organic compounds
3β-Chloro-N-methoxy-N-methylcholest-5-ene-24-carboxamide
aDepartment of Chemistry, University of Puerto Rico, PO Box 23346, San Juan 00931-3346, Puerto Rico
*Correspondence e-mail: karilysgn@yahoo.com
The title compound, C26H42ClNO2, is a 3β-chloro steroid with a Weinreb amide at the C-24 position. The two cyclohexane and the cyclohexene rings adopt chair and boat conformations, respectively. The cyclopentane ring has an envelope conformation.
Related literature
The title compound was obtained as part of our studies on the synthesis of chlorinated β-hydroxyl-5-Δ see: Liu et al. (2005). For antimalarial see: Corrales et al. (2011); Sharma et al. (2008). For the emerging role of chlorinated and in pathology, see: Spickett (2007). For the use of steryl chlorides as synthetic intermediates, see: Ochi et al. (1977). For properties of steryl chlorides, see: Leder (1971). For chloroquine-resistant malaria, see: Wellems & Plowe (2001). For drug resistance in malaria, see: Bloland (2001).
as antimalarial agents. For chlorination of 3Experimental
Crystal data
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Data collection: APEX2 (Bruker, 2005); cell SAINT (Bruker, 1999); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008b); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008b); molecular graphics: SHELXTL (Sheldrick, 2008b); software used to prepare material for publication: SHELXTL.
Supporting information
10.1107/S160053681204679X/fy2071sup1.cif
contains datablocks I, global. DOI:Supporting information file. DOI: 10.1107/S160053681204679X/fy2071Isup2.cdx
Structure factors: contains datablock I. DOI: 10.1107/S160053681204679X/fy2071Isup3.hkl
Compound 1 was synthesized by the reaction of 5-cholenic acid 3β-ol methyl ester (259 mg, 0.67 mmol) and imidazole (114 mg, 1.68 mmol) in 15 ml of CH2Cl2/DMF (2:1) with 1.0 M tert-butyldimethylsilyl chloride (TBSCl) in CH2Cl2 (1.0 ml, 1.0 mmol). The reaction mixture was stirred for 24 h at room temperature, quenched with NH4Cl (aq) (20 ml), and extracted with CH2Cl2 (3 x 15 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude (378.1 mg) was dissolved in CH2Cl2 (10 ml), then (OMe)NH(Me).HCl (87.8 mg, 0.9 mmol) and 1.0 M Me2AlCl in hexane (1.5 ml, 1.5 mmol) were added. The reaction mixture was stirred at room temperature for 24 h, quenched with a solution of 1.0 M NaOH(aq), and extracted with CH2Cl2 (3 x 10 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification by flash-Silica Gel [Hex/EtOAc (4:1)] afforded the chlorinated steroid 1 as a white solid in 75% yield (217 mg). Crystals of 1 were obtained by slow evaporation from Hex/CH2Cl2 (2:1) at room temperature. Mp 111–113°C; [α]D20 -27.0 (c 1.0, CHCl3); IR (film) νmax 2948, 1662, 1386, 994 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.33 (br d, 1H), 3.71 (m, 1H), 3.65 (s, 3H), 3.13 (s, 3H), 2.53–2.25 (broad envelope, 4H), 2.04–1.71 (broad envelope, 7H), 1.58–0.82 (broad envelope, 14H), 0.98 (s, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.64 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 175.1 (C),140.6 (C), 122.3 (CH), 61.1 (CH3), 60.1 (CH), 56.5 (CH), 55.8 (CH), 49.9(CH), 43.3 (CH2), 42.2 (C), 39.5 (CH2), 39.0 (CH2), 36.2 (C), 35.4 (CH), 33.2 (CH2), 32.1 (CH3), 31.7 (CH2), 31.6 (CH), 30.6 (CH2), 28.7 (CH3), 28.0 (CH2), 24.1 (CH2), 20.8 (CH2), 19.1 (CH3), 18.4 (CH3), 11.7 (CH3); HRESIMS m/z [M+ H]+ 436.2977 (calcd for C26H43NO2Cl, 436.2982).
All non-H atoms were refined anisotropically. H atoms were positioned geometrically with C—H=0.96 (CH3), 0.97 (CH2), 0.98 (CH) Å and constrained with Uiso(H) = 1.5 Ueq(parent) for methyl H and Uiso(H) = 1.2 Ueq(parent) for all other atoms.
Data collection: APEX2 (Bruker, 2005); cell
SAINT (Bruker, 1999); data reduction: SAINT (Bruker, 1999); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008b); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008b); molecular graphics: SHELXTL (Sheldrick, 2008b); software used to prepare material for publication: SHELXTL (Sheldrick, 2008b.C26H42ClNO2 | F(000) = 952 |
Mr = 436.06 | Dx = 1.136 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 5845 reflections |
a = 7.5263 (2) Å | θ = 2.7–20.9° |
b = 16.2157 (4) Å | µ = 0.17 mm−1 |
c = 20.8850 (5) Å | T = 296 K |
V = 2548.89 (11) Å3 | Needle, colourless |
Z = 4 | 0.31 × 0.09 × 0.08 mm |
Bruker APEXII CCD diffractometer | 6244 independent reflections |
Radiation source: fine-focus sealed tube | 3307 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.035 |
ϕ and ω scans | θmax = 28.3°, θmin = 1.6° |
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a) | h = −9→10 |
Tmin = 0.949, Tmax = 0.987 | k = −19→21 |
23203 measured reflections | l = −27→25 |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.056 | H-atom parameters constrained |
wR(F2) = 0.157 | w = 1/[σ2(Fo2) + (0.0698P)2 + 0.2353P] where P = (Fo2 + 2Fc2)/3 |
S = 1.01 | (Δ/σ)max = 0.001 |
6244 reflections | Δρmax = 0.19 e Å−3 |
276 parameters | Δρmin = −0.14 e Å−3 |
0 restraints | Absolute structure: Flack (1983), 2662 Friedel pairs |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −0.04 (9) |
C26H42ClNO2 | V = 2548.89 (11) Å3 |
Mr = 436.06 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 7.5263 (2) Å | µ = 0.17 mm−1 |
b = 16.2157 (4) Å | T = 296 K |
c = 20.8850 (5) Å | 0.31 × 0.09 × 0.08 mm |
Bruker APEXII CCD diffractometer | 6244 independent reflections |
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a) | 3307 reflections with I > 2σ(I) |
Tmin = 0.949, Tmax = 0.987 | Rint = 0.035 |
23203 measured reflections |
R[F2 > 2σ(F2)] = 0.056 | H-atom parameters constrained |
wR(F2) = 0.157 | Δρmax = 0.19 e Å−3 |
S = 1.01 | Δρmin = −0.14 e Å−3 |
6244 reflections | Absolute structure: Flack (1983), 2662 Friedel pairs |
276 parameters | Absolute structure parameter: −0.04 (9) |
0 restraints |
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. |
x | y | z | Uiso*/Ueq | ||
C1 | 0.4754 (4) | 0.8660 (2) | 0.82833 (14) | 0.0888 (8) | |
H1A | 0.5059 | 0.8075 | 0.8234 | 0.107* | |
C2 | 0.3024 (4) | 0.8823 (2) | 0.79438 (14) | 0.0873 (8) | |
H2A | 0.2679 | 0.9395 | 0.8001 | 0.105* | |
H2B | 0.2095 | 0.8476 | 0.8120 | 0.105* | |
C3 | 0.3269 (3) | 0.86371 (18) | 0.72355 (14) | 0.0786 (7) | |
H3A | 0.2150 | 0.8735 | 0.7018 | 0.094* | |
H3B | 0.3551 | 0.8057 | 0.7188 | 0.094* | |
C4 | 0.4729 (3) | 0.91473 (15) | 0.69012 (13) | 0.0666 (6) | |
C5 | 0.6421 (3) | 0.90625 (15) | 0.72909 (14) | 0.0721 (7) | |
C6 | 0.6235 (4) | 0.9177 (2) | 0.80067 (14) | 0.0901 (9) | |
H6A | 0.7345 | 0.9028 | 0.8213 | 0.108* | |
H6B | 0.6005 | 0.9753 | 0.8098 | 0.108* | |
C7 | 0.4179 (4) | 1.00624 (17) | 0.68853 (16) | 0.0969 (9) | |
H7A | 0.4991 | 1.0365 | 0.6620 | 0.145* | |
H7B | 0.4205 | 1.0283 | 0.7312 | 0.145* | |
H7C | 0.2999 | 1.0110 | 0.6715 | 0.145* | |
C8 | 0.7984 (3) | 0.89137 (17) | 0.70284 (15) | 0.0805 (7) | |
H8 | 0.8945 | 0.8844 | 0.7303 | 0.097* | |
C9 | 0.8336 (3) | 0.88485 (18) | 0.63301 (14) | 0.0823 (8) | |
H9A | 0.8636 | 0.8282 | 0.6228 | 0.099* | |
H9B | 0.9354 | 0.9189 | 0.6224 | 0.099* | |
C10 | 0.6762 (3) | 0.91138 (15) | 0.59167 (13) | 0.0655 (6) | |
H10 | 0.6733 | 0.9718 | 0.5903 | 0.079* | |
C11 | 0.5021 (3) | 0.88085 (15) | 0.62200 (13) | 0.0653 (6) | |
H11 | 0.5154 | 0.8211 | 0.6268 | 0.078* | |
C12 | 0.3419 (3) | 0.8934 (2) | 0.57734 (13) | 0.0838 (8) | |
H12A | 0.3119 | 0.9516 | 0.5768 | 0.101* | |
H12B | 0.2410 | 0.8640 | 0.5950 | 0.101* | |
C13 | 0.3702 (3) | 0.86456 (19) | 0.50792 (14) | 0.0820 (8) | |
H13A | 0.3805 | 0.8049 | 0.5071 | 0.098* | |
H13B | 0.2676 | 0.8798 | 0.4824 | 0.098* | |
C14 | 0.5371 (3) | 0.90269 (14) | 0.47859 (13) | 0.0650 (6) | |
C15 | 0.6915 (3) | 0.87954 (15) | 0.52369 (13) | 0.0661 (6) | |
H15 | 0.6880 | 0.8193 | 0.5272 | 0.079* | |
C16 | 0.8581 (3) | 0.89897 (19) | 0.48523 (13) | 0.0841 (8) | |
H16A | 0.9568 | 0.8647 | 0.4989 | 0.101* | |
H16B | 0.8911 | 0.9565 | 0.4899 | 0.101* | |
C17 | 0.8063 (3) | 0.87974 (18) | 0.41608 (15) | 0.0838 (8) | |
H17A | 0.8700 | 0.8315 | 0.4010 | 0.101* | |
H17B | 0.8355 | 0.9259 | 0.3885 | 0.101* | |
C18 | 0.6013 (3) | 0.86341 (15) | 0.41517 (13) | 0.0683 (7) | |
H18 | 0.5847 | 0.8037 | 0.4193 | 0.082* | |
C19 | 0.5143 (4) | 0.88930 (16) | 0.35166 (13) | 0.0748 (7) | |
H19 | 0.5342 | 0.9486 | 0.3463 | 0.090* | |
C20 | 0.3108 (4) | 0.8747 (2) | 0.35159 (16) | 0.0934 (9) | |
H20A | 0.2551 | 0.9125 | 0.3807 | 0.140* | |
H20B | 0.2863 | 0.8191 | 0.3648 | 0.140* | |
H20C | 0.2650 | 0.8834 | 0.3092 | 0.140* | |
C21 | 0.6022 (4) | 0.84559 (17) | 0.29503 (14) | 0.0828 (8) | |
H21A | 0.7299 | 0.8516 | 0.2989 | 0.099* | |
H21B | 0.5753 | 0.7872 | 0.2978 | 0.099* | |
C22 | 0.5466 (4) | 0.87628 (18) | 0.22971 (15) | 0.0924 (9) | |
H22A | 0.4238 | 0.8610 | 0.2222 | 0.111* | |
H22B | 0.5535 | 0.9360 | 0.2292 | 0.111* | |
C23 | 0.6578 (5) | 0.84295 (18) | 0.17692 (17) | 0.0880 (9) | |
C24 | 0.6782 (7) | 0.8149 (3) | 0.06221 (17) | 0.169 (2) | |
H24A | 0.6617 | 0.8600 | 0.0331 | 0.253* | |
H24B | 0.6373 | 0.7648 | 0.0426 | 0.253* | |
H24C | 0.8021 | 0.8098 | 0.0725 | 0.253* | |
C25 | 0.2820 (7) | 0.8083 (4) | 0.1041 (3) | 0.206 (3) | |
H25A | 0.2553 | 0.7869 | 0.1459 | 0.308* | |
H25B | 0.3244 | 0.7644 | 0.0773 | 0.308* | |
H25C | 0.1766 | 0.8316 | 0.0857 | 0.308* | |
C26 | 0.5199 (4) | 0.99713 (16) | 0.47055 (16) | 0.0927 (9) | |
H26A | 0.4993 | 1.0220 | 0.5116 | 0.139* | |
H26B | 0.4221 | 1.0092 | 0.4426 | 0.139* | |
H26C | 0.6275 | 1.0187 | 0.4525 | 0.139* | |
Cl1 | 0.45336 (14) | 0.88904 (7) | 0.91266 (4) | 0.1218 (4) | |
N1 | 0.5778 (4) | 0.83019 (19) | 0.12042 (14) | 0.1117 (10) | |
O1 | 0.8116 (3) | 0.82332 (15) | 0.18387 (12) | 0.1129 (7) | |
O2 | 0.4135 (4) | 0.86944 (18) | 0.10918 (12) | 0.1320 (10) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.0777 (19) | 0.097 (2) | 0.091 (2) | −0.0030 (17) | −0.0064 (16) | −0.0126 (16) |
C2 | 0.0667 (16) | 0.102 (2) | 0.093 (2) | −0.0062 (16) | 0.0050 (15) | 0.0007 (17) |
C3 | 0.0428 (12) | 0.1019 (19) | 0.091 (2) | −0.0067 (12) | 0.0009 (12) | 0.0023 (15) |
C4 | 0.0453 (12) | 0.0642 (14) | 0.0902 (18) | 0.0023 (10) | 0.0011 (12) | −0.0030 (13) |
C5 | 0.0516 (14) | 0.0700 (15) | 0.0948 (19) | −0.0081 (11) | −0.0044 (13) | −0.0106 (14) |
C6 | 0.0706 (17) | 0.107 (2) | 0.092 (2) | −0.0107 (16) | −0.0056 (15) | −0.0163 (17) |
C7 | 0.094 (2) | 0.0828 (19) | 0.114 (2) | 0.0204 (16) | 0.0149 (19) | −0.0036 (16) |
C8 | 0.0492 (14) | 0.0975 (19) | 0.095 (2) | −0.0045 (14) | −0.0098 (13) | −0.0044 (16) |
C9 | 0.0358 (12) | 0.0944 (19) | 0.117 (2) | 0.0002 (12) | −0.0061 (13) | −0.0015 (17) |
C10 | 0.0367 (11) | 0.0642 (13) | 0.0956 (18) | −0.0018 (10) | 0.0029 (11) | −0.0019 (13) |
C11 | 0.0356 (11) | 0.0671 (14) | 0.0932 (17) | −0.0009 (11) | 0.0039 (11) | 0.0005 (13) |
C12 | 0.0402 (12) | 0.121 (2) | 0.0902 (19) | 0.0062 (13) | 0.0041 (12) | −0.0024 (18) |
C13 | 0.0367 (11) | 0.111 (2) | 0.098 (2) | −0.0021 (13) | −0.0015 (12) | 0.0061 (16) |
C14 | 0.0389 (11) | 0.0667 (14) | 0.0894 (17) | 0.0043 (10) | 0.0049 (11) | 0.0033 (13) |
C15 | 0.0379 (11) | 0.0656 (13) | 0.0947 (18) | 0.0012 (10) | 0.0050 (11) | 0.0048 (14) |
C16 | 0.0430 (12) | 0.110 (2) | 0.099 (2) | −0.0041 (13) | 0.0065 (13) | 0.0074 (17) |
C17 | 0.0508 (13) | 0.0987 (19) | 0.102 (2) | 0.0067 (14) | 0.0164 (14) | 0.0180 (17) |
C18 | 0.0510 (13) | 0.0613 (14) | 0.0927 (18) | 0.0052 (10) | 0.0045 (13) | 0.0092 (13) |
C19 | 0.0675 (15) | 0.0658 (15) | 0.0912 (19) | 0.0138 (13) | 0.0064 (14) | 0.0027 (14) |
C20 | 0.0644 (16) | 0.110 (2) | 0.106 (2) | 0.0140 (17) | −0.0067 (16) | 0.0072 (18) |
C21 | 0.0738 (17) | 0.0792 (18) | 0.095 (2) | 0.0127 (14) | 0.0052 (16) | 0.0098 (14) |
C22 | 0.092 (2) | 0.0893 (19) | 0.096 (2) | 0.0216 (18) | −0.0097 (18) | −0.0166 (18) |
C23 | 0.089 (2) | 0.0821 (19) | 0.093 (2) | 0.0076 (16) | 0.0044 (19) | 0.0093 (16) |
C24 | 0.187 (5) | 0.238 (5) | 0.080 (3) | 0.081 (4) | 0.019 (3) | 0.009 (3) |
C25 | 0.130 (4) | 0.230 (6) | 0.257 (7) | −0.053 (4) | −0.007 (4) | −0.138 (6) |
C26 | 0.091 (2) | 0.0758 (17) | 0.112 (2) | 0.0209 (15) | −0.0037 (18) | −0.0001 (16) |
Cl1 | 0.1189 (7) | 0.1578 (9) | 0.0887 (5) | −0.0178 (6) | −0.0027 (5) | −0.0117 (6) |
N1 | 0.111 (2) | 0.138 (2) | 0.0864 (19) | 0.045 (2) | 0.0087 (18) | −0.0013 (17) |
O1 | 0.0845 (16) | 0.1295 (17) | 0.1247 (19) | 0.0151 (14) | 0.0060 (14) | −0.0026 (15) |
O2 | 0.140 (2) | 0.146 (2) | 0.1100 (18) | 0.051 (2) | −0.0210 (16) | −0.0116 (15) |
C1—C2 | 1.506 (4) | C14—C18 | 1.547 (4) |
C1—C6 | 1.510 (4) | C15—C16 | 1.522 (3) |
C1—Cl1 | 1.808 (3) | C15—H15 | 0.9800 |
C1—H1A | 0.9800 | C16—C17 | 1.528 (4) |
C2—C3 | 1.521 (4) | C16—H16A | 0.9700 |
C2—H2A | 0.9700 | C16—H16B | 0.9700 |
C2—H2B | 0.9700 | C17—C18 | 1.566 (4) |
C3—C4 | 1.543 (4) | C17—H17A | 0.9700 |
C3—H3A | 0.9700 | C17—H17B | 0.9700 |
C3—H3B | 0.9700 | C18—C19 | 1.538 (4) |
C4—C5 | 1.518 (3) | C18—H18 | 0.9800 |
C4—C7 | 1.541 (4) | C19—C21 | 1.529 (4) |
C4—C11 | 1.541 (4) | C19—C20 | 1.550 (4) |
C5—C8 | 1.320 (4) | C19—H19 | 0.9800 |
C5—C6 | 1.513 (4) | C20—H20A | 0.9600 |
C6—H6A | 0.9700 | C20—H20B | 0.9600 |
C6—H6B | 0.9700 | C20—H20C | 0.9600 |
C7—H7A | 0.9600 | C21—C22 | 1.511 (4) |
C7—H7B | 0.9600 | C21—H21A | 0.9700 |
C7—H7C | 0.9600 | C21—H21B | 0.9700 |
C8—C9 | 1.486 (4) | C22—C23 | 1.486 (4) |
C8—H8 | 0.9300 | C22—H22A | 0.9700 |
C9—C10 | 1.527 (3) | C22—H22B | 0.9700 |
C9—H9A | 0.9700 | C23—O1 | 1.209 (4) |
C9—H9B | 0.9700 | C23—N1 | 1.341 (4) |
C10—C15 | 1.515 (4) | C24—N1 | 1.453 (4) |
C10—C11 | 1.537 (3) | C24—H24A | 0.9600 |
C10—H10 | 0.9800 | C24—H24B | 0.9600 |
C11—C12 | 1.538 (3) | C24—H24C | 0.9600 |
C11—H11 | 0.9800 | C25—O2 | 1.405 (5) |
C12—C13 | 1.538 (4) | C25—H25A | 0.9600 |
C12—H12A | 0.9700 | C25—H25B | 0.9600 |
C12—H12B | 0.9700 | C25—H25C | 0.9600 |
C13—C14 | 1.529 (3) | C26—H26A | 0.9600 |
C13—H13A | 0.9700 | C26—H26B | 0.9600 |
C13—H13B | 0.9700 | C26—H26C | 0.9600 |
C14—C15 | 1.542 (3) | N1—O2 | 1.410 (4) |
C14—C26 | 1.546 (3) | ||
C2—C1—C6 | 111.1 (2) | C15—C14—C18 | 100.81 (18) |
C2—C1—Cl1 | 110.1 (2) | C26—C14—C18 | 109.9 (2) |
C6—C1—Cl1 | 109.0 (2) | C10—C15—C16 | 119.1 (2) |
C2—C1—H1A | 108.9 | C10—C15—C14 | 115.59 (19) |
C6—C1—H1A | 108.9 | C16—C15—C14 | 104.4 (2) |
Cl1—C1—H1A | 108.9 | C10—C15—H15 | 105.5 |
C1—C2—C3 | 108.6 (2) | C16—C15—H15 | 105.5 |
C1—C2—H2A | 110.0 | C14—C15—H15 | 105.5 |
C3—C2—H2A | 110.0 | C15—C16—C17 | 104.3 (2) |
C1—C2—H2B | 110.0 | C15—C16—H16A | 110.9 |
C3—C2—H2B | 110.0 | C17—C16—H16A | 110.9 |
H2A—C2—H2B | 108.4 | C15—C16—H16B | 110.9 |
C2—C3—C4 | 114.8 (2) | C17—C16—H16B | 110.9 |
C2—C3—H3A | 108.6 | H16A—C16—H16B | 108.9 |
C4—C3—H3A | 108.6 | C16—C17—C18 | 107.3 (2) |
C2—C3—H3B | 108.6 | C16—C17—H17A | 110.3 |
C4—C3—H3B | 108.6 | C18—C17—H17A | 110.3 |
H3A—C3—H3B | 107.5 | C16—C17—H17B | 110.3 |
C5—C4—C7 | 108.9 (2) | C18—C17—H17B | 110.3 |
C5—C4—C11 | 110.07 (19) | H17A—C17—H17B | 108.5 |
C7—C4—C11 | 111.2 (2) | C19—C18—C14 | 119.5 (2) |
C5—C4—C3 | 107.8 (2) | C19—C18—C17 | 112.6 (2) |
C7—C4—C3 | 109.6 (2) | C14—C18—C17 | 103.2 (2) |
C11—C4—C3 | 109.2 (2) | C19—C18—H18 | 106.9 |
C8—C5—C6 | 121.0 (2) | C14—C18—H18 | 106.9 |
C8—C5—C4 | 122.8 (3) | C17—C18—H18 | 106.9 |
C6—C5—C4 | 116.2 (2) | C21—C19—C18 | 110.9 (2) |
C1—C6—C5 | 112.2 (2) | C21—C19—C20 | 110.9 (2) |
C1—C6—H6A | 109.2 | C18—C19—C20 | 112.3 (2) |
C5—C6—H6A | 109.2 | C21—C19—H19 | 107.5 |
C1—C6—H6B | 109.2 | C18—C19—H19 | 107.5 |
C5—C6—H6B | 109.2 | C20—C19—H19 | 107.5 |
H6A—C6—H6B | 107.9 | C19—C20—H20A | 109.5 |
C4—C7—H7A | 109.5 | C19—C20—H20B | 109.5 |
C4—C7—H7B | 109.5 | H20A—C20—H20B | 109.5 |
H7A—C7—H7B | 109.5 | C19—C20—H20C | 109.5 |
C4—C7—H7C | 109.5 | H20A—C20—H20C | 109.5 |
H7A—C7—H7C | 109.5 | H20B—C20—H20C | 109.5 |
H7B—C7—H7C | 109.5 | C22—C21—C19 | 115.2 (2) |
C5—C8—C9 | 125.4 (2) | C22—C21—H21A | 108.5 |
C5—C8—H8 | 117.3 | C19—C21—H21A | 108.5 |
C9—C8—H8 | 117.3 | C22—C21—H21B | 108.5 |
C8—C9—C10 | 113.4 (2) | C19—C21—H21B | 108.5 |
C8—C9—H9A | 108.9 | H21A—C21—H21B | 107.5 |
C10—C9—H9A | 108.9 | C23—C22—C21 | 113.2 (2) |
C8—C9—H9B | 108.9 | C23—C22—H22A | 108.9 |
C10—C9—H9B | 108.9 | C21—C22—H22A | 108.9 |
H9A—C9—H9B | 107.7 | C23—C22—H22B | 108.9 |
C15—C10—C9 | 112.0 (2) | C21—C22—H22B | 108.9 |
C15—C10—C11 | 109.96 (19) | H22A—C22—H22B | 107.7 |
C9—C10—C11 | 109.7 (2) | O1—C23—N1 | 119.7 (3) |
C15—C10—H10 | 108.4 | O1—C23—C22 | 123.1 (3) |
C9—C10—H10 | 108.4 | N1—C23—C22 | 117.1 (3) |
C11—C10—H10 | 108.4 | N1—C24—H24A | 109.5 |
C10—C11—C12 | 112.1 (2) | N1—C24—H24B | 109.5 |
C10—C11—C4 | 112.8 (2) | H24A—C24—H24B | 109.5 |
C12—C11—C4 | 113.62 (19) | N1—C24—H24C | 109.5 |
C10—C11—H11 | 105.9 | H24A—C24—H24C | 109.5 |
C12—C11—H11 | 105.9 | H24B—C24—H24C | 109.5 |
C4—C11—H11 | 105.9 | O2—C25—H25A | 109.5 |
C11—C12—C13 | 115.00 (19) | O2—C25—H25B | 109.5 |
C11—C12—H12A | 108.5 | H25A—C25—H25B | 109.5 |
C13—C12—H12A | 108.5 | O2—C25—H25C | 109.5 |
C11—C12—H12B | 108.5 | H25A—C25—H25C | 109.5 |
C13—C12—H12B | 108.5 | H25B—C25—H25C | 109.5 |
H12A—C12—H12B | 107.5 | C14—C26—H26A | 109.5 |
C14—C13—C12 | 111.6 (2) | C14—C26—H26B | 109.5 |
C14—C13—H13A | 109.3 | H26A—C26—H26B | 109.5 |
C12—C13—H13A | 109.3 | C14—C26—H26C | 109.5 |
C14—C13—H13B | 109.3 | H26A—C26—H26C | 109.5 |
C12—C13—H13B | 109.3 | H26B—C26—H26C | 109.5 |
H13A—C13—H13B | 108.0 | C23—N1—O2 | 118.1 (3) |
C13—C14—C15 | 106.0 (2) | C23—N1—C24 | 121.9 (3) |
C13—C14—C26 | 112.0 (2) | O2—N1—C24 | 113.2 (3) |
C15—C14—C26 | 111.8 (2) | C25—O2—N1 | 108.1 (3) |
C13—C14—C18 | 115.7 (2) |
Experimental details
Crystal data | |
Chemical formula | C26H42ClNO2 |
Mr | 436.06 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 296 |
a, b, c (Å) | 7.5263 (2), 16.2157 (4), 20.8850 (5) |
V (Å3) | 2548.89 (11) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.17 |
Crystal size (mm) | 0.31 × 0.09 × 0.08 |
Data collection | |
Diffractometer | Bruker APEXII CCD diffractometer |
Absorption correction | Multi-scan (SADABS; Sheldrick, 2008a) |
Tmin, Tmax | 0.949, 0.987 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 23203, 6244, 3307 |
Rint | 0.035 |
(sin θ/λ)max (Å−1) | 0.667 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.056, 0.157, 1.01 |
No. of reflections | 6244 |
No. of parameters | 276 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.19, −0.14 |
Absolute structure | Flack (1983), 2662 Friedel pairs |
Absolute structure parameter | −0.04 (9) |
Computer programs: APEX2 (Bruker, 2005), SAINT (Bruker, 1999), SHELXS97 (Sheldrick, 2008b), SHELXL97 (Sheldrick, 2008b), SHELXTL (Sheldrick, 2008b), SHELXTL (Sheldrick, 2008b.
Acknowledgements
The authors thank the Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT) in Panama for the antimalarial bioassay and Dr Raphel G. Raptis for the use of the X-ray facilitites.
determinations were provided by the Laboratory of the University of Illinois at Urbana–Champaign. Financial support to KN was provided by the UPR–RISE Fellowship Program (grant 2R25GM061151–11).References
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This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
The synthesis of the title compound started with the alcohol protection of 5-cholenic acid 3β-ol methyl ester with tert-butyldimethyl silyl chloride. Then it was derivatized to the Weinreb amide in the presence of N-methoxy N-methyl hydroxylamine hydrochloride and dimethyl aluminium chloride with the concomitant chlorination of the 3β-silyl ether to afford compound 1 with retention of configuration at the C-3 position.
This synthetic route is part of our studies on the synthesis of 3β-chloro steroids as antimalarial agents. There is an urgent need to develop new classes of antimalarial drugs due to the development of resistance by the parasite to the commonly used drugs, such as chloroquine [Bloland (2001) and Wellems and Plowe (2001)]. Compound 1 was screened against Plasmodium falciparum, but unfortunely, it showed negligible activity (37.4% inhibition). Our future plans include the synthesis of additional derivatives with different functional groups at C-24. The structure of the title compound was determined by one-dimensional and two-dimensional NMR spectra. To confirm the structure of compound 1, X-ray crystallography was performed.