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

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

References and Notes

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19

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.

20

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, C_{4 α}H and C_{4 β}H), 2.63 and 2.60 (each 1 H, m, C_{7 α}H and C_{7 β}H), 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.

21

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, C_{4 α}H and C_{4 β}H), 2.20 and 2.16 (each 1 H, m, C_{7 α}H and C_{7 β}H), 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.