Page 17 of 21
The Journal of Organic Chemistry
with argon for 60 minutes and cooled to 0 °C (ice/H O bath)
14.7 Hz, 1H), 2.19 (d, J = 10.6 Hz, 1H), 1.90 (dd, J = 15.3, 12.3
Hz, 1H), 1.79 (s, 3H), 1.78 (dd, J = 14.5, 5.3 Hz, 1H), 1.53 (s,
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with stirring. 1,2ꢀDiiodoethane (200 mg, 0.71 mmol, 1.00 equiv)
was then added in separate 100 mg portions 30 minutes apart.
After the addition of the second portion, the Schlenk tube was
removed from the cooling bath, allowed to warm to ambient
temperature (ca. 23 °C), and the pale yellow solution was stirred
overnight (ca. 14 h) causing the reaction to become deep blue,
indicating the formation of SmI2.
13
3H); C NMR (CDCl , 151 MHz) δ 209.8, 173.0, 146.3, 110.8,
3
105.4, 83.8, 81.0, 80.3, 54.3, 51.8, 47.4, 47.2, 45.4, 42.4, 40.9,
37.4, 35.9, 28.6, 20.5.
1
Hydroxyketone 58: R = 0.32 (3:1 EtOAc:CH Cl eluent); H
f
2
2
NMR (CDCl , 600 MHz) δ 4.84 (dt, J = 2.8, 1.4 Hz, 1H), 4.79
3
(td, J = 7.6, 5.9, 3.5 Hz, 1H), 4.77 (br s, 1H), 3.29 (d, J = 13.5
Hz, 1H), 3.23 (d, J = 8.2 Hz, 1H), 3.16 (dd, J = 17.0, 9.4 Hz,
1H), 3.13 (dt, J = 14.7, 2.8 Hz, 1H), 2.98 (ddd, J = 13.5, 8.2, 5.9
Hz, 1H), 2.84 (dd, J = 17.0, 5.9 Hz, 1H), 2.80 (br s, 1H), 2.74–
2.62 (m, 4H), 2.31 (dd, J = 14.7, 7.0 Hz, 1H), 2.26 (t, J = 14.1
Hz, 1H), 2.12 (dd, J = 14.7, 2.9 Hz, 1H), 1.77 (s, 3H), 1.71 (dd, J
= 14.1, 12.3 Hz, 1H), 1.35 (s, 3H).
Reduction of Ketopyran 55
A reaction vessel in a nitrogenꢀfilled glovebox was charged
with LiCl (49 mg, 1.15 mmol, 19.8 equiv), sealed, removed from
the glovebox, and introduced to an argon atmosphere. To the
reaction vessel was added a solution of ketopyran 55 (20 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.058 mmol, 1.00 equiv) in THF (26 mL) followed by tꢀBuOH
(
15 L, 0.16 mmol, 1.23 equiv). The white suspension was then
sparged with argon for 1 h, reducing the reaction volume to 20
mL. The reaction solution was then cooled to –78 °C (iꢀ
PrOH/dry ice bath) at which time SmI (2.00 mL, 0.07 M in
THF, 1.08 equiv) was added slowly dropwise over 5 minutes,
dropping the SmI solution down the sides of the reaction flask.
After 15 minutes, the consumption of starting material was comꢀ
plete as determined by TLC (1:3 EtOAc:CH Cl eluent). The
reaction was quenched by the addition of saturated aqueous
NH Cl (100 L), immediately removed from the cooling bath,
and allowed to warm to ambient temperature (23 °C). The yelꢀ
low reaction mixture was filtered through a silica gel plug, elutꢀ
ing the product with 100% EtOAc. The organics were concenꢀ
trated in vacuo and the crude pale yellow solid was purified by
silica gel column chromatography (75%→85% EtOAc in
CH Cl eluent) to provide a mixture of hemiketal 57 and hyꢀ
droxyketone 58 (17 mg, 85% yield) as an amorphous white solꢀ
id. Compounds 57 and 58 were initially characterized as an inꢀ
separable mixture. Colorless, translucent Xꢀray quality crystals
of hemiketal 57 were obtained by slow diffusion of 1% benzene
in heptane into a solution of hemiketal 57 and hydroxyketone 58
in EtOAc, mp: 225–228 °C: R = 0.32 (3:1 EtOAc:CH Cl eluꢀ
ent); H NMR (CDCl , 500 MHz) δ 4.92 (dd, J = 7.0, 5.1 Hz,
1.00 H), 4.84 (dt, J = 2.8, 1.4 Hz, 2.28 H), 4.82–4.76 (m, 3.44
H), 3.63 (s, 0.90 H), 3.38 (tdd, J = 10.4, 7.0, 0.7 Hz, 0.99 H),
3
3
2
2
2
2
2
2
ent-epi-Isoineleganolide B (59), ent-Isoineleganolide C (60),
and Bisenone 61. To a heterogeneous reaction mixture of
hemiketal 57 and hydroxyketone 58 (30 mg, 0.086 mmol, 1.00
4
®
equiv) in CH Cl (6.0 mL) was added Amberlyst 15 (75 mg,
2
2
2.5 equiv by wt. to diol mixture 57 and 58) as a solid in one porꢀ
tion. After 24 h, the consumption of starting material was comꢀ
plete as determined by TLC (3:1 EtOAc:CH Cl eluent). The
2
2
2
2
heterogeneous, light yellow reaction mixture was filtered and the
organics were concentrated in vacuo. The crude yellow solid was
purified by silica gel column chromatography (30% EtOAc in
CH Cl eluent) to provide entꢀepiꢀisoineleganolide B (59, 19 mg,
2
2
63% yield) as an amorphous yellow solid, isoineleganolide C
(60, 5 mg, 17% yield) as an amorphous white solid, and biseꢀ
none 61 (3 mg, 10% yield) as an amorphous white solid. Colorꢀ
less, translucent Xꢀray quality crystals of enone 59 were obꢀ
tained by layer diffusion of a dichloromethane solution of enone
f
2
2
1
3
5
9 into diethyl ether at room temperature.
ent-epi-Isoineleganolide (59): Rf
EtOAc:CH Cl eluent); H NMR (CDCl , 600 MHz) δ 4.85 (q, J
.30 (d, J = 13.6 Hz, 1.23 H), 3.24 (d, J = 8.2 Hz, 1.23 H), 3.22–
.09 (m, 3.42 H), 3.02–2.95 (m, 2.19 H), 2.86–2.80 (m, 2.48 H),
.76–2.55 (m, 8.94 H), 2.46 (dd, J = 14.0, 10.1 Hz, 1.00 H),
.39–2.22 (m, 5.58 H), 2.19 (d, J = 10.3 Hz, 0.99 H), 2.15–2.09
B
=
0.27 (2:3
1
2
2
3
= 1.4 Hz, 1H), 4.80 (ddd, J = 7.0, 5.8, 2.8 Hz, 1H), 4.69 (br s,
1
1
H), 4.21 (d, J = 15.3 Hz, 1H), 3.90 (ddt, J = 7.4, 2.6, 1.3 Hz,
H), 3.71 (dddt, J = 18.0, 4.5, 2.7, 1.3 Hz, 1H), 3.31 (ddd, J =
(
m, 1.17 H), 1.90 (dd, J = 15.3, 12.4 Hz, 1.04 H), 1.82–1.75 (m,
7.77 H), 1.72 (dd, J = 14.3, 12.1 Hz, 1.14 H), 1.53 (s, 2.88 H),
1.35 (d, J = 1.0 Hz, 3.78 H); C NMR (CDCl , 126 MHz) δ
1
3
13.5, 7.3, 5.6 Hz, 1H), 3.08 (dq, J = 15.3, 2.7 Hz, 1H), 2.87 (d, J
12.9 Hz, 1H), 2.86 (s, 1H), 2.77 (tt, J = 9.0, 4.5 Hz, 1H), 2.71
ddd, J = 16.4, 4.7, 1.2 Hz, 1H), 2.53 (ddd, J = 16.4, 9.4, 1.2 Hz,
H), 2.45 (dddt, J = 18.2, 8.2, 2.4, 1.2, 1.2 Hz, 1H), 2.39 (dd, J =
15.3, 7.0 Hz, 1H), 2.24 (dd, J = 15.0, 2.1 Hz, 1H), 1.78 (s, 3H),
3
=
(
1
2
1
5
3
3
9
09.9, 209.1, 206.1, 174.8, 173.2, 146.5, 146.2, 111.0, 110.9,
05.6, 83.9, 81.2, 80.5, 79.3, 78.9, 75.0, 58.0, 54.4, 54.3, 52.2,
1.9, 47.6, 47.4, 46.4, 46.0, 45.6, 44.5, 42.7, 41.7, 41.1, 40.3,
8.2, 37.5, 36.1, 28.8, 24.8, 20.8, 20.7; IR (Neat Film, NaCl)
358, 2921, 1752, 1711, 1689, 1358, 1261, 1182, 1098, 1026,
13
1.30 (s, 3H); C NMR (CDCl , 126 MHz) δ 207.9, 196.5, 172.1,
3
–
1
149.7, 145.6, 128.2, 111.3, 79.5, 78.2, 59.8, 51.0, 46.2, 43.0,
42.4, 39.7, 39.5, 33.8, 25.2, 21.3; IR (Neat Film, NaCl) 3458,
36, 896, 799, 756 cm ; HRMS (MM: ESIꢀAPCI) m/z calc’d for
–
25.0
D
C H O [M–H] : 347.1500, found 347.1509; [α]
0.250, CHCl3).
+3.1° (c
19
23
6
2
1
3
960, 2923, 2854, 1767, 1709, 1662, 1438, 1377, 1262, 1139,
–1
+
038 cm ; HRMS (FAB+) m/z calc’d for C H O [M+H] :
19
23
5
Subsequently, hemiketal 57 and hydroxyketone 58 were puriꢀ
25.0
31.1545, found 331.1548; [α]D –66.3° (c 0.275, CHCl3).
ent-Isoineleganolide C (60): R = 0.73 (3:1 EtOAc:CH Cl
2
fied further for the purpose of characterization by preparative
HPLC on SiO (Agilent Zorbax RXꢀSIL, 9.4 x 250 mm, 5 ꢀm
particle size) with 40% EtOAc in CH Cl as eluent to afford pure
components hemiketal 57 and hydroxyketone 58, each as white
amorphous solids.
f
2
2
1
eluent); H NMR (CDCl , 500 MHz) δ 4.99 (t, J = 5.1 Hz, 1H),
3
2
2
4
3
.83 (q, J = 1.5 Hz, 1H), 4.77 (s, 1H), 4.01 (bt, J = 7.0 Hz, 1H),
.53 (dd, J = 14.3, 2.7 Hz, 1H), 3.22 (d, J = 8.6 Hz, 1H), 3.19 (t,
1
J = 2.9 Hz, 1H), 2.95–2.77 (m, 3H), 2.77–2.64 (m, 2H), 2.54 (dd,
J = 14.3, 10.9 Hz, 1H), 2.25 (t, J = 13.3 Hz, 1H), 2.19 (s, 3H)
Hemiketal 57: R = 0.32 (3:1 EtOAc:CH Cl eluent); H
f
2
2
NMR (CDCl , 600 MHz) δ 4.91 (dd, J = 6.8, 5.0 Hz, 1H), 4.84
3
2
1
.17 (d, J = 2.7 Hz, 1H) 1.77 (s, 3H), 1.69 (app t, J = 13.9 Hz,
(dt, J = 2.8, 1.4 Hz, 1H), 4.81 (br s, 1H), 3.57 (br s, 1H), 3.38
(td, J = 10.3, 7.0 Hz, 1H), 3.20 (dt, J = 15.3, 2.6 Hz, 1H), 3.00
(br s, 1H), 2.65 (d, J = 10.6 Hz, 1H), 2.66–2.60 (m, 2H), 2.58
(dd, J = 10.0, 6.5 Hz, 1H), 2.45 (dd, J = 13.8, 10.3 Hz, 1H), 2.36
(d, J = 15.3 Hz, 1H), 2.34 (dd, J = 14.1, 6.5 Hz, 1H), 2.32 (t, J =
13
H); C NMR (CDCl , 126 MHz) δ 205.1, 195.1, 175.0, 151.2,
3
146.5, 131.3, 110.7, 79.0, 76.3, 53.5, 53.2, 49.2, 46.2, 45.7, 42.8,
38.7, 37.9, 20.9, 16.3; IR (Neat Film, NaCl) 3355, 2922, 1750,
–1
1
712, 1679, 1626, 1372, 1260, 1184, 1017, 801 cm ; HRMS
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