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E. Stefan et al. / Tetrahedron 69 (2013) 7706e7712
saturated Na2S2O3 (5 ml), and diluted with AcOEt (5 ml). The
mixture was extracted with AcOEt (5ꢂ3 ml), dried over MgSO4, and
concentrated. Purification by column chromatography on silica gel
(hexane/AcOEt 8:1) provided 12b (91 mg, 63% yield, 6:1 dr) as an
3.10. (1S,3R)-3-(2-Bromoethoxy)-4-iodo-1-phenylbutan-1-ol (15)
To a solution of 14 (1.00 g, 3.51 mmol) in dry nitromethane (70 ml)
was successively added NIS (6ꢂ0.78 g, 24.54 mmol) and 1-phenyl-
1H-tetrazole-5-thiol (6ꢂ0.62 g, 24.54 mmol) every 6 h in the dark at
room temperature under inert atmosphere. AcOEt (100 ml) was
added, andthesolventevaporated. The crude materialwas portioned
in half saturated NaS2O3/Et2O (200 ml:200 ml) and stirred for 30 min.
After extraction with AcOEt (5ꢂ20 ml), the organic layers were
combined, dried over MgSO4, and concentrated. Purification by col-
umn chromatography on silica gel (hexane/AcOEt 10:1e6:1) pro-
vided the ether transfer product (1.19 g, 64% yield) as an oil. 1H NMR
oil. 1H NMR (600 MHz, CDCl3):
d
(ppm)¼7.83e7.85 (2H, m),
7.26e7.55 (8H, m), 5.70 (1H, d, J¼11.4 Hz), 5.56 (1H, d, J¼11.4 Hz),
4.90 (1H, dd, J¼7.8, 7.8 Hz), 3.32 (1H, dd, J¼5.4,10.8 Hz), 3.26 (3H, s),
3.20 (4.2, 10.8 Hz), 2.82 (1H, dddd, J¼4.2, 5.4, 5.4, 7.8 Hz), 2.26 (1H,
ddd, J¼7.2, 7.2, 14.4 Hz), 1.94 (1H, ddd, J¼5.4, 7.2, 14.4 Hz). 13C NMR
(150 MHz, CDCl3):
d
(ppm)¼164.3, 139.8, 134.5, 129.7, 129.3, 129.2,
128.6, 128.6, 128.4, 127.0, 126.8, 123.9, 123.6, 79.1, 76.0, 74.6, 56.6,
42.5, 9.5. IR (cmꢀ1): f¼2984, 2940, 2907, 1740, 1498, 1446, 1373,
1298, 1241, 1096, 1047, 938, 847, 634, 607. HRMS calculated for
C19H22IN4O2S [MþH]þ 497.0503, found 497.0524.
(500 MHz, CDCl3):
d
(ppm)¼7.84e7.86 (2H, m), 7.30e7.58 (8H, m),
5.71 (1H, d, J¼10.8 Hz), 5.55 (1H, d, J¼10.8 Hz), 4.96 (1H, dd, J¼6.6,
6.6 Hz), 3.80 (1H, ddd, J¼5.4, 5.4, 10.2 Hz), 3.60 (1H, ddd, J¼5.4, 5.4,
10.2 Hz), 3.42 (2H, m), 3.26 (1H, dd, J¼4.8, 11.4 Hz), 3.22 (1H, dd,
J¼4.8, 11.4 Hz), 3.09 (1H, dddd, J¼4.8, 4.8, 4.8, 7.2 Hz), 2.28 (1H, ddd,
J¼7.2, 7.2,14.4 Hz), 2.00 (5.4, 7.2,14.4 Hz).13C NMR (150 MHz, CDCl3):
3.7. ( )-2,2,2-Trichloro-N-((4-iodo-3-methoxy-1-
phenylbutoxy)methyl)acetamide (12c)
Benzyl imidate (168
mg, 905
mmol) was added to a solution of 1b
d
(ppm)¼164.3, 139.6, 134.5, 129.7, 129.3, 129.2, 128.7, 128.6, 127.1,
(58 mg, 302 mol) and NIS (204 mg, 905
m
mmol) in dry nitromethane
126.9, 123.9, 123.6, 78.8, 75.5, 74.5, 69.2, 42.7, 30.5, 9.2. HRMS cal-
culated for C20H23BrIN4O2S [MþH]þ 588.9764, found 588.9745. [
ꢀ43.0 (c 1.5, CHCl3).
a]
20
(3 ml). The mixture was stirred in the dark for 12 h under inert
atmosphere, quenched by addition of half saturated Na2S2O3 (5 ml),
and diluted with AcOEt (5 ml). The mixture was extracted with
AcOEt (5ꢂ3 ml), dried over MgSO4, and concentrated. Purification
by column chromatography on silica gel (hexane/AcOEt:8:1) pro-
vided 12c (65 mg, 45% yield, 8:1 dr) as an oil. 1H NMR (600 MHz,
D
m-CPBA (0.475 g, 2.121 mmol) was added to a mixture of the
ether transfer product (0.625 g, 1.061 mmol) and NaHCO3 (0.445 g,
5.311 mmol) in AcOEt (30 ml) and vigorously stirred at room
temperature open to air. After 1 h, a 1:1 mixture of saturated
NaHCO3/Na2S2O3 (30 ml) was added and stirred for 10 min. The
aqueous layer was extracted with DCM (5ꢂ5 ml), dried over MgSO4,
and concentrated (without heating the water bath). Purification by
column chromatography on silica gel (hexane/AcOEt 4:1) provided
15 (275 mg, 65% yield) as an oil. 1H NMR (600 MHz, CDCl3):
CDCl3):
d
(ppm)¼7.23e7.37 (5H, m), 7.12 (1H, br s), 4.79 (1H, dd,
J¼7.2, 10.8 Hz), 4.71 (1H, dd, J¼6.6, 10.8 Hz), 4.60 (1H, dd, J¼5.4,
7.2 Hz), 3.31 (1H, dd, J¼5.4,10.8 Hz), 3.26 (3H, s), 3.22 (1H, dd, J¼4.2,
10.8 Hz), 2.83 (1H, dddd, J¼4.2, 5.4, 5.4, 7.8 Hz), 2.19 (1H, ddd, J¼7.2,
7.2, 13.8 Hz), 1.89 (1H, ddd, J¼5.4, 6.6, 13.8 Hz). 13C NMR (150 MHz,
CDCl3):
d
(ppm)¼162.1, 140.6, 128.7, 128.2, 127.0, 78.1, 76.0, 70.7,
d
(ppm)¼7.27e7.40 (5H, m), 4.95 (1H, dd, J¼3.6, 8.4 Hz), 3.99 (1H,
56.6, 42.5, 9.4. HRMS calculated for C14H17Cl3INNaO3 [MþNa]þ
ddd, J¼5.4, 5.4, 10.8 Hz), 3.68 (1H, ddd, J¼5.4, 5.4, 10.8 Hz), 3.51 (2H,
501.9216, found 501.9214.
m), 3.44 (1H, dddd, 4.2, 4.2, 6.0, 7.8 Hz), 3.31 (2H, m), 3.00 (1H, br s),
2.00e2.15 (2H, m). 13C NMR (150 MHz, CDCl3):
d
(ppm)¼143.9,
3.8. 1-Bromo-2-(chloromethoxy)ethane
128.5, 127.7, 125.8, 78.1, 72.7, 69.0, 44.1, 30.5, 8.7. HRMS calculated
20
for C12H17BrIO2 [MþH]þ 398.9451, found 398.9459. [
a]
ꢀ41.5 (c
D
A suspension of paraformaldehyde (3.51 g, 111.10 mmol), 2-
bromoethanol (7.50 ml, 105.81 mmol) in 10:1 mixture of pentane/
DCM (65 ml) was cooled to 0 ꢁC. HCl gas was bubbled under vig-
orous stirring until the mixture became homogeneous (approx-
imatively 30 min). In a separatory funnel, the aqueous solution was
removed and distillation over CaCl2 (82e87 ꢁC/10 mmHg) provided
1-bromo-2-(chloromethoxy)ethane (18 g, 99% yield) as an oil, which
can be kept over CaCl2 for months in a freezer. 1H NMR (600 MHz,
1.2, CHCl3). Remark: compound 15 proved to be fairly unstable and
cannot be kept as an oil. It can be stored in benzene solution in
a freezer for a long period of time.
3.11. (E)-3-(3-(2-Bromoethoxy)-4-iodo-1-phenylbutoxy)-1-
phenylprop-2-en-1-one (17)
To a mixture of 15 (260 mg, 650 mmol) and 1-phenylprop-2-yn-1-
CDCl3):
d
(ppm)¼5.52 (2H, s), 4.00 (2H, t, J¼5.4 Hz), 3.51 (2H, t,
one (0.17 g, 1.30 mmol) in dry DCM (65 ml) was added PBu3 (0.32 ml,
1.30 mmol) dropwise at 0 ꢁC over 15 min under inert atmosphere.
After 1 h, the mixture was concentrated and purified by column
chromatography on silica gel (hexane/AcOEt 7:1) provided 17 (292 mg,
J¼5.4 Hz). 13C NMR (150 MHz, CDCl3):
d
(ppm)¼82.3, 70.1, 29.0.
3.9. (S)-(1-((2-Bromoethoxy)methoxy)but-3-en-1-yl)benzene (14)
85% yield) as an oil.1H NMR (MHz, CDCl3):
d
(ppm)¼7.80e7.82(2H, m),
1-Bromo-2-(chloromethoxy)ethane (2.82 g, 16.31 mmol) was
added slowly to a solution of (S)-1-phenylbut-3-en-1-ol (1.86 g,
12.55 mmol) and DIPEA (3.93 ml, 22.59 ml) in dry DCM (25 ml). The
mixture is stirred for 24 h under argon at room temperature. Sat-
urated NH4Cl (50 ml) was added and the aqueous layer was
extracted with AcOEt (3ꢂ10 ml). The organic layers were combined,
dried over MgSO4, and concentrated. After purification by column
chromatography on silica gel hexane/AcOEt (12:1), 14 was obtained
7.67 (1H, d, J¼12.0 Hz), 7.48e7.52 (1H, m), 7.32e7.43 (7H, m), 6.45 (1H,
d, J¼12.0 Hz), 5.27 (1H, dd, J¼6.0, 7.8 Hz), 3.91 (1H, ddd, J¼4.8, 4.8,
10.2 Hz), 3.54 (1H, ddd, J¼4.8, 4.8, 10.2 Hz), 4.49 (2H, m), 3.29 (1H, dd,
J¼6.0,10.8 Hz), 3.25 (1H, dd, J¼3.6, 10.8 Hz), 3.08 (1H, dddd, J¼4.2, 4.2,
5.4, 7.8 Hz), 2.44 (1H, ddd, J¼6.0, 8.4,14.4 Hz), 2.19 (1H, ddd, J¼3.6, 8.4,
14.4 Hz). 13C NMR (150 MHz, CDCl3):
d
(ppm)¼190.4, 162.6, 140.0,
138.6, 132.3, 129.0, 128.4, 128.00, 126.8, 126.0, 104.0, 81.9, 75.1, 69.1,
42.0, 30.7, 8.0. HRMS calculated for C21H23BrIO3 [MþH]þ 528.9870,
as an oil (2.68 g, 77% yield). 1H NMR (600 MHz, CDCl3):
d
(ppm)¼
found 529.9881. [
a
]
20 ꢀ43.5 (c 0.75, CHCl3).
D
7.26e7.35 (5H, m), 5.78 (1H, dddd, J¼7.2, 7.2, 10.2, 17.4 Hz),
5.03e5.10 (2H, m), 4.68 (1H, m), 4.68 (1H, d, J¼7.2 Hz), 4.61 (1H, d,
J¼7.2 Hz), 3.96 (1H, ddd, J¼6.0, 6.0, 10.8 Hz), 3.74 (1H, ddd, J¼6.0,
6.0,10.8 Hz), 3.41 (2H, ddd, J¼1.2, 6.0, 6.0 Hz), 2.43e2.63 (2H, m). 13C
3.12. Diospongin A
AIBN (0.5 mg, 2.8
mmol) was added to 17 (15.0 mg, 28.3
mmol) and
NMR (150 MHz, CDCl3):
d
(ppm)¼141.3, 134.6, 128.4, 127.8, 127.0,
n-Bu3SnH (16 ml, 57 mmol) in dry benzene (3 ml). The mixture was
rapidly brought to reflux and stirred for 5 min under argon. After
cooling down, the reacting mixture was concentrated and purified
117.4, 93.0, 78.2, 67.9, 42.3, 30.7. HRMS calculated for C13H17BrNaO2
[MþNa]þ 307.0304, found 307.0313. [
a
]
20 ꢀ116.8 (c 0.75, CHCl3).
D