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D.-Q. Zheng et al. / Tetrahedron 72 (2016) 2164e2169
21.2
organic solvent was removed under reduced pressure and the re-
sidual was diluted with ethyl acetate and washed with brine. The
organic phase was dried over Na2SO4, concentrated under reduced
pressure, and chromatographed on silica gel to give 2b-mix as
a white solid (1.63 g).
(61 mg, 85%). Mp 90e92 ꢀC; [
(400 MHz, CDCl3)
a
]
D
¼þ44.6 (c 1, CHCl3); 1H NMR
d
7.16 (d, J¼8.6 Hz, 1H), 6.67 (dd, J¼8.5, 2.4 Hz,
1H), 6.60 (d, J¼2.2 Hz, 1H), 4.74e4.70 (m, 1H), 4.20e4.16 (m, 1H),
3.59 (d, J¼5.6 Hz, 1H), 3.31 (d, J¼28.9 Hz, 2H), 2.85e2.81 (m, 2H),
2.32e2.22 (m, 3H), 0.81 (s, 3H); 1H NMR (400 MHz, CDCl3-D2O)
Under inert atmosphere, Raney Ni (1.6 g) was washed with dry
THF for several times. The solution of 2b-mix (1.63 g) in dry THF
(180 mL) was added to Raney Ni. The suspension was stirred at
room temperature and monitored with HPLC. After the reaction
finished (1.5 h), the suspension was filtered. The filtrate was con-
centrated and chromatographed on silica gel to give estrone 3-
cyclopentyl ether (2b) as a white solid (1.62 g, 79% overall yield).
Under inert atmosphere, n-BuLi (1.2 mL, 3.0 mmol, 2.5 N) was
added to a solution of ethynyltrimethylsilane (424 ul, 3.0 mmol) in
THF (2 mL) at ꢁ20 ꢀC. After 0.5 h, a solution of ketone 2b (338 mg,
1.0 mmol) in THF (4 mL) was added into the solution of lithium
acetylene at ꢁ20 ꢀC. After 1 h, the mixture was added with meth-
anol (6 mL) and KOH (224 mg, 4 mmol) and stirred for 0.5 h at room
temperature and quenched with 2N-hydrochloric acid. The organic
solvent was removed under reduced pressure and the residual was
diluted with ethyl acetate and washed with saturated NaHCO3 and
brine. The organic phase was dried over Na2SO4, concentrated
under reduced pressure, and chromatographed on silica gel to give
quinestrol as a white solid (340 mg, 93%). Mp 94e96 ꢀC;
d
7.15 (d, J¼8.7 Hz, 1H), 6.66 (d, J¼8.6 Hz, 1H), 6.60 (s, 1H),
4.74e4.69 (m, 1H), 4.20e4.16 (m, 1H), 3.58 (d, J¼5.7 Hz, 1H),
2.89e2.77 (m, 2H), 2.32e2.20 (m, 2H), 0.81 (s, 3H); 13C NMR
(101 MHz, CDCl3) d 155.9, 137.7, 131.9, 126.0, 115.6, 112.9, 89.6, 79.0,
78.3, 47.8, 43.9, 43.8, 38.2, 36.6, 33.5, 32.8, 29.7, 27.2, 25.8, 24.0,
12.3; HRMS (ESI) calcd for C23H33O3 [MþH]þ: 357.2351, found
357.2424.
4.2.6. Synthesis of nilestriol. Under inert atmosphere, n-BuLi
(0.6 mL, 1.5 mmol, 2.5 N) was added to a solution of ethynyl-
trimethylsilane (211 ul, 1.5 mmol) in THF (1 mL) at ꢁ20 ꢀC. After
0.5 h, a solution of ketone 6 (177 mg, 0.5 mmol) in THF (2 mL) was
added into the solution of lithium acetylene at ꢁ20 ꢀC. After 1 h, the
mixture was added with methanol (3 mL) and KOH (112 mg,
2 mmol) and stirred for 0.5 h at room temperature and quenched
with 2N-hydrochloric acid. The organic solvent was removed under
reduced pressure and the residual was diluted with ethyl acetate
and washed with saturated NaHCO3 and brine. The organic phase
was dried over Na2SO4, concentrated under reduced pressure, and
chromatographed on silica gel to give nilestriol (101 mg, 53%) and
[a]D23.4¼þ11.3 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3)
d 7.19 (d,
J¼8.6 Hz, 1H), 6.68 (dd, J¼8.5, 2.3 Hz, 1H), 6.61 (d, J¼2.7 Hz 1H),
isomer 7 (80 mg, 42%).
4.74e4.70 (m, 1H), 2.91e2.79 (m, 2H), 2.61 (s, 1H), 0.89 (s, 3H); 13
NMR (101 MHz, CDCl3) 155.9, 137.8, 132.0, 126.2, 115.5, 112.9, 87.5,
C
Nilestriol: a white solid. Mp 156e158 ꢀC; [
a
]
D
¼þ0.45 (c 1,
26.0
d
CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.17 (d, J¼8.6 Hz, 1H), 6.68 (dd,
79.9, 79.0, 74.0, 49.4, 47.1, 43.5, 39.4, 38.9, 32.9, 32.7, 29.8, 27.3, 26.3,
24.0, 22.8, 12.7; HRMS (ESI) calcd for C25H33O2 [MþH]þ: 365.2402,
found 365.2472.
J¼8.6, 2.6 Hz, 1H), 6.60 (d, J¼2.4 Hz, 1H), 4.74e4.70 (m, 1H), 4.30 (s,
1H), 2.84 (s, 1H), 2.41e2.33 (m, 2H), 2.28e2.22 (m, 1H), 0.93 (s, 3H);
1H NMR (400 MHz, CDCl3-D2O)
d
7.16 (d, J¼8.6 Hz, 1H), 6.68 (dd,
J¼8.6, 2.5 Hz, 1H), 6.60 (d, J¼2.4 Hz, 1H), 4.74e4.69 (m, 1H),
4.30e4.27 (m, 1H), 2.83 (s, 1H), 2.38e2.32 (m, 1H), 2.28e2.21 (m,
4.2.5. Synthesis of quinestradol. The suspension of ketone 2b
(1.58 g, 4.68 mmol) and CuBr2(3.13 g, 14.04 mmol) in methanol was
refluxed for 3 h. The salts were removed by filtration and the filtrate
was concentrated under reduced pressure. The residual was diluted
with ethyl acetate and washed with saturated NaHCO3 and brine.
The organic phase was dried over Na2SO4, concentrated under re-
duced pressure, and chromatographed on silica gel to give bromide
5 as a white solid (1.72 g, 88%). Mp 145e147 ꢀC; [a]D21.4¼þ120.0 (c 1,
1H), 0.92 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 155.9, 137.7, 131.8,
126.0, 115.5, 112.9, 85.7, 82.0, 79.83, 79.3, 79.0, 47.3, 43.5, 38.8, 33.3,
33.1, 32.8, 29.7, 27.3, 25.8, 24.0, 13.3; HRMS (ESI) calcd for
C
25H33O3[MþH]þ: 381.2351, found 381.2421.
22.8
Isomer 7: mp 74e76 ꢀC; [
a]
¼þ47.6 (c 0.28, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
7.17 (d, J¼8.6 Hz, 1H), 6.67 (dd, J¼8.5, 2.5 Hz,
1H), 6.60 (d, J¼2.5 Hz, 1H), 4.71 (m, 1H), 4.51 (dd, J¼9.4, 2.6 Hz, 1H),
3.24 (s, 1H), 2.87e2.79 (m, 2H), 2.49 (s, 1H), 2.39e2.35 (m, 1H),
2.28e2.22 (m, 1H), 2.12e2.05 (m, 1H), 0.92 (s, 3H); 1H NMR
CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.17 (d, J¼8.6 Hz, 1H), 6.69 (dd,
J¼8.6, 2.8 Hz, 1H), 6.62 (d, J¼2.5 Hz, 1H), 4.74e4.70 (m, 1H), 4.59 (d,
J¼6.9 Hz, 1H), 2.90e2.87 (m, 2H), 0.94 (s, 3H); 13C NMR (101 MHz,
(400 MHz, CDCl3-D2O)
d
7.18 (d, J¼8.6 Hz, 1H), 6.67 (dd, J¼8.6,
CDCl3)
d
213.2, 156.2, 137.4, 131.1, 126.1, 115.6, 113.0, 79.0, 48.0, 47.0,
2.6 Hz, 1H), 6.60 (d, J¼2.5 Hz, 1H), 4.74e4.69 (m, 1H), 4.51 (dd,
J¼9.4, 2.6 Hz, 1H), 2.87e2.78 (m, 2H), 2.49 (s, 1H), 2.38e2.33 (m,
1H), 2.28e2.22 (m, 1H), 2.12e2.04 (m, 1H), 0.92 (s, 3H); 13C NMR
46.3, 43.8, 37.6, 33.9, 32.8, 32.3, 29.5, 26.5, 25.7, 24.0, 14.2; HRMS
(ESI) calcd for C23H30BrO2 [MþH]þ: 417.1351, found 417.1420.
To the solution of bromide 5 (666 mg, 1.6 mmol) in DMF (32 mL)
and water (1.6 mL) was added NaOH (128 mg, 3.2 mmol) at 25 ꢀC.
The conversion was complete within 10 min. The solution was
carefully neutralized with 2N-hydrochloric acid, diluted with ethyl
acetate and washed with saturated NaHCO3 and brine. The organic
phase was dried with Na2SO4, concentrated and chromatographed
(101 MHz, CDCl3)
d 155.9, 137.7, 131.9, 126.1, 115.5, 112.9, 84.6, 79.0,
78.4, 78.1, 73.2, 49.0, 46.6, 43.4, 39.0, 34.0, 32.8, 30.0, 29.8, 27.9,
25.6, 24.0, 16.4; HRMS (ESI) calcd for C25H31O3[MꢁH]þ: 379.2351,
found 379.2277.
16-Acetoxy product 8 was synthesized from isomer 7 to provide
22.8
single crystal. Mp 130e132 ꢀC; [
NMR (400 MHz, CDCl3)
a]
¼þ106.8 (c 0.24, CHCl3); 1H
D
on silica gel to give alcohol 6 as a white solid (408 mg, 72%). Mp
d
7.18 (d, J¼8.6 Hz, 1H), 6.68 (dd, J¼8.5,
21.5
202e204 ꢀC; [
d
a]
¼þ108.6 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3)
2.5 Hz, 1H), 6.60 (d, J¼2.3 Hz, 1H), 5.00e4.98 (m, 1H), 4.74e4.70 (m,
1H), 4.46 (s, 1H), 2.86e2.80 (m, 2H), 2.65 (s, 1H), 2.18 (s, 3H), 0.98 (s,
D
7.16 (d, J¼8.6 Hz,1H), 6.68 (dd, J¼8.5, 2.3 Hz,1H), 6.61 (d, J¼2.6 Hz,
1H), 4.74e4.70 (m, 1H), 4.42 (d, J¼7.8 Hz, 1H), 2.90e2.84 (m, 2H),
3H); 13C NMR (101 MHz, CDCl3)
d 173.9, 155.0, 137.6, 131.7, 126.2,
1.00 (s, 3H); 13C NMR (101 MHz, CDCl3)
d
219.3, 156.1, 137.5, 131.2,
115.6, 112.9, 85.7, 83.9, 82.1, 79.0, 76.9, 48.5, 47.7, 43.3, 38.8, 33.4,
32.9, 30.7, 29.7, 27.4, 25.9, 24.0, 21.1, 13.6; HRMS (ESI) calcd for
C
126.1, 115.6, 113.0, 79.0, 71.3, 47.9, 47.3, 43.8, 38.2, 32.8, 31.3, 30.3,
29.6, 26.2, 25.5, 24.0, 14.1; HRMS (ESI) calcd for C23H31O3 [MþH]þ:
355.2195, found 355.2264.
27H33O4[MꢁH]þ: 421.2457, found 421.2374.
To the solution of alcohol 6 (71 mg, 0.2 mmol) in methanol
(2 mL) was added NaBH4 (16 mg, 0.4 mmol) at 0 ꢀC. After stirring
for 5 min, the reaction was quenched with 2N-hydrochloric acid,
diluted with ethyl acetate and washed with saturated NaHCO3 and
brine. The organic phase was dried with Na2SO4, concentrated and
chromatographed on silica gel to give quinestradol as a white solid
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 20902098 and No.
U1362111).