Stereoselective Construction of Steroidal Side Chain from 16-Dehydropregnenolone Acetate

Abstract

Stereoselective construction of steroidal side chain at C-20 having ‘natural’ configuration using 16-dehydropregnalone acetate (16-DPA) as a starting material has been carried out. Palladium-catalyzed carbon-carbon bond-forming Heck reaction between C-20 vinyl iodide with methyl acrylate and transfer hydrogenation with triethylsilane and Pd/C are the key steps for stereoselective side-chain synthesis.

Key words

stereoselectivity - 16-dehydropregnenolone acetate - Heck coupling - transfer hydrogenation - steroidal side chain

References and Notes

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Methyl [20 (21),22]-3β-Acetoxychol-5-trienoate (10) To a solution of vinyl iodide 9 (0.234 g, 0.5 mmol) in dry DMF (10 mL), methyl acrylate (0.9 mL 1 mmol), Pd catalyst (0.005 g, 0.02 mmol), and K₂CO₃ (0.414 g, 1.5 mmol) were added, and the reaction mixture was stirred under argon at 25-28 ˚C for 12 h. Ice was added to the reaction mixture, and it was extracted with EtOAc (3 × 25 mL). The extract was washed 5% HCI (2 × 25 mL), sat. aq NaHCO₃ (20 mL) and brine, and dried over Na₂SO₄. The product was purified by chromatography on silica gel (2% EtOAc-PE) to give pure product 10 (0.163 g) in 77% yield and starting material 9 (0.047 g). Colorless solid; mp 93-94 ˚C; [α]_D ^²6 -32.0 (c 2.58, CHCl₃); IR (mull): 1691, 1724 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 0.56 (s, 3 H, 18-CH₃), 1.02 (s, 3 H, 19-CH₃), 2.04 (s, 3 H, OCOCH₃), 3.76 (s, 3 H, COOCH₃), 4.61 (m, 1 H, 3-CH), 5.34 (s, 1 H, 21-CH₂), 5.38 (d, J = 5.0 Hz, 1 H, 6-CH), 5.55 (s, 1 H, 21-CH₂), 6.02 (d, J = 16.0 Hz, 1 H, 23-CH), 7.36 (d, J = 16.0 Hz, 1 H, 22-CH). ^¹³C NMR (50 MHz, CDCl₃): δ = 12.8, 19.2, 20.9, 21.3, 24.2, 26.3, 27.6, 31.7, 32.3, 36.5, 36.9, 38.0, 38.6, 43.2, 50.0, 51.1, 51.5, 56.6, 73.8, 117.3, 122.0, 122.3, 139.6, 144.0, 149.1, 167.6, 170.4. Anal. Calcd for C₂₇H₃₈O₄: C, 76.02; H, 8.98. Found: C, 75.79; H, 8.78. ESI-LCMS: m/z = 427.58 [M⁺ + 1].

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Hydrogenation of Compound 10 To a stirred solution of compound 10 (0.100 g 0.24 mmol) in MeOH (4 mL) 10% Pd/C (0.015 g, 15% by weight) was added under an argon-filled balloon. Neat TES (0.4 mL, 2.4 mmol) was added dropwise to the reaction mixture. Within 10 min the reaction was complete. The reaction mixture was filtered through Celite, and the solvent was removed under vacuum. The product was purified by column chromatography on silica gel (2% EtOAc-hexane) to furnish a mixture of compounds 11a,b and 12a,b (0.094 g). Catalytic hydrogenation of this mixture (0.094 g) was carried out using 10% Pd/C (0.009 g) at 3.1 bar, in 10 mL EtOAc at 30 ˚C for 10 h. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to obtain diastereomeric mixture of 12a/12b (0.091 g) in 90% yield (Overall after 2 steps). Crystallization of the crude product from 10 mL MeOH-CH₂Cl₂ (9:1) gave major product C-20 (R)-ol, 12a (0.063 g) in 62% yield and after several crystallization minor product C-20 (R)-ol 12b (0.008 g) in 8% yield.
Methyl (20 R )-3β-Acetoxychol-5-en-24-oate (12a) Colorless solid; mp 160-162 ˚C; [α]_D ^²6 (CHCl₃, c 2.0) -46.0. IR (mull): 1724 cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 0.67 (s, 3 H, 18-CH₃), 0.92 (d, J = 6.3 Hz, 3 H, 21-CH₃), 1.01 (s, 3 H, 19-CH₃), 2.03 (s, 3 H, OCOCH₃), 3.66 (s, 3 H, COOCH₃), 4.60 (m, 1 H, 3-CH), 5.36 (d, J = 5.0 Hz, 1 H, 6-CH). ^¹³C NMR (50 MHz, CDCl₃): δ = 11.8, 18.3, 19.3, 21.0, 21.4, 24.2, 27.7, 28.1, 31.0, 31.0, 31.8, 31.9, 35.3, 36.5, 37.0, 38.1, 39.7, 42.3, 50.0, 51.4, 55.7, 56.6, 73.9, 122.5, 139.6, 170.4, 174.7. Anal. Calcd for C₂₇H₄₂O₄: C, 75.31; H, 9.83. Found: C, 75.27; H, 9.71. ESI-LCMS: m/z = 431.62 [M⁺ + 1].

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Crystallographic Data for Compound 12a
Empirical formula: C₂₇H₄₂O₄; formula weight: 430.61, temp, 297 (2) K, wavelength, 0.71073 A; crystal system; space group, monoclinic, P21; unit cell dimensions, a = 11.0178 (18) A, α = 90˚, β = 7.4633 (13) A, β = 92.080 (3)˚, c = 14.950 (3) A, γ = 90˚; volume, 1228.5 (4) A^³, Z; calcd density, 2, 1.164 mg/m^³; absorption coefficient, 0.076 mm^-¹, F(000) 472; crystal size, 0.40 × 0.29 × 0.03 mm; θ range for data collection 1.36-25.99˚; limiting indices, -13< = h< = 13, -9< = k< = 9, -18< = l < = 17, reflections collected/unique 9650/4755 [R(int) = 0.0275]; completeness to θ = 25.99, 99.9%; absorption correction, semi-empirical from equivalents; max. and min. transmission 0.9977 and 0.9702; refinement method, full-matrix least-squares on F^²; data/restraints/ arameters, 4755/1/285; goodness-of-fit on F^², 1.182; final R indices [I > 2σ(I)] R1 = 0.0655, wR2 = 0.1285, R indices (all data), R1 = 0.0784, wR2 = 0.1346; largest diff. peak and hole, 0.194 and -0.174 e A^-³. CCDC 725609 contains the supplementary crystallographic data for this structure. These data can be obtained free of charge from the Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Methyl (20 S )-3β-Acetoxychol-5-en-24-oate (12b) Colorless solid; mp 120-121 ˚C. ^¹H NMR (200 MHz, CDCl₃): δ = 0.69 (s, 3 H, 18-CH₃), 0.85 (d, J = 4.0 Hz, 3 H, 21-CH₃), 1.02 (s, 3 H, 19-CH₃), 2.03 (s, 3 H, OCOCH₃), 3.67 (s, 3 H, COOCH₃), 4.63 (m, 1 H, 3-CH), 5.38 (d, J = 5.0 Hz, 1 H, 6-CH).