D. Chen et al. / Tetrahedron 70 (2014) 1975e1983
1981
4H), 7.43 (d, J¼8.7 Hz, 2H), 6.96 (d, J¼8.4 Hz, 2H), 5.37 (s, 2H), 3.86
4.10.1. 1-((Benzyloxy)methyl)-4-methoxybenzene
(23a
or
(s, 3H).
16f).18 Colorless oil, 0.69 g (84% yield). 1H NMR (300 MHz, CDCl3)
d
7.42e7.40 (m, 4H), 7.36e7.33 (m, 3H), 6.96e6.93 (m, 2H), 4.59 (s,
4.8.5. 4-Methoxybenzyl 2-(4-chlorophenyl)acetate (21d). White
2H), 4.55 (s, 2H), 3.86 (s, 3H).
solid, 0.80 g (76% yield). 1H NMR (500 MHz, CDCl3)
d
7.28e7.24 (m,
4H), 7.19 (d, J¼8.0 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H), 5.06 (s, 2H), 3.80
(s, 3H), 3.60 (s, 2H). 13C NMR (75 MHz, CDCl3)
171.0, 159.7, 133.0,
4.10.2. 1-Methoxy-4-((3-phenylpropoxy)methyl)benzene
d
(23b).13i Colorless oil, 0.55 g (60% yield). 1H NMR (300 MHz, CDCl3)
132.4, 130.6, 130.1, 128.7, 127.8, 114.0, 66.6, 55.3, 40.6. ESI-MS m/z
313.1 [MþNa]þ. HRMS calcd for C16H15ClO3Na [MþNa]þ 313.0607,
found 313.0613.
d 7.29e7.24 (m, 5H), 7.19e7.16 (m, 2H), 6.90e6.86 (m, 2H), 4.43 (s,
2H), 3.81 (s, 3H), 3.46 (t, J¼6.4 Hz, 2H), 2.70 (t, J¼7.5 Hz, 2H),
1.97e1.87 (m, 2H).
4.8.6. 4-Methoxybenzyl nicotinate (21g).25 Colorless oil, 0.83 g (95%
4.10.3. 3-O-Methyl-17-(4-methoxybenzyl)-
b-estradiol
yield). 1H NMR (300 MHz, CDCl3)
d 9.25e9.24 (m, 1H), 8.76
(23c).26 White solid, 0.88 g (60% yield). 1H NMR (500 MHz, CDCl3)
(dd, J¼4.9, 1.7 Hz, 1H), 8.31 (dt, J¼7.9, 2.0 Hz, 1H), 7.39 (d, J¼8.7 Hz,
2H), 7.39e7.35 (m, 1H), 6.92 (d, J¼8.6 Hz, 2H), 5.34 (s, 2H), 3.83
(s, 3H).
d
7.27 (d, J¼8.5 Hz, 2H), 7.20 (d, J¼8.6 Hz, 1H), 6.87 (d, J¼8.1 Hz, 2H),
6.70 (dd, J¼8.5, 2.5 Hz, 1H), 6.62 (d, J¼2.2 Hz, 1H), 4.50 (s, 2H), 3.80
(s, 3H), 3.77 (s, 3H), 3.48 (t, J¼8.4 Hz, 1H), 2.86e2.79 (m, 2H),
2.29e2.26 (m, 1H), 2.20e2.14 (m, 1H), 2.09e1.99 (m, 2H), 1.88e1.85
(m, 1H), 1.69e1.15 (m, 8H), 0.85 (s, 3H).
4.9. General procedure for the preparation of 21e and 21f
To a solution of phthalic anhydride (250 mg, 1.69 mmol) in
pyridine (3 mL) was added p-methoxybenzyl alcohol (280 mg,
2.03 mmol) and catalytic amount of 4-dimethylaminopyridine. The
reaction mixture was stirred overnight at room temperature, and
then concentrated in vacuo to dryness. An aqueous solution of 10%
HCl (25 mL) was added to the reaction mixture. The aqueous layer
was extracted with EtOAc (3ꢁ10 mL). The combined organic layers
were washed with brine and dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was dissolved in
acetone (5 mL), then methyl iodide or benzyl bromide (2.53 mmol)
and K2CO3 (467 mg, 3.38 mmol) were added. The reaction mixture
was stirred at room temperature until the TLC indicated the con-
sumption of the starting material. Then the mixture was filtered to
remove K2CO3, and the filtrate was evaporated under reduced
pressure. The residue was purified by flash chromatography (pe-
troleum ether/ethyl acetate 20:1 to 15:1) to give the product.
4.10.4. 3-O-(4-Methoxybenzyl)-
b
-estradiol
(23d). White
solid,
0.57 g (40% yield). 1H NMR (300 MHz, CDCl3)
d
7.36e7.33 (m, 2H),
7.19 (d, J¼8.4 Hz, 1H), 6.93e6.88 (m, 2H), 6.77 (dd, J¼8.5, 2.7 Hz,
1H), 6.70 (d, J¼2.6 Hz, 1H), 4.95 (s, 2H), 3.81(s, 3H), 3.73 (t, J¼8.7 Hz,
1H), 2.87e2.79 (m, 2H), 2.33e2.28 (m, 1H), 2.23e2.04 (m, 2H),
1.97e1.84 (m, 2H), 1.74e1.64 (m,1H), 1.56e1.14 (m, 8H), 0.77 (s, 3H).
13C NMR (75 MHz, CDCl3)
d 159.4, 156.8, 138.0, 132.9, 129.4, 129.2,
126.3, 114.9, 114.0, 112.3, 81.9, 69.8, 55.3, 50.1, 44.0, 43.3, 38.9, 36.7,
30.6, 29.8, 27.3, 26.3, 23.1, 11.1. ESI-MS m/z 415.2 [MþNa]þ. HRMS
calcd for C26H32O3Na [MþNa]þ 415.2249, found 415.2253.
4.10.5. Benzyl-3
b
-(4-methoxybenzyl)olean-12-en-28-oic
acid
(23e). White solid, 2.09 g (87% yield). 1H NMR (300 MHz, CDCl3)
d
7.35e7.29 (m, 7H), 6.89e6.85 (m, 2H), 5.29 (t, J¼3.4 Hz, 1H),
5.13e5.00 (m, 2H), 4.59 (d, J¼11.5 Hz, 1H), 4.36 (d, J¼11.5 Hz, 1H),
3.80 (s, 3H), 2.92e2.86 (m, 2H), 2.02e0.68 (m, 22H), 1.16 (s, 3H),
0.96 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.81 (s, 3H), 0.61
4.9.1. 4-Methoxybenzyl methyl phthalate (21e). Colorless oil,
(s, 3H). 13C NMR (75 MHz, CDCl3)
d 177.3, 158.8, 143.6, 136.4, 131.5,
213 mg (42% yield). 1H NMR (500 MHz, CDCl3)
d
7.75e7.73 (m, 1H),
128.9, 128.3, 127.9, 127.8, 122.5, 113.5, 86.0, 70.9, 65.8, 55.7, 55.1,
47.5, 46.7, 45.8, 41.6, 41.3, 39.3, 38.8, 38.3, 36.9, 33.8, 33.1, 32.7, 32.3,
30.6, 28.2, 27.5, 25.8, 23.6, 23.4, 23.0, 22.7, 18.2, 16.8, 16.6, 15.2.
HRMS calcd for C45H62O4Na [MþNa]þ 689.4540, found 689.4541.
7.70e7.68 (m, 1H), 7.53e7.51 (m, 2H), 7.37e7.35 (m, 2H), 6.91e6.89
(m, 2H), 5.28 (s, 2H), 3.81 (s, 3H), 3.74 (s, 3H).
4.9.2. Benzyl 4-methoxybenzyl phthalate (21f). Colorless oil,
509 mg (80% yield). 1H NMR (500 MHz, CDCl3)
d
7.74e7.72 (m, 2H),
4.10.6. (R)-N-(2-((4-Methoxybenzyl)oxy)-1-phenylethyl)benzamide
7.52e7.50 (m, 2H), 7.37e7.33 (m, 5H), 7.31e7.29 (m, 2H), 6.88e6.86
(23f). White solid, 1.18 g (91% yield). 1H NMR (500 MHz, CDCl3)
(m, 2H), 5.23 (s, 2H), 5.17 (s, 2H), 3.79 (s, 3H). 13C NMR (75 MHz,
d
7.82e7.78 (m, 2H), 7.53e7.27 (m, 8H), 7.21e7.20 (m, 2H),
6.87e6.85 (m, 2H), 5.40e5.37 (m, 1H), 4.53e4.47 (m, 2H),
3.87e3.79 (m, 2H), 3.81 (s, 3H). 13C NMR (75 MHz, CDCl3)
167.0,
CDCl3)
d 167.4, 159.8, 135.5, 132.1, 132.0, 131.1, 131.1, 130.3, 129.0,
129.0, 128.6, 128.4, 128.3, 127.6, 114.0, 67.4, 67.3, 55.3. ESI-MS m/z
399.2 [MþNa]þ. HRMS calcd for C23H20O5Na [MþNa]þ 399.1208,
found 399.1212.
d
159.4, 139.9, 134.5, 131.5, 129.4, 128.5, 128.4, 127.5, 127.1, 126.9,
113.9, 72.8, 72.0, 55.3, 53.1. ESI-MS m/z 384.2 [MþNa]þ. HRMS calcd
for C23H23NO3Na [MþNa]þ 384.1576, found 384.1580.
4.10. General procedure for the preparation of 23aeh
4.10.7. (S)-2-(((4-Methoxybenzyl)oxy)diphenylmethyl)-1-
To a solution of the corresponding alcohol (3.6 mmol) in an-
hydrous DMF (5 mL) was added sodium hydride (60% in mineral
oil, 216 mg, 5.4 mmol) in several portions at 0 ꢀC. The reaction
mixture was stirred at 0 ꢀC for 30 min, and then p-methoxybenzyl
chloride (564 mg, 3.6 mmol) was added. The mixture was stirred
at room temperature until the TLC indicated the consumption of
the starting material. An aqueous solution of ammonium chloride
was added to the reaction mixture. The aqueous layer was
extracted with EtOAc (3ꢁ10 mL). The combined organic layers
were washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (petroleum ether/ethyl acetate 200:1 to
20:1) to give the product. Following the procedure, 23aeg were
prepared.
tosylpyrrolidine (23g). White solid, 1.25 g (66% yield). 1H NMR
(500 MHz, CDCl3)
d
7.57 (d, J¼8.1 Hz, 2H), 7.48 (m, 2H), 7.42 (m,
2H), 7.36e7.27 (m, 6H), 7.22 (d, J¼8.5 Hz, 2H), 7.16 (d, J¼8.0 Hz, 2H),
6.83 (d, J¼8.6 Hz, 2H), 4.22 (d, J¼11.1 Hz, 1H), 3.83 (d, J¼11.1 Hz,
1H), 3.79 (s, 3H), 3.35e3.30 (m, 1H), 2.39 (s, 3H), 1.97e1.92 (m, 2H),
1.86e1.80 (m, 2H), 1.25e1.21 (m, 2H). 13C NMR (75 MHz, CDCl3)
d
158.6, 142.7, 139.9, 139.3, 137.4, 131.3, 130.0, 130.0, 129.7, 129.2,
128.5, 128.2, 127.9, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 113.4, 86.3,
65.8, 65.2, 55.2, 49.3, 28.1, 24.2, 21.4. ESI-MS m/z 550.2 [MþNa]þ.
HRMS calcd for
550.2034.
C
32H33NO4SNa [MþNa]þ 550.2028, found
4.10.8. (Z)-Benzyl 7-((1R,2S,3R,5S)-5-hydroxy-2-(hydroxymethyl)-3-
( ( 4 - m e t h o x y b e n z y l ) o x y ) c y c l o p e n t y l ) h e p t - 5 - e n o a t e