 (3) | N4B—C4B—N3B | 117.5 (3) |
N4A—C4A—C5A | 119.9 (3) | N4B—C4B—C5B | 120.3 (3) |
N3A—C4A—C5A | 121.8 (3) | N3B—C4B—C5B | 122.2 (3) |
C4A—N4A—H4A1 | 120.0 | C4B—N4B—H4B1 | 120.0 |
C4A—N4A—H4A2 | 120.0 | C4B—N4B—H4B2 | 120.0 |
H4A1—N4A—H4A2 | 120.0 | H4B1—N4B—H4B2 | 120.0 |
C6A—C5A—C4A | 117.3 (3) | C6B—C5B—C4B | 117.2 (3) |
C6A—C5A—H5A | 121.4 | C6B—C5B—H5B | 121.4 |
C4A—C5A—H5A | 121.4 | C4B—C5B—H5B | 121.4 |
C5A—C6A—N1A | 121.7 (3) | C5B—C6B—N1B | 120.9 (3) |
C5A—C6A—H6A | 119.1 | C5B—C6B—H6B | 119.5 |
N1A—C6A—H6A | 119.1 | N1B—C6B—H6B | 119.5 |
C5'A—O1'A—C2'A | 110.3 (3) | C5'B—O1'B—C2'B | 109.1 (3) |
O1'A—C2'A—C6'A | 109.9 (4) | O1'B—C2'B—C3'B | 104.3 (3) |
O1'A—C2'A—C3'A | 104.6 (3) | O1'B—C2'B—C6'B | 111.3 (3) |
C6'A—C2'A—C3'A | 112.0 (3) | C3'B—C2'B—C6'B | 113.2 (3) |
O1'A—C2'A—H2'A | 110.1 | O1'B—C2'B—H2'B | 109.3 |
C6'A—C2'A—H2'A | 110.1 | C3'B—C2'B—H2'B | 109.3 |
C3'A—C2'A—H2'A | 110.1 | C6'B—C2'B—H2'B | 109.3 |
C4'A—C3'A—C2'A | 109.6 (3) | C4'B—C3'B—C2'B | 109.5 (3) |
C4'A—C3'A—H3'A | 125.2 | C4'B—C3'B—H3'B | 125.3 |
C2'A—C3'A—H3'A | 125.2 | C2'B—C3'B—H3'B | 125.3 |
C3'A—C4'A—N1A | 126.0 (3) | C3'B—C4'B—N1B | 126.1 (3) |
C3'A—C4'A—C5'A | 110.7 (3) | C3'B—C4'B—C5'B | 110.8 (3) |
N1A—C4'A—C5'A | 123.0 (3) | N1B—C4'B—C5'B | 122.8 (3) |
O1'A—C5'A—C4'A | 104.7 (3) | O1'B—C5'B—C4'B | 103.8 (3) |
O1'A—C5'A—H5'3 | 110.8 | O1'B—C5'B—H5'1 | 111.0 |
C4'A—C5'A—H5'3 | 110.8 | C4'B—C5'B—H5'1 | 111.0 |
O1'A—C5'A—H5'4 | 110.8 | O1'B—C5'B—H5'2 | 111.0 |
C4'A—C5'A—H5'4 | 110.8 | C4'B—C5'B—H5'2 | 111.0 |
H5'3—C5'A—H5'4 | 108.9 | H5'1—C5'B—H5'2 | 109.0 |
O6'A—C6'A—C2'A | 111.8 (3) | O6'B—C6'B—C2'B | 109.4 (3) |
O6'A—C6'A—H6'3 | 109.3 | O6'B—C6'B—H6'1 | 109.8 |
C2'A—C6'A—H6'3 | 109.3 | C2'B—C6'B—H6'1 | 109.8 |
O6'A—C6'A—H6'4 | 109.3 | O6'B—C6'B—H6'2 | 109.8 |
C2'A—C6'A—H6'4 | 109.3 | C2'B—C6'B—H6'2 | 109.8 |
H6'3—C6'A—H6'4 | 107.9 | H6'1—C6'B—H6'2 | 108.2 |
C7'A—O6'A—C6'A | 116.2 (4) | C7'B—O6'B—C6'B | 119.7 (3) |
O7'A—C7'A—O6'A | 124.0 (6) | O7'B—C7'B—O6'B | 122.9 (5) |
O7'A—C7'A—C8'A | 125.6 (6) | O7'B—C7'B—C8'B | 125.9 (5) |
O6'A—C7'A—C8'A | 110.4 (6) | O6'B—C7'B—C8'B | 111.1 (4) |
C7'A—C8'A—H8'4 | 109.5 | C7'B—C8'B—H8'1 | 109.5 |
C7'A—C8'A—H8'5 | 109.5 | C7'B—C8'B—H8'2 | 109.5 |
H8'4—C8'A—H8'5 | 109.5 | H8'1—C8'B—H8'2 | 109.5 |
C7'A—C8'A—H8'6 | 109.5 | C7'B—C8'B—H8'3 | 109.5 |
H8'4—C8'A—H8'6 | 109.5 | H8'1—C8'B—H8'3 | 109.5 |
H8'5—C8'A—H8'6 | 109.5 | H8'2—C8'B—H8'3 | 109.5 |
| | | |
C6A—N1A—C2A—O2A | 174.8 (3) | C6B—N1B—C2B—O2B | −178.6 (3) |
C4'A—N1A—C2A—O2A | −0.7 (5) | C4'B—N1B—C2B—O2B | −2.7 (5) |
C6A—N1A—C2A—N3A | −5.4 (4) | C6B—N1B—C2B—N3B | 1.7 (5) |
C4'A—N1A—C2A—N3A | 179.1 (3) | C4'B—N1B—C2B—N3B | 177.5 (3) |
O2A—C2A—N3A—C4A | −178.9 (3) | O2B—C2B—N3B—C4B | 179.9 (3) |
N1A—C2A—N3A—C4A | 1.4 (4) | N1B—C2B—N3B—C4B | −0.3 (5) |
C2A—N3A—C4A—N4A | −175.5 (3) | C2B—N3B—C4B—N4B | 178.8 (3) |
C2A—N3A—C4A—C5A | 4.1 (5) | C2B—N3B—C4B—C5B | −0.8 (5) |
N4A—C4A—C5A—C6A | 174.1 (3) | N4B—C4B—C5B—C6B | −179.0 (3) |
N3A—C4A—C5A—C6A | −5.6 (5) | N3B—C4B—C5B—C6B | 0.6 (5) |
C4A—C5A—C6A—N1A | 1.4 (5) | C4B—C5B—C6B—N1B | 0.8 (5) |
C2A—N1A—C6A—C5A | 3.9 (5) | C2B—N1B—C6B—C5B | −1.9 (5) |
C4'A—N1A—C6A—C5A | 179.5 (3) | C4'B—N1B—C6B—C5B | −177.7 (3) |
C5'A—O1'A—C2'A—C6'A | −122.7 (3) | C5'B—O1'B—C2'B—C3'B | 15.9 (4) |
C5'A—O1'A—C2'A—C3'A | −2.3 (4) | C5'B—O1'B—C2'B—C6'B | −106.5 (3) |
O1'A—C2'A—C3'A—C4'A | 0.2 (4) | O1'B—C2'B—C3'B—C4'B | −10.2 (4) |
C6'A—C2'A—C3'A—C4'A | 119.2 (4) | C6'B—C2'B—C3'B—C4'B | 111.0 (4) |
C2'A—C3'A—C4'A—N1A | 175.6 (3) | C2'B—C3'B—C4'B—N1B | −172.6 (3) |
C2'A—C3'A—C4'A—C5'A | 1.9 (4) | C2'B—C3'B—C4'B—C5'B | 0.8 (4) |
C6A—N1A—C4'A—C3'A | −38.5 (5) | C6B—N1B—C4'B—C3'B | 54.7 (5) |
C2A—N1A—C4'A—C3'A | 137.0 (4) | C2B—N1B—C4'B—C3'B | −121.2 (4) |
C6A—N1A—C4'A—C5'A | 134.5 (3) | C6B—N1B—C4'B—C5'B | −118.0 (4) |
C2A—N1A—C4'A—C5'A | −50.0 (4) | C2B—N1B—C4'B—C5'B | 66.2 (4) |
C2'A—O1'A—C5'A—C4'A | 3.3 (4) | C2'B—O1'B—C5'B—C4'B | −15.3 (4) |
C3'A—C4'A—C5'A—O1'A | −3.2 (4) | C3'B—C4'B—C5'B—O1'B | 8.9 (4) |
N1A—C4'A—C5'A—O1'A | −177.1 (3) | N1B—C4'B—C5'B—O1'B | −177.4 (3) |
O1'A—C2'A—C6'A—O6'A | −54.0 (4) | O1'B—C2'B—C6'B—O6'B | 55.5 (4) |
C3'A—C2'A—C6'A—O6'A | −169.8 (3) | C3'B—C2'B—C6'B—O6'B | −61.6 (4) |
C2'A—C6'A—O6'A—C7'A | −88.5 (5) | C2'B—C6'B—O6'B—C7'B | 108.8 (4) |
C6'A—O6'A—C7'A—O7'A | −3.2 (7) | C6'B—O6'B—C7'B—O7'B | −1.6 (7) |
C6'A—O6'A—C7'A—C8'A | 175.4 (4) | C6'B—O6'B—C7'B—C8'B | 178.0 (4) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N4A—H4A1···N3Bi | 0.86 | 2.19 | 3.031 (4) | 164 |
N4A—H4A2···O2Aii | 0.86 | 2.27 | 3.002 (4) | 144 |
N4B—H4B1···N3Aiii | 0.86 | 2.15 | 3.004 (4) | 170 |
N4B—H4B2···O2Biv | 0.86 | 2.12 | 2.901 (4) | 150 |
Symmetry codes: (i) −x+3/2, y+1/2, −z+1/2; (ii) x, y+1, z; (iii) −x+3/2, y−1/2, −z+1/2; (iv) x, y−1, z. |
Experimental details
Crystal data |
Chemical formula | C11H13N3O4 |
Mr | 251.24 |
Crystal system, space group | Monoclinic, I2 |
Temperature (K) | 213 |
a, b, c (Å) | 15.995 (2), 6.865 (1), 21.934 (5) |
β (°) | 94.16 (2) |
V (Å3) | 2402.1 (7) |
Z | 8 |
Radiation type | Mo Kα |
µ (mm−1) | 0.11 |
Crystal size (mm) | 0.33 × 0.22 × 0.18 |
|
Data collection |
Diffractometer | Enraf-Nonius CAD4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 8222, 2283, 1774 |
Rint | 0.052 |
(sin θ/λ)max (Å−1) | 0.595 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.035, 0.098, 1.10 |
No. of reflections | 2283 |
No. of parameters | 327 |
No. of restraints | 1 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.19, −0.15 |
Selected geometric parameters (Å, º) topN1A—C6A | 1.379 (4) | N1B—C6B | 1.376 (4) |
N1A—C2A | 1.407 (4) | N1B—C2B | 1.401 (4) |
N1A—C4'A | 1.425 (4) | N1B—C4'B | 1.432 (4) |
C2A—O2A | 1.239 (4) | C2B—O2B | 1.235 (4) |
C2A—N3A | 1.359 (4) | C2B—N3B | 1.350 (4) |
N3A—C4A | 1.331 (4) | N3B—C4B | 1.346 (4) |
C4A—N4A | 1.331 (4) | C4B—N4B | 1.323 (4) |
C4A—C5A | 1.435 (4) | C4B—C5B | 1.429 (4) |
C5A—C6A | 1.326 (5) | C5B—C6B | 1.343 (5) |
O1'A—C5'A | 1.421 (4) | O1'B—C5'B | 1.429 (4) |
O1'A—C2'A | 1.428 (4) | O1'B—C2'B | 1.442 (5) |
C2'A—C6'A | 1.499 (6) | C2'B—C3'B | 1.488 (5) |
C2'A—C3'A | 1.503 (5) | C2'B—C6'B | 1.513 (6) |
C3'A—C4'A | 1.308 (5) | C3'B—C4'B | 1.312 (5) |
C4'A—C5'A | 1.492 (5) | C4'B—C5'B | 1.492 (5) |
C6'A—O6'A | 1.452 (5) | C6'B—O6'B | 1.440 (5) |
O6'A—C7'A | 1.315 (6) | O6'B—C7'B | 1.340 (6) |
C7'A—O7'A | 1.210 (8) | C7'B—O7'B | 1.181 (5) |
C7'A—C8'A | 1.515 (8) | C7'B—C8'B | 1.484 (7) |
| | | |
C6A—N1A—C2A | 119.7 (3) | C6B—N1B—C2B | 120.7 (3) |
C6A—N1A—C4'A | 119.1 (3) | C6B—N1B—C4'B | 120.1 (3) |
C2A—N1A—C4'A | 121.1 (3) | C2B—N1B—C4'B | 119.1 (3) |
O2A—C2A—N3A | 121.9 (3) | O2B—C2B—N3B | 121.9 (3) |
O2A—C2A—N1A | 119.2 (3) | O2B—C2B—N1B | 119.0 (3) |
N3A—C2A—N1A | 118.9 (3) | N3B—C2B—N1B | 119.0 (3) |
C4A—N3A—C2A | 120.2 (3) | C4B—N3B—C2B | 120.0 (3) |
N4A—C4A—N3A | 118.2 (3) | N4B—C4B—N3B | 117.5 (3) |
N4A—C4A—C5A | 119.9 (3) | N4B—C4B—C5B | 120.3 (3) |
N3A—C4A—C5A | 121.8 (3) | N3B—C4B—C5B | 122.2 (3) |
C6A—C5A—C4A | 117.3 (3) | C6B—C5B—C4B | 117.2 (3) |
C5A—C6A—N1A | 121.7 (3) | C5B—C6B—N1B | 120.9 (3) |
C5'A—O1'A—C2'A | 110.3 (3) | C5'B—O1'B—C2'B | 109.1 (3) |
O1'A—C2'A—C6'A | 109.9 (4) | O1'B—C2'B—C3'B | 104.3 (3) |
O1'A—C2'A—C3'A | 104.6 (3) | O1'B—C2'B—C6'B | 111.3 (3) |
C6'A—C2'A—C3'A | 112.0 (3) | C3'B—C2'B—C6'B | 113.2 (3) |
C4'A—C3'A—C2'A | 109.6 (3) | C4'B—C3'B—C2'B | 109.5 (3) |
C3'A—C4'A—N1A | 126.0 (3) | C3'B—C4'B—N1B | 126.1 (3) |
C3'A—C4'A—C5'A | 110.7 (3) | C3'B—C4'B—C5'B | 110.8 (3) |
N1A—C4'A—C5'A | 123.0 (3) | N1B—C4'B—C5'B | 122.8 (3) |
O1'A—C5'A—C4'A | 104.7 (3) | O1'B—C5'B—C4'B | 103.8 (3) |
O6'A—C6'A—C2'A | 111.8 (3) | O6'B—C6'B—C2'B | 109.4 (3) |
C7'A—O6'A—C6'A | 116.2 (4) | C7'B—O6'B—C6'B | 119.7 (3) |
O7'A—C7'A—O6'A | 124.0 (6) | O7'B—C7'B—O6'B | 122.9 (5) |
O7'A—C7'A—C8'A | 125.6 (6) | O7'B—C7'B—C8'B | 125.9 (5) |
O6'A—C7'A—C8'A | 110.4 (6) | O6'B—C7'B—C8'B | 111.1 (4) |
| | | |
C6A—N1A—C4'A—C3'A | −38.5 (5) | C6B—N1B—C4'B—C3'B | 54.7 (5) |
C3'A—C2'A—C6'A—O6'A | −169.8 (3) | C2'B—O1'B—C5'B—C4'B | −15.3 (4) |
C2'A—C6'A—O6'A—C7'A | −88.5 (5) | C3'B—C4'B—C5'B—O1'B | 8.9 (4) |
C5'B—O1'B—C2'B—C3'B | 15.9 (4) | C3'B—C2'B—C6'B—O6'B | −61.6 (4) |
O1'B—C2'B—C3'B—C4'B | −10.2 (4) | C2'B—C6'B—O6'B—C7'B | 108.8 (4) |
C2'B—C3'B—C4'B—C5'B | 0.8 (4) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N4A—H4A1···N3Bi | 0.86 | 2.19 | 3.031 (4) | 164 |
N4A—H4A2···O2Aii | 0.86 | 2.27 | 3.002 (4) | 144 |
N4B—H4B1···N3Aiii | 0.86 | 2.15 | 3.004 (4) | 170 |
N4B—H4B2···O2Biv | 0.86 | 2.12 | 2.901 (4) | 150 |
Symmetry codes: (i) −x+3/2, y+1/2, −z+1/2; (ii) x, y+1, z; (iii) −x+3/2, y−1/2, −z+1/2; (iv) x, y−1, z. |
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Dideoxydidehydrocytidine (d4C) has potent anti-HIV activity (Balzarini et al., 1986). Our interest in the design of novel isomeric nucleosides of potential anti-HIV activity (Nair et al., 1995) led to the synthesis of compound (II) and its lipophilic derivative (I) which are structural analogues of d4C. Because of the complex synthetic pathway to (II), it was necessary to confirm its structure through its more crystalline pro-drug derivative (I). Compound (I) was synthesized via a rearrangement reaction of 4(R)-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]-2(R)-(benzoyloxymethyl)- tetrahydrofuran-3(S)—O-methanesulfonate followed by conversion of the uracil base to cytosine (Bera et al., 1999, Nair & Nuesca, 1992; Kakefuda et al., 1994). Compound (I) was characterized by NMR and HRMS data.
Compound (I) crystallizes with two confomers, A and B, in the asymmetric unit (atoms of a conformer are identified by A or B in the labels). For both conformers, the pyrimidine rings are planar (0.025 and 0.006 Å r.m.s. deviation from planarity for A and B, respectively) as are the acetyl substituents (0.004 and 0.001 Å r.m.s. deviation for A and B, respectively). Although the dihydrofuran (DHF) ring of A is planar (0.014 Å r.m.s. deviation) the DHF ring of B has an O1'B-envelope conformation [O1'B is 0.231 (6) Å from the C2'B, C3'B, C4'B, C5'B plane, 0.004 Å r.m.s. deviation]. Rotation about the N1–C4' bond relieves steric repulsion between the pyrimidine and DHF rings; however, the sense of rotation is reversed between A and B (see Table 1) and B is rotated to a greater degree. The greatest difference in conformation between A and B is the orientation of the C6' acetyl substituent. When considering rotation about the C2'—C6' bond, in A, O6'A is anti to C3'A which positions the acetyl moiety anti to the DHF ring resulting in an extended conformation. In B, O6'B is gauche to C3'B which positions the acetyl group syn to the DHF ring giving a hook-shaped molecule.
The two conformers form dimers via two N4—H4···N3 hydrogen bonds (see Table 2) to a symmetry-related molecule generated via the 1/2 − x, 1/2 + y, 1/2 − z symmetry operation. The dimers are linked via N4—H4···O2 hydrogen bonds to form chains of dimers parallel to the b unit-cell direction.