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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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McMurray JS.
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Vanderah DJ.
Djerassi C.
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1978,
43:
1442
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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].
<A NAME="RG11209ST-32">32</A>
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).
