3β-Chloro-N-methoxy-N-methyl­cholest-5-ene-24-carboxamide

Karilys González; Karinel Nieves; Abimael D Rodríguez

doi:10.1107/S160053681204679X

. 2012 Nov 28;68(Pt 12):o3471. doi: 10.1107/S160053681204679X

3β-Chloro-N-methoxy-N-methylcholest-5-ene-24-carboxamide

Karilys González ^a,^*, Karinel Nieves ^a, Abimael D Rodríguez ^a

PMCID: PMC3589044 PMID: 23476280

Abstract

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 steroids as antimalarial agents. For chlorination of 3β-hydroxyl-5-Δ steroids, see: Liu et al. (2005 ▶). For antimalarial steroids, see: Corrales et al. (2011 ▶); Sharma et al. (2008 ▶). For the emerging role of chlorinated lipids and fatty acids in pathology, see: Spickett (2007 ▶). For the use of steryl chlorides as synthetic intermediates, see: Ochi et al. (1977 ▶). For liquid crystal properties of steryl chlorides, see: Leder (1971 ▶). For chloroquine-resistant malaria, see: Wellems & Plowe (2001 ▶). For drug resistance in malaria, see: Bloland (2001 ▶). graphic file with name e-68-o3471-scheme1.jpg

Experimental

Crystal data

C₂₆H₄₂ClNO₂
M _r = 436.06
Orthorhombic,
a = 7.5263 (2) Å
b = 16.2157 (4) Å
c = 20.8850 (5) Å
V = 2548.89 (11) Å³
Z = 4
Mo Kα radiation
μ = 0.17 mm⁻¹
T = 296 K
0.31 × 0.09 × 0.08 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a ▶) T _min = 0.949, T _max = 0.987
23203 measured reflections
6244 independent reflections
3307 reflections with I > 2σ(I)
R _int = 0.035

Refinement

R[F ² > 2σ(F ²)] = 0.056
wR(F ²) = 0.157
S = 1.01
6244 reflections
276 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.14 e Å⁻³
Absolute structure: Flack (1983 ▶), 2662 Friedel pairs
Flack parameter: −0.04 (9)

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: 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.

Supplementary Material

Click here for additional data file.^{(30KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S160053681204679X/fy2071sup1.cif

e-68-o3471-sup1.cif^{(30KB, cif)}

Click here for additional data file.^{(4.7KB, cdx)}

Supplementary material file. DOI: 10.1107/S160053681204679X/fy2071Isup2.cdx

Click here for additional data file.^{(305.7KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S160053681204679X/fy2071Isup3.hkl

e-68-o3471-Isup3.hkl^{(305.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

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. Mass spectrometry determinations were provided by the Mass Spectrometry Laboratory of the University of Illinois at Urbana–Champaign. Financial support to KN was provided by the UPR–RISE Fellowship Program (grant 2R25GM061151–11).

supplementary crystallographic information

Comment

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.

Experimental

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 Mtert-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 column chromatography [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) ν_max 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).