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12. The structure of (ꢀ)-12 can be explained as following: due to the steric issue of
the large group, –CH2OTBS, in dienophile (S)-7, only two possible cycloadducts,
endo-8a and exo-8b, can be obtained from the lower approach of (S)-7 to diene
6 in Diels–Alder cycloaddition. Under high pressure, that the major product is
endo-cycloadduct 8a can be explained by the various products generated from
the following reaction steps as shown in Scheme 2. For example, after several
reaction steps with the major cycloadduct, deallyloxycarbonylation afforded
a conjugated enoate ester product. If this product was generated from 8a, it
should be (ꢀ)-12. Or, if this product was generated from 8b, it should be
compound A. Herein, the coupling constant of H at C3 (see the circled H below
in structures (ꢀ)-12 and A) in 1H NMR showed a trans, trans, cis coupling
constant of ddd (J¼12.4, 8.4, 4.4 Hz) pattern. From this fact, it was concluded
that product (ꢀ)-12 was generated from the cycloadduct 8a. In addition, the
other intermediates shown in Schemes 2 and 3 also showed that the coupling
constant of H at C3 matched with the trans, trans, cis type. In case of (þ)-9,
although its stereochemistry was not clear at first, the same compound (ꢀ)-12
with the same physical data after several reaction steps was obtained.
concentrated. The residuewas subjectedtocolumn chromatography
with EtOAc as eluent to give 3.4 mg (92%) of the desired product 3a.
24
[
a]
þ11.9 (c 0.072, CHCl3). 1H NMR (300 MHz, CDCl3)
d 6.38 (d,
D
J¼10.8 Hz, 1H), 6.04 (d, J¼11.2 Hz, 1H), 5.41 (s, 1H), 5.15 (s, 1H), 4.49
(d, J¼5.6 Hz, 1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H), 3.54 (m,
1H), 2.82 (dd, J¼12.3, 2.6 Hz,1H), 2.64 (dd, J¼13.2, 3.0 Hz,1H),1.22 (s,
6H), 0.87 (d, J¼7.3 Hz, 3H), 0.55 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
143.4,142.5,131.9,125.1,117.4,116.7, 81.3, 71.1, 69.9, 65.4, 56.5, 56.4,
48.9, 45.9, 44.4, 42.7, 40.5, 36.4, 36.1, 30.4, 29.4, 29.2, 29.1, 27.6, 23.6,
22.3, 20.8, 18.8, 12.1. IR (neat, cmꢀ1) 3389, 2928, 2872, 1655, 1455,
1378, 1261, 1214, 1096, 1044, 914, 797, 761. UV (MeOH) lmax 270 (
3
1831). HRMS ([MþNa]þ) calcd 495.3445, found 495.3433.
4.10. (20-Hydroxymethyl)tetrahydrofuro[1,2-a]-25-
hydroxyvitamin D3 3b (1,2-b-THF-a-CH2OH)
A solution of 70 mg (0.11 mmol) of A-ring phosphine oxide
(ꢀ)-4 in 1.5 mL of anhydrous THF was cooled to ꢀ78 ꢁC and treated
with 68 mL (0.11 mmol, 1.6 M in hexanes) of n-BuLi under argon
atmosphere. The mixture turned deep reddish and was stirred for
15 min at ꢀ78 ꢁC. To the solution was added dropwise a precooled
(ꢀ78 ꢁC) solution of 18 mg (0.055 mmol) of the C,D-ring ketone
(þ)-5 in 1.5 mL of anhydrous THF via cannula. The reaction kept
going for 7 h with the reddish orange color at ꢀ78 ꢁC, and then kept
going at ꢀ55 ꢁC for overnight (changed to colorless). The reaction
was quenched by adding 1.0 mL of pH 7 buffer (commercially
available from ALDRICH) at ꢀ78 ꢁC, then warmed to room tem-
perature, extracted with EtOAc (25 mLꢂ2), washed with brine,
dried over MgSO4, and concentrated. The residue was subjected to
column chromatography with EtOAc–hexanes (1:15) as eluent to
afford 20 mg (50%) of the coupled product as a colorless oil.
The coupled product (20 mg, 0.026 mmol) was dissolved in 2 mL
of anhydrous THF, and to the solution was added 0.31 mL
(0.31 mmol) of a 1.0 M solution of TBAF in THF. The resulting mix-
ture was stirred in darkness overnight at room temperature, then
quenched with 2 mL of water. The solution was extracted with
EtOAc (20 mLꢂ3), washed with brine, dried over MgSO4, and con-
centrated. The residue was subjected to column chromatography
with EtOAc as eluent to give 11 mg (93%) of the desired product 3b.
25
[
a]
ꢀ3.88 (c 0.35, MeOH). 1H NMR (400 MHz, CDCl3)
d 6.39 (d,
D
J¼10.8 Hz,1H), 6.07 (d, J¼11.2 Hz,1H), 5.42 (d, J¼1.6 Hz,1H), 5.20 (d,
J¼2.0 Hz, 1H), 4.44 (d, J¼4.8 Hz, 1H), 4.23 (m, 1H), 3.66–3.76 (m,
2H), 3.53 (dd, J¼11.6, 6.0 Hz, 1H), 2.82 (dd, J¼12.4, 4.0 Hz, 1H), 2.61
(dd, J¼13.6, 4.0 Hz, 1H), 1.21 (s, 6H), 0.93 (d, J¼6.4 Hz, 3H), 0.55 (s,
3H). 13C NMR (100 MHz, CDCl3)
d 143.5, 142.2, 132.1, 124.9, 117.9,
117.3, 81.9, 71.1, 70.2, 65.2, 56.5, 56.4, 49.1, 45.9, 44.3, 43.6, 40.4,
36.3, 36.1, 30.7, 29.3, 29.2, 29.0, 27.6, 23.6, 22.3, 20.8, 18.8, 12.0. IR
(neat, cmꢀ1) 3389, 2928, 2872, 1655, 1455, 1378, 1261, 1214, 1096,
CO2Me
O
CO2Me
O
O
CO2Me
O
O
O
O
1044, 914, 797, 761. UV (MeOH) lmax 270 (
3
6629). HRMS ([MþNa]þ)
OTBS
OTBS
calcd 495.3445, found 495.3422.
OTBS
8a
(+)-9
8b
Acknowledgements
CO2Me
We thank the NIH for financial support (CA 93547) and
T. Kensler and P. Dolan (Johns Hopkins University) for in vitro
antiproliferative testing, and Lindsey Hess (Johns Hopkins Univer-
sity) for measuring the UV spectrum.
CO2Me
(-)-12
TBSO
TBSO
O
O
H
H
OTBS
OTBS
(-)-12
A
References and notes
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