Molecules 2018, 23, 821
10 of 13
J = 8.6 Hz, 2-H); 9.03 (s, 1H, OH). 13C-NMR
δ
(ppm): 17.2 (C-18); 25.3 (2C); 28.9; 32.3; 34.6; 42.3; 43.6;
46.5; 52.9; 55.6 (OCH2); 73.1 (C-15); 76.9 (C≡CH); 80.4 (C≡CH); 112.7 (C-2); 114.9 (C-4); 125.8 (C-1);
129.9 (C-10); 137.0 (C-5); 154.9 (C-3); 218.6 (C-17).
3.5. Synthesis of the Steroidal Azide 18
A stirred solution of compound 16 (268 mg, 1.0 mmol) in dry DMSO (5 mL) was treated with
acetic acid (0.24 mL, 4.0 mmol) and NaN3 (65 mg, 1.0 mmol). The mixture was stirred for 0.5 h at rt,
poured into water (50 mL), and extracted with dichloromethane (3
layers were dried (Na2SO4) and the solvents were removed under a reduced pressure. The residue
×
20 mL). The combined organic
was purified by flash chromatography with EtOAc/hexane = 1/99 as an eluent. Compound 18 was
obtained as a white solid (252 mg, 81%). M.p.: 138–139 ◦C, Rf = 0.24b. Anal calcd. for C18H21N3O2: C,
1
69.43; H, 6.80. Found: C, 69.48; H, 6.72. H-NMR (DMSO-d6)
δ (ppm): 0.89 (s, 3H, 18-H3); 2.76 (m, 2H,
6-H2); 4.16 (m, 1H, 15-H); 6.44 (d, 1H, J = 2.2 Hz, 4-H); 6.52 (dd, J = 8.6 Hz, J = 2.2 Hz, 2-H); 7.05 (d, 1H,
J = 8.6 Hz, 1-H); 9.04 (s, 1H, OH). 13C-NMR
δ
(ppm): 14.7 (C-18); 25.6; 26.3; 29.0; 31.0; 37.7; 42.0; 43.1;
49.7; 53.1; 58.1; 112.8; 114.7; 126.3; 129.3; 136.8; 155.0; 214.4.
3.6. Synthesis of Triazoles 22 and 23
To a stirred solution of
5 (322 mg, 1.0 mmol) or 17 (324 mg, 1.0 mmol) in toluene (5 mL), Ph3P
(26 mg, 0.1 mmol), CuI (9.5 mg, 0.05 mmol), DIPEA (0.52 mL, 3.0 mmol), and 18 (311 mg, 1.0 mmol) or
11 (401 mg, 1.0 mmol) were added. The reaction mixture was kept at the reflux temperature for 2 h
and then allowed to cool and evaporate in vacuo. The residue was purified by flash chromatography
with EtOAc/CH2Cl2 = 10/90 as an eluent.
◦
Compound 22 was obtained as a red solid (557 mg, 88%). M.p.: 273–275 C, Rf = 0.42c. Anal calcd. for
1
C36H34BF2N5O3: C, 68.55; H, 5.41. Found: C, 68.63; H, 5.33. H-NMR (DMSO-d6)
δ (ppm): 1.03 (s, 3H,
18-H3); 5.34 (s, 2H, OCH2); 5.42 (m, 1H, 15-H); 6.32 (d, 1H, J = 2.2 Hz, 4-H); 6.50 (dd, 1H, J = 8.6 Hz,
J = 2.2 Hz, 2-H); 6.64 (m, 2H); 7,01 (m, 2H); 7,03 (d, 1H, J = 8.6 Hz, 1-H); 7.27 (m, 2H); 7.64 (m, 2H); 8.09
(s, 2H); 8.59 (s, 1H); 9.00 (s, 1H). 13C-NMR
δ (ppm): 14.5 (C-18); 24.4; 28.6; 31.0; 37.7; 43.0; 44.0; 50.0;
53.2; 57.6; 61.4; 112.8; 114.6; 115.1 (2C); 118.9 (2C); 123.4; 125.6; 126.2; 129.1; 131.4 (2C); 132.5 (2C); 133.9;
136.5; 142.8; 143.9 (2C); 146.8; 154.9; 160.5; 213.6. MS m/z (%): 143 (100); 634 (80, [M + H]+).
Compound 23 was obtained as a red solid (588 mg, 81%). M.p.: 177–179 ◦C, Rf = 0.24c. Anal calcd.
1
for C42H54BF2N5O3: C, 69.51; H, 7.50. Found: C, 69.59; H, 7.40. H-NMR (DMSO-d6)
δ (ppm): 0.95
(t, 6H, J = 7.5 Hz, 2xCH2CH3); 1.01 (s, 3H, 18-H3); 2.24 (overlapping multiplets, 4H, 2xCH2CH3); 2.33
(overlapping singlets, 12H, 4xCH3); 2.96 (m, 2H, 6-H2); 4.13 (m, 1H, 15-H); 4.41 and 4.61 (2xd, 2x1H,
J = 12.5 Hz, OCH2); 4.45 (m, 2H); 6.39 (d, 1H, J = 2.2 Hz, 4-H); 6.50 (dd, 1H, J = 8.6 Hz, J = 2.2 Hz, 2-H);
7.01 (d, 1H, J = 8.6 Hz, 1-H); 8.10 (s, 1H, C δ (ppm): 12.7 (2C); 14.0
CH); 9.01 (s, 1H, OH). 13C-NMR
≡
(2C); 14.6 (2C); 16.4; 17.2 (C-18); 25.3; 25.4; 27.2; 28.0; 28.8; 30.0; 32.3; 34.4; 42.6; 43.3; 46.5; 48.9; 53.0; 54.8;
61.6; 73.0; 112.5; 114.9; 123.9; 125.7; 130.0 (3C); 132.2 (2C); 136.0; 136.1; 137.0; 143.9 (2C); 144.3; 154.9
(2C); 218.7. MS m/z (%): 706 (100, [M − F]+).
3.7. Synthesis of 3-Hydroxy-2-trimethylsilylethynyl-estra-1,3,5(10)-trien-17-one 20
3-Hydroxy-2-iodo-estra-1,3,5(10)-trien-17-one (19, 276 mg, 1.0 mmol), Pd(PPh3)4 (115 mg,
0.01 mmol), CuI (19 mg, 0.01 mmol), and THF (3 mL) were added together under a nitrog◦en
atmosphere. Then, Et3N (0.56 mL, 4.0 mmol) was added and the mixture was stirred at 50 C
for 10 min. Ethynyltrimethylsilane (0.28 mL, 2.0 mmol) was added with a syringe into 10 mL Pyrex
pressure vessels (CEM, Part #: 908035) with silicone caps (CEM, Part #: 909210) and the mixture was
◦
heated in a CEM microwave reactor at 50 C for 20 min under stirring. The solvent was evaporated in
vacuo and the residue was purified by flash chromatography with diisopropyl ether/hexane = 50/50
as an eluent. Compound 20 was obtained as a white solid (1.0 g, 84%). M.p.: 179–181 ◦C, Rf = 0.26a.
Anal calcd. for C23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.42; H, 8.16 1H-NMR (CDCl3)
δ (ppm): 0.26