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Synlett 2009(12): 2005-2009  
DOI: 10.1055/s-0029-1217521
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Construction of Steroidal Side Chain from 16-Dehydropregnenolone Acetate

Nilkanth G. Ahera, Rajesh G. Gonnadeb, Vandana S. Pore*a
a Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
Fax: +91(20)25902624; e-Mail: vs.pore@ncl.res.in;
b Centre for Material Characterization, National Chemical Laboratory, Pune 411008, India
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Publication History

Received 1 April 2009
Publication Date:
01 July 2009 (online)

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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

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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) A³, Z; calcd density, 2, 1.164 mg/m³; 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 F²; data/restraints/ arameters, 4755/1/285; goodness-of-fit on F², 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).