Synthetic studies on soft coral norcembranolides: Total synthesis of (+)-10-epigyrosanolide e

Article abstract of DOI:10.1016/j.tet.2011.09.011

Total synthesis of (+)-10-epigyrosanolide E was accomplished employing SmI₂-mediated 5-exo cyclization of an aldehydo β-alkoxyvinyl sulfoxide and ring-closing metathesis reaction.

Full text of DOI:10.1016/j.tet.2011.09.011

Tetrahedron 67 (2011) 10179e10185
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies on soft coral norcembranolides: total synthesis of (þ)-10-
epigyrosanolide E
*
Min Sang Kwon, So Hee Sim, Young Keun Chung, Eun Lee
Department of Chemistry, College of Natural Sciences, Seoul National University NS60, Seoul 151-747, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2011
Received in revised form 11 July 2011
Accepted 6 September 2011
Available online 10 September 2011
Total synthesis of (þ)-10-epigyrosanolide E was accomplished employing SmI2-mediated 5-exo cycli-
zation of an aldehydo b-alkoxyvinyl sulfoxide and ring-closing metathesis reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Gilbert Stork on the
occasion of his 90th birthday
Keywords:
Total synthesis
Norcembranolides
10-Epigyrosanolide E
Samarium iodide
Beta-alkoxyvinyl sulfoxides
Ring-closing olefin metathesis
O
O
OH
6
1. Introduction
5
R
S
H
Z
S
O
O
8
S
S
O
O
S
Softcorals areknowntobearichsourceofcembranediterpenoids.
In particular, Sinularia spp. (family Alcyoniidae) produce a plethora of
unique norcembranolides each featuring an oxolanone unit imbed-
ded ina 14-membered carbon ring system.1 Interestingly, there are no
reports yet in the literature concerning synthesis of this class of nat-
ural products, and we wish to communicate here a total synthesis of
10-epigyrosanolide E (1), a representative member of soft coral nor-
cembranolides. 10-Epigyrosanolide E (1) was isolated from Sinularia
numerosa collected in habitats within the Archipelago of Palau by
Fenical and co-workers in 1985.1b,2 The most characteristic feature in
the structure of 1 is the substituted oxolanone structure, which is
derived from a tertiary alcohol. We intended to obtain the key
Tol
Tol
O
O
S
S
A
B
O
O
RO
RO
1 10-Epigyrosanolide E
Scheme 1. Retrosynthetic analysis.
dithiane produced tertiary alcohol 4. Reaction of 4 with (S)-alkynyl
sulfoxide 5 in the presence of ethylmagnesium bromide and lith-
ium chloride3 led to aldehydo (Z)-(S)-
b-alkoxyvinyl sulfoxide 6 af-
ter hydrolysis of the dithiane unit.
Reaction of 6 with SmI2 in THF/methanol (1:1)5 yielded effi-
ciently the (5S,6R)-hydroxyoxolane product 7, which was isolated
in 85% yield (Scheme 2). This reaction proceeded under high stereo
control and minor products were not isolated. Mitsunobu reaction
on 7 with p-nitrobenzoic acid, hydrolysis, and TBS-protection
afforded the hydroxyoxolane intermediate 8. The inversion at C-6
was necessary for efficiency in the later manipulations.6 Direct
structural element A through 5-exo cyclization of an aldehydo
alkoxyvinyl sulfoxide B. It is known3 that 5-exo cyclizations of alde-
hydo (E)- and (Z)- -alkoxyvinyl sulfoxides derived from a tertiary
alcohol proceed under sulfoxide chirality control, and synthesis of
b-
b
(5S,6R)-Arequiresuseof(Z)-(S)-b-alkoxyvinylsulfoxideB(Scheme 1).
2. Results and discussions
formation of the (5S,6S)-isomer was attempted using the (E)-(R)-b-
alkoxyvinyl sulfoxide,3 but the reaction produced the (5S,6S)-
hydroxyoxolane product in 28% yield along with the epimeric
(5S,6R)-isomer (24% yield). Aldehyde 9 was obtained from sulfoxide
In practice, the known (S)-epoxide PMP ether 34 was obtained
from 3-methyl-3-buten-1-ol (2). Reaction of 3 with lithiated
8
via Pummerer rearrangement mediated by trifluoroacetic
* Corresponding author. E-mail address: eunlee@snu.ac.kr (E. Lee).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.011

10180
M.S. Kwon et al. / Tetrahedron 67 (2011) 10179e10185
Diol 19 was obtained cleanly from 17 upon hydrolysis. The same
S
1,3-dithiane
diol 19 was prepared from 18 in 69% yield via DesseMartin oxidation
and L-selectride reduction, which proceeded with a w7:1 stereo-
selectivity. Oxidation of 19 with TEMPO and (diacetoxyiodo)ben-
zene8 afforded methylene lactone 20 in excellent yield. The crucial
ring-closing olefin metathesis reaction of 20 was successfully car-
ried out in the presence of the second generation Grubbs catalyst
and 1,4-benzoquinone providing macrocycle 21.9 Formation of in-
ternal olefin isomers from the starting material was a serious
problem in the absence of 1,4-benzoquinone. Double bond trans-
location in macrocycle 21 proceeded smoothly in the presence of
rhodium chloride in ethanol,10 which also effected global TBS-
deprotection yielding diol 22. DesseMartin oxidation of 22 pro-
duced (þ)-10-epigyrosanolide E [(1) (Fig. 1)11] in good yield12
(Scheme 4). In view of the rotation values reported by Fenical,13
the natural product should be represented as ent-1.
O
S
OH
n-BuLi
4 steps
S
S
Tol
99%
4
S
S
HO
2
PMPO
3
O
PMPO
5
1) EtMgBr, LiCl, 5
2) MeI, CaCO3
83%
O
OH
R
S
H
Z
S
SmI2
MeOH
O
O
1) PNBA
DIAD
Ph3P
S
S
S
Tol
Tol
O
O
S
S
85%
2) K2CO3
3) TBSOTf
96%
7
6
PMPO
PMPO
OTBS
O
S
Tol
OR
O
R=TBS
OR
OTBS
OTBS
H
8
TFAA;
KOAc
84%
TEMPO
1) MeOCHPPh3
2) Hg(OAc)2; KI
H
PMPO
O
O
K2CO3
100%
PhI(OAc)2
O
RO
RO
O
O
17
O
97%
82%
9
10
O
HO
PMPO
PMPO
19
20
O
OH
Scheme 2. Synthesis of hydroxyoxolane intermediates.
G2
46%
anhydride. Wittig methoxymethylenation of 9 and then mercuric
ion-catalyzed hydrolysis yielded the homologous aldehyde 10.
The primary iodide 12 was prepared from the chiral imide 117
via reaction with sodium hexamethyldisilazide and allyl bromide,
lithium borohydride reduction of the imide allylation product, and
iodide substitution. Treatment of the primary iodide 12 with
2 equiv of tert-butyllithium, and then aldehyde 10 led to the effi-
cient formation of a mixture (w3:2) of alcohols 13 and 14. Stereo-
selectivity did not improve under different reaction conditions.
TBS-protection of the hydroxyl group in 13, ceric ammonium
nitrate-mediated PMP-deprotection, and DesseMartin oxidation
provided aldehyde 15. In the presence of indium and the allylic
bromide 16, a mixture (w2:1) of secondary alcohols 17 and 18 was
obtained from aldehyde 15 (Scheme 3).
OR
O
OH
O
RhCl3
80%
DMP
88%
HO
RO
1
O
O
O
22
21
O
Scheme 4. Synthesis of (þ)-10-epigyrosanolide E (1).
O
O
N
O
11
Bn
1) NaHMDS; CH2CHCH2Br
2) LiBH4
3) I2, Ph3P, imid.
62%
OTBS
OTBS
O
I
t-BuLi;
S
R
O
HO
HO
10
Fig. 1. The structure of (þ)-10-epigyrosanolide E (1).
12
PMPO
PMPO
13 (57%)
14 (38%)
In summary, the key oxolanone fragment of (þ)-10-
epigyrosanolide E (1) was prepared through SmI2-mediated 5-exo
cyclizations of an aldehydo b-alkoxyvinyl sulfoxide. Ring-closing
olefin metathesis reaction of a methylene lactone provided the
13-membered macrocycle. A member of the soft coral norcem-
branolides is now synthesized for the first time, establishing the
absolute stereochemistry of the natural products.
OR
1) TBSOTf
2) CAN
3) DMP
84%
O
H
RO
16, In
R=TBS
OR
O
OR
O
O
15
Br
RO
RO
3. Experimental
3.1. General
HO
HO
OAc
16
17 (59%)
18 (30%)
OAc
OAc
NMR spectra were obtained on
a Varian/Oxford As-500
Scheme 3. Synthesis the triene intermediates.
(500 MHz) spectrophotometer. Chemical shift values were

M.S. Kwon et al. / Tetrahedron 67 (2011) 10179e10185
10181
recorded as parts per million relative to tetramethylsilane as an
internal standard unless otherwise indicated, and coupling con-
stants in hertz. Mass spectra were recorded on a XEOL JMS-600 W
or a XEOL JMS-700 spectrometer using fast atom bombardment
(FAB) method. Significant fragments are reported in the following
fashion: m/z (relative intensity). Optical rotation data were ob-
tained on a JASCO P-1030 automatic polarimeter.
25.3, 24.6, 21.6. IR (neat): nmax¼2932, 1613, 1508, 1231, 1085, 1035,
908, 827, 811, 738, 516 cmꢀ1. MS m/z (EI, relative intensity): 492
(Mþ, 4), 476 (8), 369 (4), 353 (6), 310 (26), 187 (60), 177 (39), 166
(12), 137 (20), 119 (100), 107 (11), 92 (6), 81 (7). HRMS (EI) calcd for
C25H32O4S3 (Mþ) 492.1463, found 492.1465. ½a 2D5
ꢃ
ꢀ211.8 (c 0.580,
CHCl3).
A stirred solution of (Z)-
b-alkoxyvinyl sulfoxide 4A (161 mg,
The progress of reaction was checked on TLC plates (Merck 5554
Kiesel gel 60 F254), and the spots were visualized under 254 nm UV
light and/or charring after dipping the TLC plate into a vanillin
solution (1.8 g of vanillin and 8.0 mL of concentrated sulfuric acid in
250 mL of methanol) or a KMnO4 solution (3 g of KMnO4, 20 g of
K2CO3, and 5 mL of 5% NaOH solution in 300 mL of water). Column
chromatography was performed on silica gel (Merck 9385 Kiesel gel
60) using hexanes/EtOAc (v/v) or hexanes/acetone (v/v). The sol-
vents were simple distilled unless otherwise noted.
Unless otherwise specified, all reactions were conducted under
a slight positive pressure of dry nitrogen. The usual work-up refers
to washing the quenched reaction mixture with brine, drying the
organic extracts over anhydrous MgSO4 or Na2SO4 and evaporating
under reduced pressure using a rotary evaporator.
0.327 mmol), CH3I (1.02 mL, 16.4 mmol), and CaCO3 (818 mg,
8.18 mmol) in CH3CN (26 mL) and H2O (7 mL) was heated to 40 ꢁC.
After stirring for 12 h, the reaction was quenched by addition of
satd NH4Cl solution (10 mL) at room temperature. The reaction
mixture was extracted with EtOAc (25 mLꢂ3). The organic extracts
were dried over MgSO4, filtered, and concentrated. The crude
aldehydo (Z)-
subjected to further purification. Rf 0.18 (hexanes/acetone, 2:1). 1H
NMR (500 MHz, CDCl3):
b-alkoxyvinyl sulfoxide 6 (132 mg, 100%) was not
d
9.87 (t, J¼2.2 Hz, 1H), 7.50 (d, J¼8.2 Hz,
2H), 7.25 (d, J¼7.9 Hz, 2H), 6.85 (d, J¼5.6 Hz,1H), 6.85e6.78 (m, 4H),
5.53 (d, J¼5.6 Hz,1H), 4.10e4.01 (m, 2H), 3.77 (s, 3H), 2.92e2.80 (m,
2H), 2.39 (s, 3H), 2.31e2.20 (m, 2H), 1.58 (s, 3H). 13C NMR (125 MHz,
CDCl3):
d 199.5, 154.3, 152.5, 146.4, 142.4, 141.1, 130.1, 124.1, 116.0,
115.4, 114.9, 81.1, 63.6, 55.9, 52.4, 38.4, 25.1, 21.6. IR (neat):
nmax¼3335, 2925, 2651, 1723, 1672, 1614, 1509, 1384, 1231, 1085,
1036, 827, 811, 729, 514 cmꢀ1. MS m/z (FAB, relative intensity): 403
(Mþþ1, 10), 337 (3), 307 (3), 282 (7), 220 (3), 211 (11), 183 (12), 154
(32), 136 (25), 95 (53), 69 (85), 55 (100), 43 (61), 29 (12). HRMS
Solvents used in reaction were dried under nitrogen atmo-
sphere. THF was distilled from sodium-benzophenone and CH2Cl2
was distilled from P2O5. Et2O was distilled from LAH.
3.1.1. Alcohol 4. n-BuLi (2.5 M in hexane, 1.32 mL, 3.29 mmol) was
added to a solution of 1,3-dithiane (424 mg, 3.53 mmol) in THF
(18 mL) at ꢀ20 ꢁC under argon. After 1 h, the solution was treated
with a solution of epoxide 3 (508 mg, 2.35 mmol) in THF (5 mL) and
allowed to warm to room temperature. After stirring for 1 h, the
reaction was quenched by addition of satd NH4Cl solution (10 mL).
The reaction mixture was extracted with Et2O (20 mLꢂ3). The or-
ganic extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography (hex-
anes/EtOAc, 5:1) provided the tertiary alcohol 4 (761 mg, 99%). Rf
(FAB) calcd for C22H27O5S (Mþþ1) 403.1579, found 403.1579. ½a 2D5
ꢃ
þ70.9 (c 0.520, CHCl3).
3.1.3. Hydroxyoxolane 7. To a solution of aldehydo (Z)-b-alkox-
yvinyl sulfoxide 6 (1.02 g, 2.53 mmol) in THF (12.5 mL) and MeOH
(12.5 mL) was added a 0.1 M solution of SmI2 in THF (53 mL,
5.31 mmol) at 0 ꢁC under argon. After stirring for 10 min, the
mixture was diluted with EtOAc (10 mL) and washed with H2O
(10 mLꢂ2). The aqueous layer was extracted with EtOAc (20 mLꢂ3),
and the combined organic extracts were dried over MgSO4 and
evaporated in vacuo. The residue was purified by flash column
chromatography (hexanes/acetone, 5:1) to give hydroxyoxolane 7
(870 mg, 85%). Rf 0.30 (hexanes/acetone, 2:1). 1H NMR (500 MHz,
0.26 (hexanes/EtOAc, 2:1). 1H NMR (500 MHz, CDCl3):
d 6.86e6.82
(m, 4H), 4.27e4.25 (t, J¼6.9 Hz, 1H), 4.16e4.09 (m, 2H), 3.77 (s, 3H),
2.98 (s, 1H), 2.96e2.91 (m, 2H), 2.87e2.83 (m, 2H), 2.13e1.96 (m,
5H), 1.94e1.85 (m, 1H), 1.34 (s, 3H). 13C NMR (125 MHz, CDCl3):
CDCl3):
d
7.52 (d, J¼8.2 Hz, 2H), 7.34 (d, J¼8.2 Hz, 2H), 6.86e6.81 (m,
d
154.1, 152.9, 115.6, 114.8, 77.3, 65.3, 55.8, 47.5, 42.3, 40.7, 30.4, 27.3,
4H), 4.50e4.45 (m, 1H), 4.19 (d, J¼6.8 Hz, 1H), 4.13e4.07 (m, 3H),
3.76 (s, 3H), 3.38 and 3.19 (ABX, JAB¼14.0 Hz, JAX¼8.5 Hz, JBX¼3.2 Hz,
2H), 2.43 (s, 3H), 2.22e2.13 (m, 2H), 2.15e2.08 (m, 2H), 1.21 (s, 3H).
25.5. IR (neat): nmax¼3463, 2930, 2898, 1509, 1465, 1231, 1038, 900,
729, 626 cmꢀ1. MS m/z (EI, relative intensity): 328 (Mþ, 23), 310 (5),
205 (100), 194 (7), 187 (27), 178 (9), 163 (9), 159 (11), 145 (7), 137
(17), 124 (42), 119 (27), 109 (13), 101 (10), 81 (7), 75 (29), 61 (5), 55
(4). HRMS (EI) calcd for C16H24O3S2 (Mþ) 328.1167, found 328.1169.
13C NMR (125 MHz, CDCl3):
d 153.9, 153.1, 141.9, 138.6, 130.3, 124.3,
115.6, 114.8, 81.6, 76.6, 73.3, 65.2, 55.9, 55.3, 46.1, 40.7, 26.6, 21.6. IR
(neat): nmax¼3378, 2927, 1735, 1593, 1509, 1443, 1397, 1232, 1085,
1038, 826, 812, 739, 505 cmꢀ1. MS m/z (EI, relative intensity): 404
(Mþ, 21), 388 (52), 281 (44), 265 (47), 194 (5), 177 (25), 137 (100),
124 (80), 97 (17), 84 (20), 69 (23), 55 (10). HRMS (EI) calcd for
½
a 2D5
ꢃ
þ12.5 (c 0.805, CHCl3).
3.1.2. Aldehydo (Z)- -alkoxyvinyl sulfoxide 6. Ethylmagnesium
b
bromide (3.0 M in Et2O, 0.734 mL, 2.20 mmol) was added to a so-
lution of tertiary alcohol 4 (761 mg, 2.32 mmol) and lithium chlo-
ride (492 mg, 11.6 mmol) in THF (20 mL) at room temperature
under argon. After stirring for 5 min, (þ)-(S)-ethynyl p-tolyl sulf-
oxide 5 (419 mg, 2.55 mmol) in THF (3 mL) was added dropwise.
After stirring for 12 h at room temperature, the reaction was
quenched by addition of satd NH4Cl solution (10 mL). The reaction
mixture was extracted with EtOAc (20 mLꢂ3). The organic extracts
were dried over MgSO4, filtered, and concentrated. Purification of
the residue by flash column chromatography (hexanes/acetone,
C22H28O5S (Mþ) 404.1657, found 404.1652. ½a 2D5
ꢀ73.2 (c 0.245,
ꢃ
CHCl3).
3.1.4. Hydroxyoxolane derivative 8. DIAD (1.06 mL, 5.38 mmol) was
added dropwise to a solution of hydroxyoxolane 7 (870 mg,
2.15 mmol), p-nitrobenzoic acid (899 mg, 5.38 mmol), and PPh3
(1.41 g, 5.38 mmol) in toluene (21 mL) at room temperature under
argon. After stirring for 1 h, the reaction mixture was concentrated
and the residue was purified by flash column chromatography to
provide p-nitrobenzoate 7A (1.16 g,100%). Rf 0.37 (hexanes/acetone,
2:1).
K2CO3 (298 mg, 2.15 mmol) was added to a solution of p-
nitrobenzoate 7A (1.16 g, 2.15 mmol) in MeOH (20 mL) at room
temperature. After stirring for 1 h, the reaction was quenched by
addition of satd NH4Cl solution (10 mL). The reaction mixture was
extracted with EtOAc (20 mLꢂ3). The organic extracts were dried
over MgSO4, filtered, and concentrated. Purification of the residue
by flash column chromatography (hexanes/acetone, 5:1) provided
5:1) provided (Z)-
b
-alkoxyvinyl sulfoxide 4A (946 mg, 83%). Rf 0.25
7.53 (d,
(hexanes/acetone, 2:1). 1H NMR (500 MHz, CDCl3):
d
J¼8.2 Hz, 2H), 7.24 (d, J¼8.0 Hz, 2H), 6.82 (s, 4H), 6.79 (d, J¼5.5 Hz,
1H), 5.47 (d, J¼5.5 Hz, 1H), 4.24 (t, J¼5.7 Hz, 1H), 4.04 (t, J¼6.5 Hz,
2H), 3.77 (s, 3H), 3.02e2.94 (m, 2H), 2.83e2.80 (m, 2H), 2.38 (s, 3H),
2.28e2.15 (m, 2H), 2.14e2.04 (m, 3H), 1.88e1.79 (m, 1H), 1.52 (s,
3H). 13C NMR (125 MHz, CDCl3):
d
154.1, 152.7, 146.8, 142.8, 140.8,
129.9, 124.2, 115.5, 115.2, 114.9, 82.4, 63.9, 55.9, 45.7, 41.9, 38.7, 31.4,

10182
M.S. Kwon et al. / Tetrahedron 67 (2011) 10179e10185
the alcohol 7B (868 mg, 100%). Rf 0.24 (hexanes/acetone, 2:1). 1H
NMR (500 MHz, CDCl3):
(240 mg, 0.608 mmol) in THF (2 mL). The reaction mixture was
stirred for 1 h at 0 ꢁC. The reaction was quenched by addition of satd
NaHCO3 solution (5 mL) and the product mixture was extracted
with Et2O (10 mLꢂ3). The organic phase was dried over MgSO4,
filtered, and concentrated. The crude enol ether was dissolved in
THF (12 mL) and H2O (1.2 mL) then cooled to 0 ꢁC. Mercuric acetate
(194 mg, 0.608 mmol) was added to the solution in one portion and
the mixture was stirred for 30 min at 0 ꢁC, and then treated with
satd KI solution (10 mL). The reaction mixture was extracted with
Et2O (10 mLꢂ3), and the organic phase was dried over MgSO4, fil-
tered, and concentrated. Flash column chromatography (hexanes/
EtOAc, 10:1) provided aldehyde 10 (203 mg, 82%). Rf 0.55 (hexanes/
d
7.47 (d, J¼8.2 Hz, 2H), 7.35 (d, J¼8.2 Hz,
2H), 6.82 (m, 4H), 5.05 (d, J¼1.9 Hz, 1H), 4.22e4.17 (m, 1H),
4.00e3.96 (m, 2H), 3.77 (s, 3H), 3.77e3.73 (m, 1H), 3.32 and 3.02
(ABX, JAB¼14.0 Hz, JAX¼9.6 Hz, JBX¼2.9 Hz, 2H), 2.43 (s, 3H),
1.97e1.94 (m, 2H), 1.27 (s, 3H). 13C NMR (125 MHz, CDCl3):
d 154.0,
153.1, 141.8, 137.4, 130.3, 124.6, 115.5, 114.9, 82.5, 78.7, 76.0, 65.0,
57.0, 55.9, 45.3, 41.6, 27.7, 21.7. IR (neat): nmax¼3354, 2929, 1734,
1509, 1444, 1377, 1231, 1180, 1085, 1038, 827, 739, 506 cmꢀ1. MS m/z
(EI, relative intensity): 420 (14), 404 (Mþ, 61), 388 (26), 281 (100),
265 (26), 177 (33), 137 (87), 124 (84), 109 (18), 95 (20), 69 (15), 55
(5). HRMS (EI) calcd for C22H28O5S (Mþ) 404.1657, found 404.1660.
½
a 2D5
2,6-Lutidine (0.300 mL, 2.58 mmol) and TBSOTf (0.474 mL,
ꢃ
ꢀ75.1 (c 0.895, CHCl3).
EtOAc, 4:1). 1H NMR (500 MHz, CDCl3):
d
9.78 (t, J¼2.5 Hz, 1H), 6.83
(m, 4H), 4.20e4.16 (m, 1H), 4.05e3.94 (m, 3H), 3.77 (s, 3H),
2.66e2.60 (m, 1H), 2.54e2.48 (m, 1H), 2.30 and 1.74 (ABX,
JAB¼12.8 Hz, JAX¼7.4 Hz, JBX¼6.0 Hz, 2H), 1.97 (t, J¼6.6 Hz, 2H), 1.39
(s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR (125 MHz,
2.06 mmol) were added to a solution of alcohol 7B (694 mg,
1.72 mmol) in CH2Cl2 (18 mL) at 0 ꢁC under argon. This reaction
mixture was stirred for 2 h and the reaction was quenched by ad-
dition of H2O (10 mL). The reaction mixture was extracted with
Et2O (40 mLꢂ3) and the organic phase was washed with brine
(10 mL), dried over MgSO4, filtered, and concentrated. Purification
of the residue by flash column chromatography (hexanes/EtOAc,
5:1) gave the hydroxyoxolane derivative 8 (853 mg, 96%). Rf 0.68
CDCl3):
d 201.2, 153.9, 153.1, 115.4, 114.9, 81.9, 79.3, 76.7, 64.9, 55.9,
47.5, 46.1, 41.6, 27.7, 25.9, 18.1, ꢀ4.4, ꢀ4.7. IR (neat): nmax¼2954,
2930, 2857, 2729, 1728, 1509, 1472, 1389, 1232, 1117, 1041, 837,
778 cmꢀ1. MS m/z (EI, relative intensity): 408 (Mþ, 52), 333 (4), 241
(4), 215 (4), 209 (8), 195 (18), 183 (9), 177 (100), 157 (25), 137 (28),
131 (18), 124 (36), 109 (24), 101 (10), 81 (7), 73 (31), 69 (15). HRMS
(hexanes/EtOAc, 2:1). 1H NMR (500 MHz, CDCl3):
d
7.57 (d, J¼8.2 Hz,
2H), 7.32 (d, J¼7.9 Hz, 2H), 6.84 (s, 4H), 4.31e4.28 (m, 1H),
4.09e4.01 (m, 2H), 3.77 (s, 3H), 3.76e3.73 (m, 1H), 3.12 and 2.91
(ABX, JAB¼13.0 Hz, JAX¼6.8 Hz, JBX¼4.4 Hz, 2H), 2.41 (s, 3H), 2.32
and 1.69 (ABX, JAB¼12.8 Hz, JAX¼7.4 Hz, JBX¼5.6 Hz, 2H), 2.03 (t,
J¼6.6 Hz, 2H), 1.36 (s, 3H), 0.82 (s, 9H), 0.02 (s, 6H). 13C NMR
(EI) calcd for C22H36O5Si (Mþ) 408.2332, found 408.2332. ½a 2D5
ꢃ
þ27.5 (c 0.790, CHCl3).
3.1.6. Iodide 12. NaHMDS (1.0 M in THF, 11.4 mL, 11.37 mmol) was
added to a solution of imide 11 (2.68 g, 10.33 mmol) in THF (35 mL)
at ꢀ78 ꢁC under argon. After 1 h, the solution was treated with allyl
bromide (1.89 mL, 20.66 mmol) at ꢀ78 ꢁC and then stirred for 5 h at
the same temperature. The reaction was quenched by addition of
satd NH4Cl solution and the reaction mixture was extracted with
Et2O. The extracts were dried over MgSO4, filtered, and concen-
trated. Purification of the residue by flash column chromatography
(hexanes/EtOAc, 10:1) provided imide 11A (2.21 g, 71%). Rf 0.41
(125 MHz, CDCl3):
d 153.9, 153.1, 141.8, 140.8, 130.1, 124.6, 115.4,
114.8, 82.5, 79.6, 76.2, 64.9, 61.1, 55.9, 46.1, 41.5, 27.4, 25.9, 21.6, 18.0,
ꢀ4.46, ꢀ4.67. IR (neat): nmax¼2954, 2929, 2856, 1509, 1471, 1376,
1231, 1121, 1042, 837, 778 cmꢀ1. MS m/z (EI, relative intensity): 518
(Mþ, 21), 502 (44), 477 (18), 461 (74), 445 (100), 395 (19), 379 (16),
222 (14), 177 (38), 137 (69), 115 (18), 73 (48), 57 (28). HRMS (EI)
calcd for C28H42O5SiS (Mþ) 518.2522, found 518.2515. ½a 2D5
ꢀ6.53 (c
ꢃ
0.49, CHCl3).
(hexanes/EtOAc, 4:1). 1H NMR (500 MHz, CDCl3):
d 7.36e7.31 (m,
2H), 7.30e7.26 (m, 1H), 7.24e7.20 (m, 2H), 5.87e5.78 (m, 1H), 5.13
(dd, J¼17.2, 1.6 Hz, 1H), 5.03 (dd, J¼10.2, 1.0 Hz, 1H), 4.90 (s, 2H),
4.68e4.63 (m, 1H), 4.56 (dd, J¼8.9, 5.7 Hz, 1H), 4.17e4.12 (m, 2H),
3.30 and 2.74 (ABX, JAB¼13.4 Hz, JAX¼9.7 Hz, JBX¼3.2 Hz, 2H),
2.70e2.64 (m, 1H), 2.44e2.37 (m, 1H), 1.82 (s, 3H). 13C NMR
3.1.5. Aldehyde 10. To a solution of hydroxyoxolane derivative 8
(863 mg, 1.66 mmol) in CH3CN (33 mL) was added pyridine
(0.270 mL, 3.32 mmol) and trifluoroacetic anhydride (0.470 mL,
3.32 mmol) at 0 ꢁC under argon. After stirring for 1 h, H2O (0.85 mL)
and potassium acetate (815 mg, 8.30 mmol) were added. The re-
action mixture was then allowed to warm up to room temperature.
After stirring for 12 h, the reaction mixture was partitioned be-
tween H2O (15 mL) and Et2O (30 mL). The organic layer was sep-
arated, and the aqueous layer was extracted with Et2O (30 mLꢂ2).
The combined organic layers were washed with brine (10 mL),
dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (hexanes/
EtOAc, 8:1) to give aldehyde 9 (554 mg, 84%). Rf 0.32 (hexanes/
(125 MHz, CDCl3):
d 173.0, 153.2, 142.8, 135.7, 135.5, 129.6, 129.0,
127.4, 116.9, 113.9, 65.9, 55.8, 49.8, 38.1, 35.1, 21.4. IR (neat):
nmax¼3078, 2923,1782, 1698, 1642, 1386, 1366, 1208, 1099, 912, 748,
702 cmꢀ1. MS m/z (EI, relative intensity): 299 (Mþ, 22), 284 (12),
258 (48), 208 (10), 178 (20), 122 (100), 95 (65), 79 (36), 55 (14).
HRMS (EI) calcd for C18H21O3N (Mþ) 299.1521, found 299.1523. ½a 2D5
ꢃ
ꢀ98.6 (c 0.740, CHCl3).
LiBH4 (2.0 M in THF, 9.72 mL,19.4 mmol) was added to a solution
of imide 11A (1.94 g, 6.48 mmol) and catalytic amount of EtOH
(0.7 mL) in Et2O (65 mL) at 0 ꢁC under argon. After stirring for 1 h,
the reaction was quenched by addition of satd NH4Cl solution at
EtOAc, 4:1). 1H NMR (500 MHz, CDCl3):
d
9.65 (d, J¼1.3 Hz, 1H), 6.83
(s, 4H), 4.48e4.45 (m, 1H), 4.26 (q, J¼1.7 Hz, 1H), 4.13e4.01 (m, 2H),
3.77 (s, 3H), 2.11 and 1.87 (ABX, JAB¼13.0 Hz, JAX¼6.8 Hz, JBX¼3.4 Hz,
2H), 2.06 (t, J¼7.9 Hz, 2H), 1.47 (s, 3H), 0.89 (s, 9H), 0.07 (s, 6H). 13C
0
ꢁC. The reaction mixture was extracted with Et2O. The extracts
were dried over MgSO4, filtered, and concentrated. Purification of
the residue by flash column chromatography (hexanes/EtOAc, 15:1)
provided the alcohol 11B (799 mg, 98%). Rf 0.57 (hexanes/EtOAc,
NMR (125 MHz, CDCl3): d 201.5, 154.0, 152.9, 115.4, 114.8, 90.7, 84.6,
74.9, 64.9, 55.9, 46.8, 41.4, 26.7, 25.8, 18.0, ꢀ4.7, ꢀ4.8. IR (neat):
nmax¼2954, 2930, 2657, 1736, 1509, 1471, 1232, 1180, 1041, 829, 778,
522 cmꢀ1. MS m/z (EI, relative intensity): 394 (Mþ, 18), 319 (5), 227
(2), 213 (5), 203 (4), 177 (100), 145 (30), 137 (35), 124 (34), 117 (18),
109 (11), 84 (12), 75 (25), 73 (25). HRMS (EI) calcd for C21H34O5Si
4:1). 1H NMR (500 MHz, CDCl3):
d 5.79e5.70 (m, 1H), 5.08e4.99 (m,
2H), 4.95 (s, 1H), 4.83 (s, 1H), 3.61e3.49 (m, 2H), 2.39e2.32 (m, 1H),
2.16 (t, J¼7.2 Hz, 2H), 1.70 (s, 3H), 1.38 (dd, J¼7.5, 4.7 Hz, 1H). 13C
NMR (125 MHz, CDCl3):
d 145.0, 136.6, 116.2, 113.7, 63.7, 49.5, 34.3,
(Mþ) 394.2176, found 394.2179. ½a 2D5
ꢃ
þ28.1 (c 0.485, CHCl3).
19.6. IR (neat): nmax¼3364, 2930, 1748, 1265, 1054, 911, 837,
Potassium tert-butoxide (1.0 M in THF, 1.52 mL, 1.52 mmol) was
added to a solution of (methoxymethyl)triphenylphosphonium
chloride (626 mg, 1.82 mmol) in THF (10 mL) at 0 ꢁC under argon.
The resulting red solution was stirred for 1 h at the same temper-
ature, followed by dropwise addition of a solution of aldehyde 9
738 cmꢀ1
½
a 2D5
ꢃ
ꢀ2.2 (c 0.835, CHCl3).
To a solution of alcohol 11B (602 mg, 4.77 mmol) in THF (48 mL)
was added imidazole (810 mg, 11.9 mmol) and PPh3 (3.12 g,
11.9 mmol), followed by I2 (3.02 g, 11.9 mmol) at 0 ꢁC. After stirring
for 2 h, the reaction was quenched by addition of H2O at 0 ꢁC. The

M.S. Kwon et al. / Tetrahedron 67 (2011) 10179e10185
10183
reaction mixture was extracted with Et2O. The extracts were dried
over MgSO4, filtered, and concentrated. Purification of the residue
by flash column chromatography (pentanes/Et2O, 10:1) gave iodide
12 (1.02 g, 90%). Rf 0.83 (hexanes/EtOAc, 4:1). 1H NMR (500 MHz,
3.85e3.79 (m, 2H), 3.77 (s, 3H), 3.73e3.70 (m, 1H), 2.42e2.36 (m,
1H), 2.20e2.16 (m, 1H), 2.10e2.08 (m, 2H), 1.94e1.91 (m, 2H),
1.70e1.63 (m, 3H),1.62 (s, 3H),1.58e1.52 (m, 1H),1.42e1.37 (m, 1H),
1.32 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H), 0.02 (s, 6H). 13C
CDCl3):
d
5.72e5.64 (m, 1H), 5.10e5.02 (m, 2H), 4.92 (t, J¼1.5 Hz,
NMR (125 MHz, CDCl3): d 154.0, 153.3, 147.1, 137.6, 115.5, 115.4,
1H), 4.76 (t, J¼0.8 Hz, 1H), 3.28 and 3.19 (ABX, JAB¼9.9 Hz,
114.9, 112.1, 80.9, 80.5, 78.0, 68.6, 65.2, 55.9, 46.7, 43.4, 42.8, 42.0,
39.4, 39.1, 27.5, 26.3, 26.0, 18.8, 18.3, 18.2, ꢀ3.5, ꢀ4.1, ꢀ4.4, ꢀ4.5. IR
(neat): nmax¼3075, 2955, 2930, 2857, 1643, 1509, 1472, 1375, 1252,
1231, 1108, 712, 890, 775, 671 cmꢀ1. MS m/z (EI, relative intensity):
632 (Mþ, 17), 575 (4), 521 (10), 443 (42), 383 (23), 365 (13), 329
(12), 291 (75), 251 (23), 189 (100), 177 (50), 159 (38), 137 (18), 121
(51), 93 (21), 73 (75). HRMS (EI) calcd for C36H64O5Si2 (Mþ)
JAX¼7.4 Hz, JBX¼6.0 Hz, 2H), 2.39e2.18 (m, 3H),1.68 (s, 3H). 13C NMR
(125 MHz, CDCl3): d 145.1, 136.0, 116.9, 113.4, 48.8, 37.7, 19.6, 11.1. IR
(neat): nmax¼3076, 2973, 2925,1642,1439,1375,1180, 992, 916, 897,
602 cmꢀ1. MS m/z (CI, relative intensity): 253(25), 235 (Mþꢀ1, 29),
217 (5), 199 (5), 181 (2), 157 (3), 143 (35), 127 (100), 109 (6), 91 (87),
71 (16), 57 (1). HRMS (CI) calcd for C8H12I (Mþꢀ1) 234.9984, found
234.9978. ½a 2D5
ꢃ
þ2.9 (c 1.02, CHCl3).
632.4292, found 632.4286. ½a D25
þ38.3 (c 0.260, CHCl3).
ꢃ
CAN (1.17 g, 2.14 mmol) was added to a solution of 13A (452 mg,
0.714 mmol) in CH3CN (30 mL) and H2O (3 mL) at 0 ꢁC. After stirring
at room temperature for 5 min, the mixture was diluted with EtOAc
(30 mL) and washed with satd NaHCO3 solution (30 mL). The
aqueous layer was extracted with EtOAc (30 mLꢂ3), and the com-
bined organic extracts were dried over MgSO4 and evaporated in
vacuo. The crude product alcohol 13B was used without further
purification.
DesseMartin periodinane (454 mg, 1.07 mmol) was added to
a solution of crude product alcohol 13B in CH2Cl2 (10 mL). The re-
action mixture was stirred at room temperature for 30 min and the
reaction was quenched by addition of satd Na2S2O3 solution (10 mL).
The reaction mixture was extracted with CH2Cl2 (20 mLꢂ3). The
organic extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography (hex-
anes/EtOAc, 20:1) gave aldehyde 15 (332 mg, 88%, two steps). Rf 0.85
3.1.7. Alcohols 13 and 14. To a solution of iodide 12 (592 mg,
2.51 mmol) in Et2O (20 mL) at ꢀ80 ꢁC was added t-BuLi (1.7 M in
pentane, 2.95 mL, 5.02 mmol) dropwise over 10 min under argon.
After 1 h, the solution was treated with a solution of aldehyde 10
(640 mg, 1.57 mmol) in THF (5 mL) and allowed to warm to room
temperature. After stirring for 1 h, the reaction was quenched by
addition of satd NH4Cl solution (10 mL). The reaction mixture was
extracted with Et2O (20 mLꢂ2). The organic extracts were dried
over MgSO4, filtered, and concentrated. Purification of the residue
by flash column chromatography (hexanes/EtOAc, 25:1) provided
alcohols 13 (463 mg, 57%) and 14 (306 mg, 38%). (13) Rf 0.61
(hexanes/EtOAc, 4:1). 1H NMR (500 MHz, CDCl3):
d 6.82 (s, 4H),
5.75e5.70 (m, 2H), 5.02e4.95 (m, 1H), 4.81e4.80 (m, 1H), 4.78 (s,
1H), 4.04e3.92 (m, 2H), 3.88e3.84 (m, 2H), 3.80e3.76 (m, 1H), 3.77
(s, 3H), 3.53 (s,1H), 2.51e2.45 (m,1H), 2.28e2.24 (m,1H), 2.13e2.09
(m, 2H), 2.00e1.91 (m, 2H), 1.74e1.70 (m, 1H), 1.69e1.65 (m, 1H),
1.64 (s, 3H), 1.55e1.50 (m, 1H), 1.46e1.39 (m, 2H), 1.39 (s, 3H), 0.87
(hexanes/EtOAc, 4:1). 1H NMR (500 MHz, CDCl3):
d
9.77 (t, J¼2.8 Hz,
1H), 5.75e5.67 (m,1H), 5.01e4.95 (m, 2H), 4.78 (t, J¼1.8 Hz,1H), 4.70
(d, J¼2.0 Hz, 1H), 3.90e3.86 (m, 1H), 3.81e3.76 (m, 2H), 2.56e2.46
(m, 2H), 2.41e2.35 (m, 1H), 2.10e2.07 (m, 3H), 1.78e1.74 (m, 1H),
1.72e1.66 (m, 1H), 1.64e1.61 (m, 1H), 1.62 (s, 3H), 1.59e1.52 (m, 1H),
1.43e1.38 (m, 1H), 1.39 (s, 3H), 0.88 (s, 18H), 0.05 (s, 3H), 0.04 (s, 3H),
(s, 9H), 0.03 (s, 3H), 0.01 (s, 3H). 13C NMR (125 MHz, CDCl3):
d 154.0,
153.1, 147.0, 137.5, 115.6, 115.4, 114.8, 112.3, 84.3, 82.1, 77.6, 69.4,
64.9, 55.9, 46.1, 43.5, 41.7, 41.3, 40.9, 39.0, 27.6, 26.0, 18.7, 18.1, ꢀ4.4,
ꢀ4.7. IR (neat): nmax¼3519, 3073, 2930, 2857, 1737, 1642, 1509, 1472,
1231, 1122, 1042, 836, 777 cmꢀ1. MS m/z (EI, relative intensity): 518
(Mþ, 39), 422 (4), 307 (5), 279 (3), 251 (7), 233 (6), 215 (8), 181 (12),
177 (100), 139 (20), 137 (23), 124 (34), 109 (14), 81 (20), 73 (42), 55
(13). HRMS (EI) calcd for C30H50O5Si (Mþ) 518.3428, found
0.03 (s, 6H). 13C NMR (125 MHz, CDCl3):
d 202.7, 147.0, 137.6, 115.5,
112.2,110.0, 81.5, 80.1, 77.7, 68.3, 55.8, 46.6, 43.3, 42.6, 39.3, 39.1, 27.8,
26.2, 26.0, 18.8, 18.3, 18.2, ꢀ3.6, ꢀ4.2, ꢀ4.4, ꢀ4.5. IR (neat):
nmax¼3076, 2956, 2930, 2857, 1726, 1643, 1473, 1375, 1255, 1124,
1068, 836, 775, 665 cmꢀ1. MS m/z (CI, relative intensity): 509 (Mþþ1,
10), 481 (17), 467 (8), 415 (13), 393 (22), 377 (19), 349 (61), 329 (59),
291 (42), 257 (100), 217 (96), 189 (21), 159 (26), 121 (36), 95 (20), 73
(13), 57 (7). HRMS (CI) calcd for C29H57O4Si2 (Mþþ1) 525.3795, found
518.3427. ½a 2D5
ꢃ
þ26.1 (c 0.480, CHCl3). (14) Rf 0.56 (hexanes/EtOAc,
4:1). 1H NMR (500 MHz, CDCl3):
d
6.82 (s, 4H), 5.73e5.65 (m, 1H),
5.02e4.95 (m, 2H), 4.75 (t, J¼1.7 Hz, 1H), 4.72 (s, 1H), 4.05e4.01 (m,
1H), 3.99e3.95 (m, 3H), 3.81e3.78 (m, 1H), 3.77 (s, 3H), 3.09 (d,
J¼4.9 Hz, 1H), 2.27e2.21 (m, 2H), 2.16e2.08 (m, 2H), 1.99e1.96 (m,
2H),1.78e1.68 (m, 2H),1.66 (s, 3H),1.66e1.62 (m,1H),1.53e1.48 (m,
2H), 1.38 (s, 3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR
525.3799. ½a 2D5
þ38.0 (c 0.295, CHCl3).
ꢃ
3.1.9. Diol 19. In powder (72 mg, 0.624 mmol) was added to a so-
lution of aldehyde 15 (218 mg, 0.416 mmol) and allylic bromide 16
(120 mg, 0.624 mmol) in THF (2.1 mL) and satd NH4Cl solution
(6.2 mL) at room temperature. After 12 h, the reaction mixture was
diluted with H2O (5 mL) and extracted with Et2O (10 mLꢂ3). The
organic extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography (hex-
anes/EtOAc, 18:1) gave the secondary alcohols 17 (157 mg, 59%) and
18 (79 mg, 30%). Compound (17) Rf 0.68 (hexanes/EtOAc, 4:1).
Compound (18) Rf 0.64 (hexanes/EtOAc, 4:1).
(125 MHz, CDCl3):
d 154.0, 153.1, 147.8, 137.1, 115.9, 115.4, 114.9,
112.0, 82.1, 81.9, 77.0, 67.9, 65.0, 56.0, 46.5, 44.4, 41.8, 40.1, 38.7,
38.3, 27.3, 26.0, 18.6, 18.1, ꢀ4.3, ꢀ4.6. IR (neat): nmax¼3501, 3073,
2930, 2857, 1643, 1509, 1472, 1375, 1231, 1117, 1042, 836, 777,
734 cmꢀ1. MS m/z (EI, relative intensity): 518 (Mþ, 40), 307 (5), 251
(8), 233 (7), 215 (8), 195 (8), 177 (100), 159 (12), 139 (24), 124 (35),
109 (16), 95 (21), 73 (44), 57 (14). HRMS (EI) calcd for C30H50O5Si
(Mþ) 518.3428, found 518.3420. ½a 2D5
þ21.1 (c 0.510, CHCl3).
ꢃ
3.1.8. Aldehyde 15. 2,6-Lutidine (0.137 mL, 1.18 mmol) and TBSOTf
(0.217 mL, 0.944 mmol) were added to a solution of alcohol 13
(408 mg, 0.786 mmol) in CH2Cl2 (8 mL) at 0 ꢁC under argon. This
reaction mixture was stirred for 2 h and the reaction was quenched
by addition of H2O (10 mL). The reaction mixture was extracted
with Et2O (10 mLꢂ3) and the organic phase was washed with brine,
dried over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (hexanes/EtOAc, 20:1)
gave the 13A (475 mg, 95%). Rf 0.88 (hexanes/EtOAc, 4:1). 1H NMR
K2CO3 (34 mg, 0.246 mmol) was added to a solution of the
secondary alcohol 17 (157 mg, 0.246 mmol) in MeOH (2.5 mL) at
room temperature. After stirring for 1 h, the reaction was quenched
by addition of satd NH4Cl solution (5 mL). The reaction mixture was
extracted with Et2O (10 mLꢂ3). The organic extracts were dried
over MgSO4, filtered, and concentrated. Purification of the residue
by flash column chromatography (hexanes/EtOAc, 8:1) provided
diol 19 (147 mg, 100%). Rf 0.31 (hexanes/EtOAc, 4:1) 1H NMR
(500 MHz, CDCl3):
d
5.74e5.66 (m, 1H), 5.07 (d, J¼1.3 Hz, 1H),
(500 MHz, CDCl3):
d
6.82 (s, 4H), 5.75e5.67 (m, 1H), 5.00e4.94 (m,
5.01e4.95 (m, 2H), 4.90 (s, 1H), 4.80 (t, J¼1.7 Hz, 1H), 4.70 (s, 1H),
4.58 (s, 1H), 4.16e4.11 (m, 1H), 4.11e4.04 (m, 2H), 3.92e3.88 (m,
2H), 4.76 (t, J¼1.7 Hz, 1H), 4.70 (d, J¼2.0 Hz, 1H), 4.06e3.96 (m, 2H),

10184
M.S. Kwon et al. / Tetrahedron 67 (2011) 10179e10185
1H), 3.86e3.84 (m, 1H), 3.80e3.76 (m, 1H), 3.73e3.69 (m, 1H),
2.39e2.33 (m, 1H), 2.32e2.23 (m, 2H), 2.14e2.03 (m, 2H), 1.98 and
1.77 (ABX, JAB¼12.7 Hz, JAX¼7.3 Hz, JBX¼5.7 Hz, 2H), 1.74e1.69 (m,
1H), 1.61 (s, 3H), 1.64e1.51 (m, 2H), 1.42e1.37 (m, 1H), 1.38 (s, 3H),
0.89 (s, 9H), 0.87 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H), 0.04 (s, 3H), 0.05
80.2, 77.9, 74.9, 68.5, 47.9, 45.1, 43.3, 42.4, 39.3, 39.1, 35.5, 29.0, 26.2,
26.0, 18.8, 18.3, 18.2, ꢀ3.5, ꢀ4.1, ꢀ4.4, ꢀ4.6. IR (neat): nmax¼3075,
2956, 2930, 2857, 1771, 1472, 1375, 1255, 1121, 837, 775, 738 cmꢀ1
.
MS m/z (CI, relative intensity): 593 (Mþþ1, 2), 577 (33), 535 (43),
483 (14), 461 (41), 445 (8), 399 (9), 351 (8), 325 (100), 291 (20), 267
(21), 251 (6), 217 (13), 189 (13), 159 (12), 121 (16), 85 (8), 57 (13).
HRMS (CI) calcd for C33H61O5Si2 (Mþþ1) 593.4058, found 593.4049.
(s, 3H). 13C NMR (125 MHz, CDCl3):
d 146.8, 146.7, 137.4, 115.6, 114.5,
112.4, 83.1, 82.1, 77.0, 68.9, 68.3, 67.0, 48.8, 48.7, 43.3, 42.9, 42.5,
39.3, 39.1, 26.2, 26.0, 25.5, 18.8, 18.3, 18.2, ꢀ3.5, ꢀ4.3, ꢀ4.4, ꢀ4.5. IR
(neat): nmax¼3426, 3075, 2955, 2930, 2857, 1644, 1472, 1441, 1377,
1254, 1073, 837 cmꢀ1. MS m/z (CI, relative intensity): 597 (Mþþ1,
47), 581 (19), 539 (30), 465 (67), 447 (40), 407 (18), 393 (19), 309
(80), 291 (73), 257 (31), 215 (97), 197 (100), 159 (46), 139 (49), 121
(80), 73 (27), 57 (19). HRMS (CI) calcd for C33H65O5Si2 (Mþþ1)
½
a 2D5
ꢃ
þ52.6 (c 0.135, CHCl3).
The second generation Grubbs catalyst (18.6 mg, 0.0219 mmol)
was added to solution of methylene lactone 20 (26 mg,
a
0.0438 mmol) and 1,4-benzoquinone (7 mg, 0.0658 mmol) in DCE
(8.8 mL) under Ar. This reaction mixture was heated to 95 ꢁC. After
48 h, the reaction mixture was quenched under air for 2 h at room
temperature. The solvent was then removed under reduced pressure
and the crude product was purified by flash column chromatography
(hexanes/EtOAc, 12:1) to afford macrocycle 21 (11.5 mg, 46%). Rf 0.45
597.4371, found 597.4374. ½a D25
þ16.6 (c 0.375, CHCl3).
ꢃ
DesseMartin periodinane (108 mg, 0.254 mmol) was added to
a solution of alcohol 18 (108 mg, 0.169 mmol) in CH2Cl2 (2 mL). The
reaction mixture was stirred at room temperature for 3 h and the
reaction was quenched by addition of satd Na2S2O3 solution (5 mL).
The reaction mixture was extracted with CH2Cl2 (10 mLꢂ3). The
organic extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography (hex-
anes/EtOAc, 20:1) gave ketone 18A (103 mg, 96%). Rf 0.69 (hexanes/
(hexanes/EtOAc, 4:1) 1H NMR (500 MHz, CDCl3):
d 6.74e6.71 (m,1H),
4.93e4.90 (m, 1H), 4.79 (s, 1H), 4.75 (s, 1H), 4.00e3.93 (m, 2H),
3.84e3.81 (m, 1H), 3.39 (d, J¼16.8 Hz, 1H), 2.90e2.83 (m, 1H),
2.52e2.47 (m, 1H), 2.38e2.34 (m, 1H), 2.32e2.28 (m, 1H), 2.29e2.26
(m, 1H), 2.03e1.96 (m, 1H), 1.93e1.89 (m, 1H), 1.82e1.77 (m,1H),1.73
(s, 3H),1.69e1.66 (m,1H),1.64e1.61 (m,1H),1.42e1.37 (m,1H),1.35 (s,
3H), 1.32e1.26 (m, 1H), 0.88 (s, 9H), 0.86 (s, 9H), 0.02(s, 6H), 0.01 (s,
EtOAc, 4:1) 1H NMR (500 MHz, CDCl3):
d 5.75e5.67 (m, 1H), 5.25 (d,
J¼1.2 Hz, 1H), 5.04 (d, J¼0.8 Hz, 1H), 5.01e4.95 (m, 2H), 4.78 (q,
J¼1.2 Hz, 1H), 4.71 (d, J¼2.1 Hz, 1H), 4.55 (s, 2H), 3.84e3.80 (m, 1H),
3.79e3.76 (m, 1H), 3.73e3.69 (m, 1H), 3.30 and 3.22 (ABq,
JAB¼16.4 Hz, 2H), 2.65e2.58 (m, 2H), 2.42e2.37 (m, 1H), 2.21e2.17
(m, 1H), 2.11e2.06 (m, 1H), 2.07 (s, 3H), 1.74e1.70 (m, 1H), 1.71e1.66
(m, 1H), 1.64e1.62 (m, 1H), 1.62 (s, 3H), 1.58e1.52 (m, 1H), 1.42e1.37
(m, 2H), 1.32 (s, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.05 (s, 3H), 0.04 (s,
6H).13C NMR (125 MHz, CDCl3):
d 172.1,147.6,139.0,129.5,110.5, 81.5,
80.4, 77.9, 76.1, 68.8, 51.3, 45.4, 42.4, 40.8, 38.2, 35.5, 30.2, 26.2, 25.9,
25.5, 18.3, 18.0, ꢀ3.7, ꢀ4.5, ꢀ4.5, ꢀ4.6. IR (neat): nmax¼2955, 2930,
2857, 1746, 1670, 1472, 1257, 1231, 1118, 1088, 1062, 1007, 836, 775,
738 cmꢀ1. MS m/z (CI, relative intensity): 639 (2), 593 (10), 565
(Mþþ1, 10), 549 (17), 507 (37), 461 (3), 433 (76), 391 (100), 347 (4),
301 (18), 279 (21), 261 (4), 177 (9), 167 (20), 149 (46), 113 (23), 71 (5),
57 (5). HRMS (CI) calcd for C31H57O5Si2 (Mþþ1) 565.3745, found
3H), 0.03 (s, 6H). 13C NMR (125 MHz, CDCl3):
d 206.8, 170.6, 147.0,
137.7, 137.5, 117.4, 115.5, 112.2, 81.0, 80.6, 77.6, 68.4, 66.8, 54.3, 49.6,
45.9, 43.3, 42.5, 39.2, 39.1, 27.4, 26.2, 26.0, 21.1, 18.7, 18.3, 18.1, ꢀ3.5,
ꢀ4.1, ꢀ4.4, ꢀ4.6. IR (neat): nmax¼2956, 2930, 2857, 1746, 1715, 1472,
1253, 1228,1076, 912, 836, 775 cmꢀ1. MS m/z (CI, relative intensity):
637(Mþþ1, 6), 621 (4), 579 (6), 505 (12), 489 (20), 447 (16), 383 (11),
349 (100), 291 (31), 251 (9), 217 (91), 159 (24), 121 (22), 95 (13), 61
(10). HRMS (CI) calcd for C35H65O6Si2 (Mþþ1) 637.4320, found
565.3739. ½a 2D5
þ18.2 (c 0.150, CHCl3).
ꢃ
3.1.11. 10-Epigyrosanolide E 1. RhCl3$3H2O (6.7 mg, 0.0319 mmol)
was added to a solution of macrocycle 21 (18 mg, 0.0319 mmol) in
EtOH (6.4 mL) at room temperature. This reaction mixture was
heated under reflux. After stirring for 5 h, the reaction was diluted
with EtOH (20 mL), filtered through silica, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (hexanes/acetone, 2:1) to give diol 22 (8.6 mg, 80%). Rf
637.4320. ½a 2D5
þ27.3 (c 2.56, CHCl3).
ꢃ
L-selectride (0.463 mmol) was added dropwise to a solution of
ketone 18A (59 mg, 0.093 mmol) in THF (1 mL) at ꢀ78 ꢁC under
argon. After stirring for 18 h, the reaction was quenched with satd
NH4Cl solution (5 mL) at ꢀ78 ꢁC and the reaction mixture was
allowed to warm to room temperature. The product mixture was
extracted with Et2O (10 mLꢂ3). The organic extracts were dried
over MgSO4, filtered, and concentrated. The residue was purified by
flash column chromatography (hexanes/EtOAc, 8:1) to give diol 19
(40 mg, 72%).
0.12 (hexanes/acetone, 2:1) 1H NMR (500 MHz, CDCl3):
d 7.22 (s,
1H), 5.17 (d, J¼2.6 Hz, 1H), 4.77 (t, J¼1.6 Hz, 1H), 4.65 (s, 1H),
4.05e4.01 (m, 1H), 4.00e3.93 (m, 1H), 3.80e3.75 (m, 1H),
2.49e2.46 (m, 1H), 2.44e2.34 (m, 2H), 2.22e2.15 (m, 1H), 1.96e1.87
(m, 3H), 1.86e1.68 (m, 5H), 1.66 (s, 3H), 1.62e1.53 (m, 1H), 1.28 (s,
3H). 13C NMR (125 MHz, CDCl3):
d 175.1, 151.8, 148.0, 130.5, 112.2,
81.2, 80.3, 79.9, 78.1, 67.9, 50.1, 43.1, 42.9, 42.8, 40.6, 29.4, 24.3, 21.0,
18.8. IR (neat): nmax¼3405, 2926, 1733, 1444, 1373, 1265, 1095, 898,
755 cmꢀ1. MS m/z (EI, relative intensity): 336 (Mþ, 5), 318 (9), 237
(4), 208 (4), 178 (9), 163 (5), 143 (100), 135 (8), 123 (6), 115 (8), 108
(18), 95 (16), 83 (21), 69 (12), 55 (13). HRMS (EI) calcd for C19H28O5
3.1.10. Macrocycle 21. TEMPO (14 mg, 0.0871 mmol) was added to
a solution of diol 19 (52 mg, 0.0871 mmol) and PhI(OAc)2 (84 mg,
0.261 mmol) in CH2Cl2 (8 mL) at room temperature. After stirring
for 24 h, the reaction was quenched with H2O (10 mL). The reaction
mixture was extracted with CH2Cl2 (20 mLꢂ3). The organic extracts
were dried over MgSO4, filtered, and concentrated. The residue was
purified by flash column chromatography (toluene/EtOAc, 25:1) to
give methylene lactone 20 (52 mg, 97%). Rf 0.60 (hexanes/EtOAc,
(Mþ) 336.1937, found 336.1934. ½a 2D5
ꢀ72.2 (c 0.130, CHCl3).
ꢃ
DesseMartin periodinane (26 mg, 0.0606 mmol) was added to
a solution of diol 22 (6.8 mg, 0.0202 mmol) in CH2Cl2 (2 mL). The
reaction mixture was stirred at room temperature for 1 h and the
reaction was quenched by addition of satd Na2S2O3 solution (2 mL).
The reaction mixture was extracted with CH2Cl2 (5 mLꢂ3). The
organic extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography (hex-
anes/acetone, 5:1) gave 10-epigyrosanoldie E 1 (5.9 mg, 88%). Rf
4:1) 1H NMR (500 MHz, CDCl3):
d
6.22 (t, J¼2.7 Hz, 1H), 5.75e5.67
(m, 1H), 5.60 (s, 1H), 5.01e4.95 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H),
4.66e4.61 (m,1H), 3.86e3.82 (m,1H), 3.79e3.76 (m,1H), 3.73e3.70
(m, 1H), 3.08e3.03 (m, 1H), 2.68e2.62 (m, 1H), 2.42e2.36 (m, 1H),
2.33e2.29 (m, 1H), 2.11e2.08 (m, 2H), 1.97 and 1.79 (ABX,
JAB¼14.7 Hz, JAX¼6.9 Hz, JBX¼5.0 Hz, 2H), 1.74e1.69 (m, 1H), 1.62 (s,
3H), 1.57e1.52 (m, 1H), 1.42e1.35 (m, 1H), 1.31 (s, 3H), 0.89 (s, 9H),
0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H). 13C NMR
0.35 (hexanes/acetone, 2:1). 1H NMR (500 MHz, C6D6):
d 6.67 (s,
1H), 4.70 (s, 1H), 4.61 (s, 1H), 4.26 (m, 1H), 3.58 (dd, J¼8.7, 3.5 Hz,
1H), 2.46 (dd, J¼15.0, 3.6 Hz, 1H), 2.44e2.36 (m, 1H), 2.39e2.33 (m,
1H), 2.18 (dd, J¼15.0, 8.7 Hz,1H), 2.02e1.96 (m, 1H),1.95 (dd, J¼11.3,
2.5 Hz, 1H), 1.91e1.84 (m, 1H), 1.82 (t, J¼11.1 Hz, 1H), 1.70 (d,
J¼17.6 Hz, 1H), 1.59 (d, J¼17.6 Hz, 1H), 1.57e1.51 (m, 1H), 1.54 (dd,
(125 MHz, CDCl3): d 170.4, 147.1, 137.6, 134.8, 121.9, 115.5, 112.1, 80.9,

M.S. Kwon et al. / Tetrahedron 67 (2011) 10179e10185
10185
J. Chem. 1978, 31, 2049e2056; (b) Sato, A.; Fenical, W.; Zheng, Q.-T.; Clardy, J.
Tetrahedron 1985, 41, 4303e4308; (c) Shoji, N.; Umeyama, A.; Arihara, S. J. Nat.
Prod. 1993, 56, 1651e1653; (d) Rudi, A.; Lev-Ari Dayan, T.; Aknin, M.; Gaydou, E.
M.; Kashman, Y. J. Nat. Prod. 1998, 61, 872e875; (e) Sheu, J.-H.; Ahmed, A. F.;
Shiue, R.-T.; Dai, C.-F.; Kuo, Y.-H. J. Nat. Prod. 2002, 65, 1904e1908; (f) Ahmed, A.
F.; Shiue, R.-T.; Wang, G.-H.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H. Tetrahedron 2003,
59, 7337e7344; (g) Ahmed, A. F.; Su, J.-H.; Kuo, Y.-H.; Sheu, J.-H. J. Nat. Prod.
2004, 67, 2079e2082; (h) Cheng, S.-Y.; Chuang, C.-T.; Wen, Z.-H.; Wang, S.-K.;
Chiou, S.-F.; Hsu, C.-H.; Dai, C.-F.; Duh, C.-Y. Bioorg. Med. Chem. 2010, 18,
3379e3385.
J¼15.0, 6.6 Hz, 1H), 1.39 (s, 3H), 1.27 (dd, J¼15.0, 4.7 Hz, 1H), 0.72 (s,
3H). 13C NMR (125 MHz, CDCl3):
213.0, 208.0, 174.2, 150.8, 145.9,
d
131.3, 113.2, 78.8, 78.4, 74.8, 48.3, 46.8, 45.7, 43.2, 41.0, 27.7, 25.5,
20.9, 18.2. IR (neat): nmax¼3405, 2926, 1733, 1444, 1373, 1265, 1095,
898, 755 cmꢀ1. MS m/z (EI, relative intensity): 332 (Mþ, 100), 314
(6), 289 (15), 270 (5), 256 (7), 239 (9), 221 (11), 201 (10), 178 (15),
163 (12), 149 (26), 135 (20), 124 (31), 109 (44), 83 (38), 71 (38), 57
(59). HRMS (EI) calcd for C19H24O5 (Mþ) 332.1624 found 332.1627.
2. As the compound was not named by Fenical at the time of its isolation, it was
named in reference to a natural product isolated and named more recently by
Duh.1h
½
a 2D5
ꢃ
þ139 (c 0.065, CHCl3).
3. Jung, J. H.; Lee, E. Angew. Chem., Int. Ed. 2009, 48, 5698e5700.
4. Chen, C.-L.; Sparks, S. M.; Martin, S. F. J. Am. Chem. Soc. 2006, 128,
13696e13697.
5. Higher concentration of methanol probably prevented retro Michael reaction,
and higher yield of 7 was obtained.
6. It was difficult to protect the hydroxyl group of the (6R)-isomers. For example,
TBS-protection did not proceed.
7. Cases, M.; Gonzalez-Lopez de Turiso, F.; Hadjisoteriou, M. S.; Pattenden, G. Org.
Biomol. Chem. 2005, 3, 2786e2804.
Acknowledgements
This work was supported by a grant from Marine Biotechnology
Program funded by Ministry of Land, Transport and Maritime Af-
fairs, Republic of Korea, and a grant from the Centre for Bioactive
Molecular Hybrids (Yonsei University and KOSEF). BK21 graduate
fellowship grants and Seoul Science Fellowship grants to M.S.K. and
S.H.S. are gratefully acknowledged.
8. Serra, S.; Fuganti, C. Helv. Chim. Acta 2004, 87, 2100e2109.
9. Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127,
17160e17161.
10. Grieco, P. A.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J. J. Am. Chem. Soc. 1976,
98, 7102e7104.
Supplementary data
11. The structure of 1 was confirmed by X-ray diffraction studies. CCDC 812599
contains the supplementary crystallographic data for this compound. This data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.011.
12. From 14, 3-epi-22 was obtained in 27% yield following the same reaction se-
quence. It was converted into 1 in 84% yield via DesseMartin oxidation. The
mixture of 13 and 14 may be used in the reaction sequence to yield a mixture of
22 and 3-epi-22.
References and notes
1. For selected reports on isolation of norcembranolide natural products from soft
corals, see: (a) Bowden, B. F.; Coll, J. C.; Mitchell, S. J.; Mulder, J.; Stokie, G. J. Aust.
13. The specific rotation of the natural sample:1b
a D
½ ꢃ ꢀ47 (c 0.01, CHCl3).