supplementary materials


hb5290 scheme

Acta Cryst. (2010). E66, o570    [ doi:10.1107/S1600536810003958 ]

(3R*,5'S*)-6,7-Dimethoxy-3-(4'-methoxy-6'-methyl-5',6',7',8'-tetrahydro-1,3-dioxolo[4,5-g]isoquinolin-5'-yl)isobenzofuran-1(3H)-one (racemic [alpha]-noscapine)

J. von von Langermann, H. Lorenz, O. Boehm, A. Flemming, A. Bernsdorf, M. Köckerling, D. Schinzer and A. Seidel-Morgenstern

Abstract top

In the racemic title compound, C22H23NO7, the dihedral angle between the fused ring systems is 51.87 (6)°. Two of the methoxy groups are disordered over two orientations in 0.688 (5):0.312 (5) and 0.672 (15):0.328 (15) ratios. In the crystal, weak C-H...O interactions link the molecules.

Comment top

The antitussive properties of S,R-noscapine [(-)-narcotin], a main alkaloid of opium poppy, were investigated for several decades (e.g. Bergmann et al., 1956). Also anti-cancer properties were recently discussed. Unfortunately, the main production source of this compound is still the illegal crop growing. Therefore, for a drug-independent noscapine-source total synthesis is required, which yield in racemic alpha-noscapine (racemic mixture of S,R- and R,S-noscapine). This compound may be used as an intermediate to obtain S,R-noscapine by separation procedures. Its synthesis will be reported later.

For the biological activity of noscapine and related compounds, see: Aneja et al. (2007); Mahmoudian & Rahimi-Moghaddam (2009); Dahlstrom et al. (1982); Aneja et al. (2006); Anderson et al. (2005). For the crystal structure of the naturally occurring chiral molecule, see: Seetharaman & Rajan (1995).

Related literature top

For the antitussive properties of S,R-noscapine [(-)-narcotin], a main alkaloid of the opium poppy, see: Bergmann & Stolzer (1956). For the biological activity of noscapine and related compounds, see: Aneja et al. (2006, 2007); Mahmoudian et al. (2009); Dahlstrom et al. (1982); Anderson et al. (2005). For the crystal structure of the naturally occurring chiral molecule, see: Seetharaman et al. (1995).

Refinement top

The H atoms were geometrically placed (C—H = 0.95–1.00Å) and refined as riding with Uiso(H) = 1.2Ueq(C) or 1.5Ueq(methyl C). The deepest difference hole is -0.71 e/Å3 at x = 0.3614, y = 0.2316, z = 0.5208 (0.85 Å apart from C16).

Computing details top

Data collection: SMART (Bruker, 2007); cell refinement: SAINT (Bruker, 2007); data reduction: SAINT (Bruker, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of (I) with displacement ellipsoids shown at the 50% probability level. The O6—C22H3 methoxy group is disordered on two positions.
[Figure 2] Fig. 2. Partial packing diagram of (I).
(3R*,5'S*)-6,7-Dimethoxy-3-(4'-methoxy-6'-methyl-5',6',7',8'- tetrahydro-1,3-dioxolo[4,5-g]isoquinolin-5'-yl)isobenzofuran- 1(3H)-one top
Crystal data top
C22H23NO7F(000) = 872
Mr = 413.41Dx = 1.431 Mg m3
Monoclinic, P21/cMelting point: 501.9 K
Hall symbol: -P 2ybcMo Kα radiation, λ = 0.71073 Å
a = 15.5242 (8) ÅCell parameters from 6930 reflections
b = 9.3581 (5) Åθ = 2.5–29.9°
c = 13.2801 (7) ŵ = 0.11 mm1
β = 95.781 (2)°T = 173 K
V = 1919.48 (17) Å3Block, colourless
Z = 40.59 × 0.36 × 0.11 mm
Data collection top
Bruker SMART CCD
diffractometer
3864 independent reflections
Radiation source: fine-focus sealed tube2989 reflections with I > 2σ(I)
graphiteRint = 0.018
ω scansθmax = 26.3°, θmin = 3.4°
Absorption correction: multi-scan
(SADABS; Bruker, 2007)
h = 1819
Tmin = 0.939, Tmax = 0.988k = 118
14003 measured reflectionsl = 1516
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.057H-atom parameters constrained
wR(F2) = 0.169 w = 1/[σ2(Fo2) + (0.0785P)2 + 1.390P]
where P = (Fo2 + 2Fc2)/3
S = 1.12(Δ/σ)max = 0.001
3864 reflectionsΔρmax = 0.56 e Å3
310 parametersΔρmin = 0.71 e Å3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0057 (18)
Crystal data top
C22H23NO7V = 1919.48 (17) Å3
Mr = 413.41Z = 4
Monoclinic, P21/cMo Kα radiation
a = 15.5242 (8) ŵ = 0.11 mm1
b = 9.3581 (5) ÅT = 173 K
c = 13.2801 (7) Å0.59 × 0.36 × 0.11 mm
β = 95.781 (2)°
Data collection top
Bruker SMART CCD
diffractometer
3864 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2007)
2989 reflections with I > 2σ(I)
Tmin = 0.939, Tmax = 0.988Rint = 0.018
14003 measured reflectionsθmax = 26.3°
Refinement top
R[F2 > 2σ(F2)] = 0.057H-atom parameters constrained
wR(F2) = 0.169Δρmax = 0.56 e Å3
S = 1.12Δρmin = 0.71 e Å3
3864 reflectionsAbsolute structure: ?
310 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
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
xyzUiso*/UeqOcc. (<1)
N10.73446 (12)0.3640 (2)0.27455 (14)0.0344 (5)
O11.04337 (10)0.66824 (18)0.09956 (12)0.0386 (4)
O20.95148 (11)0.68699 (18)0.04776 (12)0.0404 (4)
O30.98826 (10)0.53115 (19)0.28872 (11)0.0374 (4)
O40.79757 (10)0.49937 (17)0.46248 (11)0.0342 (4)
O50.69655 (18)0.5011 (2)0.56862 (18)0.0843 (9)
C11.03115 (17)0.7361 (3)0.00278 (19)0.0428 (6)
H1A1.02960.84120.01110.051*
H1B1.07960.71200.03730.051*
C20.90820 (15)0.6242 (2)0.02642 (16)0.0324 (5)
C30.96312 (14)0.6128 (2)0.11444 (17)0.0305 (5)
C40.93703 (14)0.5473 (2)0.19924 (16)0.0287 (5)
C50.85049 (13)0.4988 (2)0.19361 (15)0.0284 (5)
C60.81858 (13)0.4371 (2)0.28879 (16)0.0293 (5)
H6A0.86270.36690.31830.035*
C70.70645 (16)0.3236 (3)0.16978 (19)0.0412 (6)
H7A0.64750.28240.16600.049*
H7B0.74590.24960.14730.049*
C80.70633 (15)0.4513 (3)0.10059 (18)0.0412 (6)
H8A0.68580.42250.03050.049*
H8B0.66640.52510.12240.049*
C90.79610 (14)0.5116 (2)0.10352 (16)0.0323 (5)
C100.82522 (14)0.5736 (2)0.01770 (16)0.0343 (5)
H10A0.78890.58050.04410.041*
C11A1.07435 (17)0.4888 (4)0.2848 (2)0.0634 (9)
H11A1.10340.48240.35370.095*
H11B1.10420.55920.24610.095*
H11C1.07570.39530.25180.095*
C130.81365 (13)0.5602 (2)0.36560 (15)0.0279 (5)
H13A0.86990.61320.37300.033*
C140.72208 (18)0.5464 (3)0.4926 (2)0.0451 (6)
C150.68646 (15)0.6537 (2)0.41869 (19)0.0379 (6)
C160.61460 (19)0.7398 (3)0.4222 (3)0.0668 (10)
C170.59567 (16)0.8363 (3)0.3418 (2)0.0511 (7)
C180.64984 (15)0.8462 (2)0.26480 (17)0.0358 (5)
H18A0.63670.91230.21110.043*
C190.72308 (15)0.7602 (2)0.26562 (16)0.0348 (5)
H19A0.76040.76820.21340.042*
C200.74082 (13)0.6636 (2)0.34276 (15)0.0266 (5)
C120.73227 (19)0.2382 (3)0.3401 (2)0.0483 (7)
H12A0.67540.19240.32860.073*
H12B0.74280.26770.41100.073*
H12C0.77720.17050.32440.073*
O6A0.57726 (16)0.7471 (3)0.51826 (17)0.0462 (9)0.688 (5)
C22A0.4909 (3)0.7090 (9)0.5089 (4)0.0661 (17)0.688 (5)
H22A0.47310.68600.57580.099*0.688 (5)
H22B0.48220.62520.46470.099*0.688 (5)
H22C0.45590.78860.47950.099*0.688 (5)
O6B0.5332 (3)0.6839 (5)0.4441 (4)0.0319 (17)0.312 (5)
C22B0.5107 (6)0.7879 (10)0.5178 (7)0.033 (2)0.312 (5)
H22D0.44820.80540.50880.050*0.312 (5)
H22E0.54170.87740.50830.050*0.312 (5)
H22F0.52710.75130.58620.050*0.312 (5)
C21A0.4969 (5)1.0087 (11)0.2733 (6)0.0490 (17)0.672 (15)
H21A0.45011.07160.29030.074*0.672 (15)
H21B0.47490.94300.21930.074*0.672 (15)
H21C0.54391.06640.25040.074*0.672 (15)
O7A0.5288 (3)0.9287 (5)0.3606 (5)0.0431 (15)0.672 (15)
C21B0.4989 (11)1.0049 (18)0.2305 (13)0.050 (4)0.328 (15)
H21D0.43681.01830.21080.075*0.328 (15)
H21E0.52780.97930.17080.075*0.328 (15)
H21F0.52371.09370.25970.075*0.328 (15)
O7B0.5109 (4)0.8924 (8)0.3042 (11)0.039 (3)0.328 (15)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0349 (10)0.0345 (10)0.0347 (10)0.0060 (8)0.0082 (8)0.0070 (8)
O10.0367 (9)0.0398 (9)0.0405 (9)0.0031 (7)0.0103 (7)0.0054 (7)
O20.0446 (10)0.0406 (9)0.0373 (9)0.0050 (7)0.0108 (7)0.0095 (7)
O30.0266 (8)0.0546 (10)0.0311 (8)0.0044 (7)0.0038 (6)0.0008 (7)
O40.0374 (9)0.0410 (9)0.0244 (8)0.0063 (7)0.0044 (6)0.0009 (7)
O50.124 (2)0.0637 (14)0.0779 (15)0.0484 (14)0.0743 (15)0.0347 (12)
C10.0502 (14)0.0356 (13)0.0443 (14)0.0007 (11)0.0134 (11)0.0089 (11)
C20.0410 (12)0.0273 (11)0.0304 (11)0.0100 (9)0.0103 (9)0.0017 (9)
C30.0299 (11)0.0259 (10)0.0369 (12)0.0035 (8)0.0092 (9)0.0031 (9)
C40.0296 (11)0.0293 (11)0.0279 (10)0.0043 (8)0.0054 (8)0.0046 (8)
C50.0284 (11)0.0284 (10)0.0293 (11)0.0052 (8)0.0067 (8)0.0053 (9)
C60.0267 (10)0.0311 (11)0.0309 (11)0.0031 (8)0.0064 (8)0.0033 (9)
C70.0352 (13)0.0444 (14)0.0444 (14)0.0069 (10)0.0058 (10)0.0143 (11)
C80.0288 (12)0.0584 (16)0.0362 (13)0.0021 (11)0.0018 (9)0.0088 (11)
C90.0305 (11)0.0356 (12)0.0315 (11)0.0082 (9)0.0065 (9)0.0059 (9)
C100.0337 (12)0.0395 (13)0.0299 (11)0.0127 (10)0.0037 (9)0.0016 (9)
C11A0.0348 (14)0.113 (3)0.0433 (15)0.0206 (16)0.0076 (11)0.0161 (17)
C130.0259 (10)0.0338 (11)0.0244 (10)0.0008 (8)0.0046 (8)0.0020 (8)
C140.0556 (16)0.0397 (13)0.0443 (14)0.0146 (12)0.0262 (12)0.0046 (11)
C150.0360 (12)0.0314 (12)0.0492 (14)0.0029 (9)0.0182 (10)0.0049 (10)
C160.0508 (17)0.0533 (17)0.105 (3)0.0212 (14)0.0502 (17)0.0351 (17)
C170.0291 (12)0.0369 (13)0.090 (2)0.0080 (10)0.0183 (13)0.0169 (14)
C180.0405 (13)0.0312 (11)0.0342 (12)0.0024 (10)0.0038 (10)0.0041 (9)
C190.0423 (13)0.0368 (12)0.0265 (11)0.0052 (10)0.0091 (9)0.0039 (9)
C200.0249 (10)0.0290 (11)0.0258 (10)0.0035 (8)0.0020 (8)0.0081 (8)
C120.0565 (16)0.0399 (14)0.0502 (15)0.0148 (12)0.0127 (12)0.0041 (11)
O6A0.0358 (16)0.076 (2)0.0288 (14)0.0116 (13)0.0118 (10)0.0064 (12)
C22A0.040 (3)0.114 (5)0.046 (3)0.010 (3)0.013 (2)0.017 (3)
O6B0.027 (3)0.031 (3)0.042 (3)0.0057 (19)0.019 (2)0.004 (2)
C22B0.027 (5)0.038 (5)0.035 (4)0.003 (3)0.007 (3)0.002 (4)
C21A0.037 (2)0.059 (3)0.053 (4)0.012 (2)0.014 (3)0.028 (4)
O7A0.0393 (17)0.055 (2)0.037 (3)0.0203 (15)0.0117 (17)0.014 (2)
C21B0.041 (5)0.040 (5)0.072 (10)0.017 (4)0.017 (7)0.033 (8)
O7B0.031 (3)0.041 (4)0.044 (7)0.008 (2)0.004 (3)0.009 (3)
Geometric parameters (Å, °) top
N1—C71.465 (3)C13—H13A1.0000
N1—C121.466 (3)C14—C151.472 (4)
N1—C61.469 (3)C15—C161.381 (3)
O1—C31.382 (3)C15—C201.382 (3)
O1—C11.429 (3)C16—C171.406 (4)
O2—C21.379 (3)C16—O6B1.425 (5)
O2—C11.423 (3)C16—O6A1.455 (4)
O3—C41.370 (3)C17—C181.391 (4)
O3—C11A1.400 (3)C17—O7A1.392 (4)
O4—C141.350 (3)C17—O7B1.457 (7)
O4—C131.451 (2)C18—C191.392 (3)
O5—C141.199 (3)C18—H18A0.9500
C1—H1A0.9900C19—C201.373 (3)
C1—H1B0.9900C19—H19A0.9500
C2—C101.366 (3)C12—H12A0.9800
C2—C31.380 (3)C12—H12B0.9800
C3—C41.378 (3)C12—H12C0.9800
C4—C51.413 (3)O6A—C22A1.382 (6)
C5—C91.398 (3)C22A—H22A0.9800
C5—C61.517 (3)C22A—H22B0.9800
C6—C131.546 (3)C22A—H22C0.9800
C6—H6A1.0000O6B—C22B1.447 (10)
C7—C81.508 (4)C22B—H22D0.9800
C7—H7A0.9900C22B—H22E0.9800
C7—H7B0.9900C22B—H22F0.9800
C8—C91.500 (3)C21A—O7A1.426 (7)
C8—H8A0.9900C21A—H21A0.9800
C8—H8B0.9900C21A—H21B0.9800
C9—C101.394 (3)C21A—H21C0.9800
C10—H10A0.9500C21B—O7B1.436 (14)
C11A—H11A0.9800C21B—H21D0.9800
C11A—H11B0.9800C21B—H21E0.9800
C11A—H11C0.9800C21B—H21F0.9800
C13—C201.496 (3)
C7—N1—C12109.51 (19)C6—C13—H13A109.5
C7—N1—C6114.66 (17)O5—C14—O4120.3 (2)
C12—N1—C6111.77 (19)O5—C14—C15132.0 (2)
C3—O1—C1104.81 (18)O4—C14—C15107.71 (19)
C2—O2—C1105.30 (18)C16—C15—C20122.7 (2)
C4—O3—C11A118.17 (18)C16—C15—C14128.8 (2)
C14—O4—C13111.50 (17)C20—C15—C14108.4 (2)
O2—C1—O1108.11 (18)C15—C16—C17117.2 (2)
O2—C1—H1A110.1C15—C16—O6B121.9 (3)
O1—C1—H1A110.1C17—C16—O6B105.6 (3)
O2—C1—H1B110.1C15—C16—O6A116.8 (3)
O1—C1—H1B110.1C17—C16—O6A124.3 (2)
H1A—C1—H1B108.4C18—C17—O7A127.4 (3)
C10—C2—O2127.6 (2)C18—C17—C16120.3 (2)
C10—C2—C3122.8 (2)O7A—C17—C16111.4 (3)
O2—C2—C3109.5 (2)C18—C17—O7B108.4 (5)
C4—C3—C2121.3 (2)C16—C17—O7B127.2 (4)
C4—C3—O1128.8 (2)C17—C18—C19120.6 (2)
C2—C3—O1109.82 (19)C17—C18—H18A119.7
O3—C4—C3124.4 (2)C19—C18—H18A119.7
O3—C4—C5118.44 (19)C20—C19—C18119.3 (2)
C3—C4—C5117.1 (2)C20—C19—H19A120.4
C9—C5—C4120.45 (19)C18—C19—H19A120.4
C9—C5—C6121.71 (19)C19—C20—C15119.8 (2)
C4—C5—C6117.82 (19)C19—C20—C13131.89 (18)
N1—C6—C5115.49 (18)C15—C20—C13108.27 (19)
N1—C6—C13109.24 (16)N1—C12—H12A109.5
C5—C6—C13107.95 (17)N1—C12—H12B109.5
N1—C6—H6A108.0H12A—C12—H12B109.5
C5—C6—H6A108.0N1—C12—H12C109.5
C13—C6—H6A108.0H12A—C12—H12C109.5
N1—C7—C8110.9 (2)H12B—C12—H12C109.5
N1—C7—H7A109.5C22A—O6A—C16112.2 (3)
C8—C7—H7A109.5O6A—C22A—H22A109.5
N1—C7—H7B109.5O6A—C22A—H22B109.5
C8—C7—H7B109.5H22A—C22A—H22B109.5
H7A—C7—H7B108.1O6A—C22A—H22C109.5
C9—C8—C7109.8 (2)H22A—C22A—H22C109.5
C9—C8—H8A109.7H22B—C22A—H22C109.5
C7—C8—H8A109.7C16—O6B—C22B99.8 (5)
C9—C8—H8B109.7O6B—C22B—H22D109.5
C7—C8—H8B109.7O6B—C22B—H22E109.5
H8A—C8—H8B108.2H22D—C22B—H22E109.5
C10—C9—C5121.2 (2)O6B—C22B—H22F109.5
C10—C9—C8120.8 (2)H22D—C22B—H22F109.5
C5—C9—C8118.0 (2)H22E—C22B—H22F109.5
C2—C10—C9117.1 (2)O7A—C21A—H21A109.5
C2—C10—H10A121.5O7A—C21A—H21B109.5
C9—C10—H10A121.5H21A—C21A—H21B109.5
O3—C11A—H11A109.5O7A—C21A—H21C109.5
O3—C11A—H11B109.5H21A—C21A—H21C109.5
H11A—C11A—H11B109.5H21B—C21A—H21C109.5
O3—C11A—H11C109.5C17—O7A—C21A112.6 (4)
H11A—C11A—H11C109.5O7B—C21B—H21D109.5
H11B—C11A—H11C109.5O7B—C21B—H21E109.5
O4—C13—C20103.85 (15)H21D—C21B—H21E109.5
O4—C13—C6108.49 (17)O7B—C21B—H21F109.5
C20—C13—C6115.78 (17)H21D—C21B—H21F109.5
O4—C13—H13A109.5H21E—C21B—H21F109.5
C20—C13—H13A109.5C21B—O7B—C17123.3 (8)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
C6—H6A···O1i1.002.543.533 (3)172
C13—H13A···O2ii1.002.443.317 (3)146
C18—H18A···O5iii0.952.343.120 (3)140
Symmetry codes: (i) −x+2, y−1/2, −z+1/2; (ii) x, −y+3/2, z+1/2; (iii) x, −y+3/2, z−1/2.
Table 1
Hydrogen-bond geometry (Å, °)
top
D—H···AD—HH···AD···AD—H···A
C6—H6A···O1i1.002.543.533 (3)172
C13—H13A···O2ii1.002.443.317 (3)146
C18—H18A···O5iii0.952.343.120 (3)140
Symmetry codes: (i) −x+2, y−1/2, −z+1/2; (ii) x, −y+3/2, z+1/2; (iii) x, −y+3/2, z−1/2.
Acknowledgements top

This work was funded by the EC Seventh Framework Programme for Research and Technological Development (FP7), Project: IntEnant (contract number: NMP2-SL-2008–214129).

references
References top

Anderson, J., Ting, A., Boozer, S., Brunden, K., Crumrine, C., Danzig, J., Dent, T., Faga, L., Harrington, J., Hodrick, W., Murphy, S., Pawlowski, G., Perry, R., Raber, A., Rundlett, S., Stricker-Krongrad, A., Wang, J. & Bennani, Y. (2005). J. Med. Chem. 48, 7096–7098.

Aneja, R., Dhiman, N., Idnani, J., Awasthi, A., Arora, S., Chandra, R. & Joshi, H. (2007). Cancer Chemother. Pharm. 60, 831–839.

Aneja, R., Vangapandu, S. & Joshi, H. (2006). Bioorg. Med. Chem. 14, 8352–8358.

Bergmann, M. & Stolzer, H. (1956). Wien. Med. Wochenschr. 106, 232–233.

Bruker (2007). SMART, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.

Dahlstrom, B., Mellstrand, T., Lofdahl, C. & Johannsson, M. (1982). Eur. J. Clin. Pharmacol. 22, 535–539.

Mahmoudian, M. & Rahimi-Moghaddam, P. (2009). Recent Patents on Anti-Cancer Drug Discovery, 4, 92–97

Seetharaman, J. & Rajan, S. (1995). Z. Kristallogr. 210, 111–113.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.