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Synlett 2010(2): 215-218  
DOI: 10.1055/s-0029-1218557
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 6-Aryl-Substituted Cholesterol Derivatives from 3β-Acetoxy-6-iodocholest-5-ene and Arylboronic Acids Promoted by Palladium-Catalyzed Cross-Coupling

Dominique Brossarda, Laïla El Kihel*a, Mohamed Khalidb, Sylvain Raulta
a Centre d’Etudes et de Recherche sur le Médicament de Normandie, UFR des Sciences Pharmaceutiques, Boulevard Becquerel, 14032 Caen Cedex, France
Fax: +33(2)31566803; e-Mail: laila.elkihel@unicaen.fr;
b Université Hassan Premier, Faculté des Sciences et Techniques, Km 3, Route de Casablanca, BP 577, 26000 Settat, Morocco
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Publication History

Received 20 October 2009
Publication Date:
09 December 2009 (online)

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Abstract

3β-Acetoxy-6-iodocholest-5-ene was prepared with a convenient method from cholesterol and used as a key intermediate for the synthesis of 6-arylated cholesterol derivatives using a ­Suzuki-Miyaura cross-coupling. This versatile and efficient synthesis way can widely be used in the synthesis of other 6-aryl or 6-heteroaryl steroids as potential drugs.

Key words

cross-coupling - palladium - 6-aryl steroids - Suzuki ­reaction - 6-iodovinyl steroid

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Synthesis of 3β-Acetoxy-5α-cholestane-6-hydrazone (2) Hydrazine hydrate (0.42 mL, 13.5 mmol) was added to a solution of 3β-acetoxy-5α-cholestan-6-one (1, 3.00 g, 6.8 mmol) and AcOH (0.01 mL, 0.2 mmol) in EtOH (70 mL). The mixture was refluxed for 24 h. The reaction mixture was concentrated, diluted with H2O (70 mL) and then extracted with CH2Cl2 (4 × 30 mL). The combined CH2Cl2 extracts were dried over MgSO4 and evaporated under reduced pressure to give compound 2 as a white powder (3.06 g, 99%); mp 56 ˚C. IR (KBr): ν = 3480-3300 (NH2 hydrazone), 2950-2875 (CH alkane), 1727 (C=O ester), 1651 (C=N) cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 4.96 (s, 2 H, NH2 D2O exchange), 4.69-4.66 (m, 1 H, C3H), 2.92-2.97 (dd, 1 H, J = 13.28, 4.48 Hz, C5H), 2.04-2.10 (each 1 H, m, C7αH and 7β-CH), 2.06 (s, 3 H,CH3COO), 0.92-0.89 (m, 3 H, 19-Me), 0.87 and 0.86 (each 3 H, d, J = 1.96 Hz, 26-Me and 27-Me), 0.63 (s, 3 H, 18-Me) ppm.¹³C NMR (100 MHz, CDCl3): δ = 170.6 (CH3COO), 154.1 (C-6), 73.7 (C-3), 56.4 (C-14), 56.1 (C-17), 50.5 (C-9), 48.8 (C-13), 42.9 (C-5), 39.4 (C-12), 38.8 (C-10), 36.0 (C-1, C-20, C-22), 35.6 (C-7, C-8), 29.3 (C-4), 28.0 (C-16, C-25), 28.9 (C-2), 24.0 (C-19), 23.7 (C-15, C-23), 22.7 (C-26), 22.5 (C-27), 21.3
(C-11), 21.3 (CH3COO), 19.6 (C-21), 11.9 (C-18) ppm.

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Synthesis of 3β-Acetoxy-6-iodocholest-5-ene (3) A 100 mL round-bottomed flask equipped with a magnetic stirring bar was charged with iodine (4.76 g, 18.8 mmol) and dry THF (5 mL) and flushed with nitrogen. The reactor was pushed into an ice bath (0 ˚C), and then 1,1,3,3-tetramethyl-guanidine (6 mL, 46.9 mmol) was added. Compound 5 was then dissolved into dry THF (30 mL) and added dropwise, and the solution was kept under stirring at 0 ˚C for 2 h. The mixture was filtered and the solvent evaporated. The solution was then stirred at 50 ˚C for 48 h. The reaction mixture was dissolved in Et2O, washed with 1 N HCl, 5% NaHCO3, sat. Na2S2O3, H2O, and dried over MgSO4. The crude product was purified by column chromatography (silica gel, cyclohexane-EtOAc = 9:1) to give the product as a yellow oil (4.55 g, 88%). IR (KBr): ν = 2935 (CH alkane), 1735 (C=O ester), 1030 (C=CI) cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 4.64-4.58 (m, 1 H, C3H), 2.94 and 2.93 (each 1 H, m, C4 αH and C4 βH), 2.63 and 2.60 (each 1 H, m, C7 αH and C7 βH), 2.05 (s, 3 H, CH3COO), 1.07 (s, 3 H, 19-Me), 0.91 (d, J = 6.83 Hz, 3 H, 21-Me), 0.87 and 0.85 (each 3 H, d, J = 1.96 Hz, 26-Me and 27-Me), 0.66 (s, 3 H, 18-Me) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 170.3 (CH3COO), 142.8 (C-5), 101.3 (C-6), 72.7 (C-3), 55.9 (C-14, C-17), 49.6 (C-9), 42.4 (C-13), 41.2 (C-12), 39.5 (C-7, C-24), 36.8 (C-4), 36.1 (C-1), 35.7 (C-22), 35.3 (C-20), 34.4 (C-10), 28.2 (C-16), 27.9 (C-25), 27.7 (C-2), 24.1 (C-15), 23.8 (C-23), 22.8 (C-27), 22.5 (C-26), 21.4 (C-11), 21.2 (CH3COO), 19.7 (C-19), 18.7 (C-21), 11.8 (C-18) ppm.

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General Procedure for the Coupling of 6-Iodovinyl-steroid with Boronic Acids In a vial with a screw cap, compound 3 (0.30 g, 0.5 mmol), boronic acid (1.1 mmol), Pd(OAc)2 (0.01 g, 0.05 mmol), Ph3P (0.03 g, 0.1 mmol), and K2CO3 (0.19 g, 1.4 mmol) were mixed in DMF (6 mL) under Ar atmosphere. The mixture was stirred at 150 ˚C for 12-18 h, then diluted with H2O (30 mL), and extracted with Et2O (4 × 15 mL). The combined organic layers were dried over MgSO4. The crude product was purified by column chromatography on deactivated alumina (6% H2O), eluting by cyclohexane-EtOAc (99:1).
3β-Acetoxy-6-(4-methoxy)phenylcholest-5-ene (4a): White amorphous solid. Yield: 48 mg (50%). IR (KBr): ν = 2928 (CH alkane), 1716 (C=O ester), 1607-1509 (C=C)
cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.01 (d, 2 H, J = 8.79 Hz, H-ar), 6.85 (d, 2 H, J = 7.79 Hz, H-ar),4.62-4.50 (m, 1 H, C3H), 3.80 (s, 3 H, OCH3), 2.54 and 2.50 (each 1 H, m, C4 αH and C4 βH), 2.20 and 2.16 (each 1 H, m, C7 αH and C7 βH), 1.95 (s, 3 H, CH3COO), 1.10 (s, 3 H, 19-Me), 0.92 (d, 3 H, J = 6.83 Hz, 21-Me), 0.87 and 0.85 (each 3 H, d, J = 1.96 Hz, 26-Me and 27-Me), 0.71 (s, 3 H, 18-Me) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 170.4 (CH3COO), 157.9 (C-4ar), 136.4 (C-6), 134.7 (C-5), 133.6 (C-1-ar), 129.2 (C-2 and C-2′-ar), 113.5 (C3 and C-3′-ar), 73.9 (C-3), 56.6 (C-14), 56.1 (C-17), 55.2 (OCH3), 49.9 (C-9), 42.3 (C-13), 39.8 (C-24), 39.6 (C-12), 39.5 (C-1), 37.3 (C-22), 36.9 (C-20), 36.2 (C-7), 35.8 (C-10), 32.8 (C-8), 32.0 (C-4), 28.3 (C-16), 27.9 (C-25), 27.7 (C-2), 24.2 (C-15), 23.8 (C-23), 22.8 (C-26 and C27), 21.4 (C-11), 21.1 (CH3COO-), 19.5 (C-19), 18.7 (C-21), 11.9 (C-18). MS (30eV, IE): m/z = 534.3 (8) [M+ ], 474.3 (100) [M+ - CH3COOH], 459.3 (8), 368.3 (25). Anal. Calcd for C36H54O3 (534.81): C, 80.85; H, 10.18. Found: C, 80.42; H, 9.77.