2′,3′-Dide­hydro-3′-deoxy­thymidine N-methyl-2-pyrrolidone solvate (D4T·NMPO)

The title compound, 1-(2′,3′-di­deoxy-β-D-glycero-pent-2-eno­furan­osyl)­thymine 1-methyl-2-pyrrolidone solvate, C₁₀H₁₂N₂O₄·­C₅H₉NO, is an NMPO solvate of the anti-AIDS agent D4T. In its crystal structure, both the pyrimidine and the furan­ose rings are planar and approximately perpendicular [82.1 (4)°]. The value of the torsion angle defining the orientation of the thymine with respect to the joined furane, χ = −100.8 (4)°, and that of the torsion angle giving the orientation of the hydroxyl group linked to the furane ring, γ = 52.9 (5)°, show that the gly­cosyl­ic link adopts the so-called high-anti conformation and the 5′-hydroxyl group is in the +sc position. The NMPO solvate is linked to the nucleoside through a fairly strong hydrogen bond.

S1. Comment

Many chemotherapeutic compounds (Huryn & Okabe, 1992) have been evaluated since acquired immunodeficiency syndrome (AIDS) appeared in the world and became one of the most important epidemic diseases in modern times (De Clercq & Balzarini, 1995). Nucleosides analogues, particularly those belonging to the 2',3'-O-dideoxynucleoside and 2',3'-O-didehydro-2',3'-O-dideoxynucleoside family (Chu et al., 1989; Herdewijn et al., 1987), have shown high effectiveness in the treatment of AIDS, inhibiting the HIV (human immunodeficiency virus) reverse transcriptase after their anabolic activation to 5'-triphosphate derivatives by cellular kinases.

2',3'-Didehydro-3'-deoxythymidine (Stavudine or D4T) is a potent and selective antiviral agent that is currently in clinical trials for treatment of AIDS (Baba et al., 1987). D4T was originally synthesized by Horwitz et al. (1966) and recently different groups have developed different synthetic routes in order to obtain an easy procedure with high yield (Negron et al., 1994; Bonaffé et al., 1996). Skonezny et al. (1994) have developed a simple and gentle procedure for obtaining D4T, which included a novel purification step where D4T was isolated with N-methylpyrrolidone as solvate. \sch

The structural study of this complex was undertaken in order to gain further information on the geometry of D4T and on its link with NMPO, which is the final step of the adopted synthetic procedure. The structures of two crystal phases of D4T alone have already been solved (Gurskaya et al., 1991; Harte et al., 1991; Van Roey et al., 1993) together with those of other 2',3'-didehydro-2',3'-deoxynucleotides (D4N) (Birnbaum et al., 1989; Van Roey et al., 1993; Pugazhenthi et al., 1994).

A view of the molecular adduct is shown in Figure 1, where the numbering scheme is consistent with that adopted in the above references. Bond distances and angles of D4T in our solvate do not show any relevant deviation from the literature values.

Three parameters may be used to describe the most important conformational features of a nucleoside molecule (Saenger, 1984): the torsion angle χ = C2—N1—C1'-O4' for the geometry of the glycosylic link, the furanose ring puckering and the orientation of the 5'-hydroxyl group in terms of the torsion angle γ = C3'-C4'-C5'-O5'. The values of χ = -100.8 (4) and of γ = 52.9 (5)° in our compound show that the glycosylic link adopts the so called high-anti conformation and the 5'-hydroxyl group is in the +sc (synclynal) position, as found in a number of other D4N molecules (Van Roey et al., 1993). The value of γ is largely determined by the type of hydrogen bond in which O5' is engaged: indeed in 2',3'-didehydro-2',3'-deoxy-5-hydroxymethyluridine (D4HMUrd) (Pugazhenthi et al., 1994), where O5' acts only as hydrogen-bond acceptor, the 5'-hydroxyl group adopts the ap (antiperiplanar) conformation, while the +sc conformation is found when O5' acts as donor.

The furanose ring is significantly planar, with an r.m.s. deviation of the five-atom plane of 0.003 Å and O4' at -0.009 (2) Å from the plane of the other for atoms. A similar flat ring was found in one of the two independent molecules of 2',3'-didehydro-2',3'-deoxyuridine (D4U) (Van Roey et al., 1993) and in a 4'-C-branched derivative of D4U (Yamaguchi et al., 1992). The pyrimidine ring is also planar, but with a larger r.m.s. deviation [0.006 Å, with C2 at -0.011 (2) Å and N3 at 0.009 (2) Å from the plane]. The dihedral angle between the pyrimidine and the furanose planes is of 82.1 (4)°.

The geometry of the NMPO molecule is not well defined because it is affected by some disorder, as indicated by the high values of the atomic displacement parameters of some of the atoms.

The two moieties of our adduct are held together by a fairly strong O5'-H5'···O* hydrogen bond, with O5'···O* = 2.663 (4) Å, H5'···O* = 1.88 Å and an angle at H5' of 159°. O5' is also involved as acceptor in a medium strength intermolecular N3—H3···O5'(at 1 - x, y - 1/2, 1/2 - z) hydrogen bond, with N3···O5'= 2.853 (4) Å, H3···O5' = 2.01 Å and an angle at H3 of 166°.

S2. Experimental

The D4T·NMPO complex was synthesized from thymidine by several reaction steps. The initial step involved the mesylation of the 3' and 5' hydroxyl groups of thymidine. The bis-mesylthymidine was heated with aqueous sodium hydroxide (30%) to give 3',5'-anhydrothymidine, then treated with potassium hydroxide in isopropyl alcohol to produce D4T, which was then isolated as a D4T·NMPO complex.

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/IRIS (Sheldrick, 1990) and MOLDRAW (Ugliengo et al., 1993); software used to prepare material for publication: PARST (Nardelli, 1995), PARSTCIF (Nardelli, 1991) and SHELXL97.

Figures

Fig. 1.

1-(2',3'-dideoxy-β-D-glycero-pent-2-enofuranosyl)thimine 1-methylpyrrolidone

Crystal data

C10H12N2O4·C5H9NO	Dx = 1.306 Mg m^−3
Mr = 323.35	Mo Kα radiation, λ = 0.71069 Å
Orthorhombic, P212121	Cell parameters from 30 reflections
a = 7.471 (1) Å	θ = 12–26°
b = 13.988 (1) Å	µ = 0.10 mm^−1
c = 15.739 (2) Å	T = 293 K
V = 1644.8 (3) Å^3	Prism, colourless
Z = 4	0.65 × 0.50 × 0.35 mm
F(000) = 688

Data collection

Four circle diffractometer	Rint = 0.013
Radiation source: fine-focus sealed tube	θmax = 27.5°, θmin = 2.0°
Graphite monochromator	h = −9→1
ω scan	k = −18→1
2807 measured reflections	l = −20→1
2619 independent reflections	2 standard reflections every 98 reflections
1674 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.058	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.155	w = 1/[σ^2(Fo^2) + (0.0936P)^2 + 0.0334P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max = 0.006
2619 reflections	Δρmax = 0.26 e Å^−3
211 parameters	Δρmin = −0.41 e Å^−3
0 restraints	Absolute structure: The absolute configuration was assumed to agree with the known chirality of D4T (Gurskaya et al., 1991; Harte et al., 1991; Van Roey et al., 1993).
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 (Ų)

	x	y	z	Uiso*/Ueq
O2	0.6713 (4)	0.62562 (17)	0.35710 (16)	0.0662 (8)
O4	0.5578 (6)	0.69573 (18)	0.08198 (15)	0.0821 (10)
N1	0.6160 (4)	0.78208 (18)	0.32304 (15)	0.0450 (7)
C2	0.6367 (5)	0.6865 (2)	0.3035 (2)	0.0456 (8)
N3	0.6179 (4)	0.66464 (19)	0.21944 (16)	0.0507 (7)
H3	0.6346	0.6058	0.2056	0.061*
C4	0.5747 (6)	0.7267 (2)	0.1537 (2)	0.0529 (9)
C5	0.5527 (5)	0.8254 (2)	0.1790 (2)	0.0501 (8)
C6	0.5731 (5)	0.8469 (2)	0.2605 (2)	0.0487 (8)
H6	0.5573	0.9104	0.2765	0.058*
C7	0.5076 (8)	0.8973 (3)	0.1119 (2)	0.0768 (14)
H7A	0.6087	0.9059	0.0750	0.092*
H7B	0.4781	0.9572	0.1382	0.092*
H7C	0.4072	0.8750	0.0794	0.092*
O4'	0.4536 (3)	0.82655 (15)	0.44652 (13)	0.0496 (6)
O5'	0.2883 (4)	0.98244 (16)	0.34879 (14)	0.0552 (7)
H5'	0.2420	0.9368	0.3246	0.066*
C1'	0.6276 (5)	0.8124 (2)	0.4128 (2)	0.0484 (8)
H1'	0.6911	0.7639	0.4461	0.058*
C2'	0.7185 (5)	0.9070 (3)	0.4222 (2)	0.0550 (9)
H2'1	0.8352	0.9205	0.4055	0.066*
C3'	0.6084 (5)	0.9679 (3)	0.4578 (2)	0.0548 (9)
H3'	0.6369	1.0313	0.4696	0.066*
C4'	0.4338 (5)	0.9239 (2)	0.47675 (18)	0.0460 (8)
H4'	0.4179	0.9224	0.5385	0.055*
C5'	0.2732 (5)	0.9703 (3)	0.4379 (2)	0.0550 (9)
H5'1	0.1685	0.9316	0.4500	0.066*
H5'2	0.2553	1.0323	0.4641	0.066*
O*	0.0624 (5)	0.8601 (2)	0.2759 (2)	0.0833 (9)
N1*	0.0729 (6)	0.7285 (3)	0.1920 (2)	0.0943 (14)
C2*	0.1110 (8)	0.6253 (4)	0.1979 (4)	0.117 (2)
H2*1	0.2203	0.6094	0.1678	0.141*
H2*2	0.0133	0.5881	0.1743	0.141*
C3*	0.1308 (11)	0.6068 (4)	0.2916 (5)	0.125 (2)
H3*1	0.0332	0.5673	0.3120	0.150*
H3*2	0.2429	0.5744	0.3031	0.150*
C4*	0.1275 (7)	0.7020 (3)	0.3341 (3)	0.0818 (13)
H4*1	0.2427	0.7162	0.3596	0.098*
H4*2	0.0365	0.7037	0.3781	0.098*
C5*	0.0848 (6)	0.7725 (3)	0.2646 (2)	0.0679 (12)
C6*	0.0401 (10)	0.7775 (6)	0.1132 (3)	0.152 (3)
H6*1	0.1466	0.7763	0.0791	0.182*
H6*2	0.0074	0.8426	0.1247	0.182*
H6*3	−0.0555	0.7464	0.0833	0.182*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O2	0.098 (2)	0.0456 (12)	0.0553 (14)	0.0065 (15)	−0.0215 (15)	0.0077 (11)
O4	0.146 (3)	0.0594 (15)	0.0410 (13)	0.006 (2)	−0.0088 (18)	−0.0052 (11)
N1	0.0548 (17)	0.0415 (13)	0.0386 (13)	0.0032 (15)	−0.0050 (14)	0.0016 (11)
C2	0.0478 (19)	0.0402 (16)	0.0489 (17)	−0.0002 (17)	−0.0069 (16)	0.0006 (15)
N3	0.0672 (19)	0.0389 (13)	0.0462 (15)	0.0038 (15)	−0.0040 (15)	0.0009 (11)
C4	0.068 (3)	0.0488 (17)	0.0418 (17)	0.003 (2)	0.0005 (18)	0.0010 (15)
C5	0.063 (2)	0.0436 (16)	0.0442 (17)	0.0033 (19)	0.0006 (17)	0.0040 (14)
C6	0.063 (2)	0.0390 (16)	0.0443 (17)	0.0041 (16)	0.0044 (17)	0.0013 (13)
C7	0.124 (4)	0.057 (2)	0.0501 (19)	0.008 (3)	−0.006 (2)	0.0125 (18)
O4'	0.0623 (15)	0.0422 (11)	0.0442 (11)	−0.0028 (12)	0.0040 (12)	0.0026 (10)
O5'	0.0744 (17)	0.0463 (12)	0.0447 (12)	−0.0038 (13)	−0.0079 (12)	0.0052 (10)
C1'	0.053 (2)	0.0511 (18)	0.0408 (16)	0.0056 (18)	−0.0054 (16)	0.0000 (15)
C2'	0.0457 (19)	0.066 (2)	0.0536 (19)	−0.0070 (19)	−0.0018 (17)	−0.0099 (19)
C3'	0.064 (2)	0.0538 (19)	0.0462 (18)	−0.010 (2)	−0.0083 (19)	−0.0061 (16)
C4'	0.062 (2)	0.0437 (16)	0.0326 (14)	−0.0018 (18)	0.0054 (16)	0.0017 (13)
C5'	0.062 (2)	0.054 (2)	0.0485 (19)	0.0050 (19)	0.0087 (18)	−0.0013 (16)
O*	0.081 (2)	0.0755 (19)	0.094 (2)	−0.0141 (18)	−0.0086 (19)	−0.0160 (17)
N1*	0.085 (3)	0.133 (4)	0.065 (2)	−0.036 (3)	0.015 (2)	−0.031 (2)
C2*	0.085 (4)	0.111 (4)	0.156 (6)	−0.035 (4)	0.035 (4)	−0.082 (4)
C3*	0.122 (5)	0.099 (4)	0.154 (6)	0.001 (4)	0.031 (5)	−0.007 (4)
C4*	0.067 (3)	0.089 (3)	0.089 (3)	−0.011 (3)	−0.003 (3)	0.004 (3)
C5*	0.056 (3)	0.087 (3)	0.060 (2)	−0.029 (2)	0.007 (2)	−0.017 (2)
C6*	0.128 (5)	0.270 (9)	0.058 (3)	−0.065 (7)	−0.005 (3)	0.024 (4)

Geometric parameters (Å, º)

O2—C2	1.226 (4)	O5'—C5'	1.417 (4)
O4—C4	1.216 (4)	C1'—C2'	1.495 (5)
N1—C6	1.377 (4)	C2'—C3'	1.310 (5)
N1—C2	1.381 (4)	C3'—C4'	1.473 (5)
N1—C1'	1.478 (4)	C4'—C5'	1.495 (5)
C2—N3	1.365 (4)	O*—C5*	1.249 (5)
N3—C4	1.389 (4)	N1*—C5*	1.301 (5)
C4—C5	1.446 (5)	N1*—C6*	1.437 (7)
C5—C6	1.326 (5)	N1*—C2*	1.475 (7)
C5—C7	1.497 (5)	C2*—C3*	1.505 (9)
O4'—C1'	1.418 (4)	C3*—C4*	1.490 (8)
O4'—C4'	1.450 (4)	C4*—C5*	1.507 (6)
C6—N1—C2	120.3 (3)	N1—C1'—C2'	112.1 (3)
C6—N1—C1'	120.5 (3)	C3'—C2'—C1'	109.4 (3)
C2—N1—C1'	119.0 (3)	C2'—C3'—C4'	111.8 (3)
O2—C2—N3	122.2 (3)	O4'—C4'—C3'	103.6 (3)
O2—C2—N1	122.9 (3)	O4'—C4'—C5'	110.8 (3)
N3—C2—N1	114.9 (3)	C3'—C4'—C5'	116.5 (3)
C2—N3—C4	127.3 (3)	O5'—C5'—C4'	113.1 (3)
O4—C4—N3	119.6 (3)	C5*—N1*—C6*	122.9 (5)
O4—C4—C5	125.7 (3)	C5*—N1*—C2*	113.3 (5)
N3—C4—C5	114.7 (3)	C6*—N1*—C2*	123.6 (5)
C6—C5—C4	118.0 (3)	N1*—C2*—C3*	104.4 (4)
C6—C5—C7	123.7 (3)	C4*—C3*—C2*	106.6 (5)
C4—C5—C7	118.2 (3)	C3*—C4*—C5*	105.2 (4)
C5—C6—N1	124.7 (3)	O*—C5*—N1*	125.4 (5)
C1'—O4'—C4'	110.3 (3)	O*—C5*—C4*	124.6 (4)
O4'—C1'—N1	110.1 (3)	N1*—C5*—C4*	110.0 (5)
O4'—C1'—C2'	104.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O5′—H5′···O*	0.82	1.88	2.663 (4)	159
N3—H3···O5′^i	0.86	2.01	2.853 (4)	166

Symmetry code: (i) −x+1, y−1/2, −z+1/2.