Enantioselective total synthesis of (+)-sarcodictyenone

Article abstract of DOI:10.1016/j.tet.2007.11.088

The first enantioselective total synthesis of (+)-sarcodictyenone is described [4.3% overall yield from (5R,6R)-6-methyl-5-trimethylsily-2-cyclohexenone]. This work establishes the absolute stereochemistry of the natural product.

Full text of DOI:10.1016/j.tet.2007.11.088

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1895e1900
www.elsevier.com/locate/tet
Enantioselective total synthesis of (þ)-sarcodictyenone
Takako Yamazaki a, Minoru Ishikawa b, Miki Uemura a, Yuko Kanda a, Hisashi Takei b,
Morio Asaoka a,
*
a Department of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University, Mejirodai 2-8-1 Bunkyoku, Tokyo 112-8681, Japan
b Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of Technology, Nagatsuta Midoriku, Yokohama 226-8502, Japan
Received 22 October 2007; received in revised form 22 November 2007; accepted 26 November 2007
Available online 20 December 2007
Abstract
The first enantioselective total synthesis of (þ)-sarcodictyenone is described [4.3% overall yield from (5R,6R)-6-methyl-5-trimethylsily-
2-cyclohexenone]. This work establishes the absolute stereochemistry of the natural product.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: (þ)-Sarcodictyenone; Terpenoid; Asymmetric synthesis; Hydroxycyclohexenone
1. Introduction
has not been determined yet since the attempt to clarify the
absolute configuration by CD spectroscopy was unsuccessful.1
More recently, analogous natural products eunicenone A
and B, whose absolute stereochemistry has been elucidated
as shown in Figure 1, have been isolated from the Caribbean
gorgonian genus Eunicea.2 The enantioselective total synthesis
of eunicenone A has already been reported by Corey et al. in
2001.2 We planned to clarify the absolute chemistry of
(þ)-sarcodictyenone [(þ)-1] by the enantioselective total
synthesis.
(þ)-Sarcodictyenone [(þ)-1] isolated from the Mediterra-
nean stolonifer Sarcodictyon roseum of temperate waters is
the first example of a natural product, which has a terpenylated
optically active 4-hydroxy-2-cyclohexenone framework. The
relative structure of (þ)-1 was assigned by 1H NMR, 13C
NMR, IR, and HRMS, however, the absolute stereochemistry
2. Results and discussion
Initial straightforward attempt to introduce the geranylger-
anyl side chain via 1,4-addition of geranylgeranyl-MgBr to
enantiomerically pure enone (ꢀ)-23 resulted in failure, i.e.,
lack of diastereo- and regio-selectivity was observed. Thus
we examined the introduction of the geranylgeranyl group
via alkylation as shown in Scheme 1. Enone (ꢀ)-2 was
converted into hydroxysulfone 3 by the conjugate addition
of benzenethiol, reduction with DIBAH followed by oxidation
with m-CPBA. Dianion formation with n-BuLi followed by al-
kylation with geranylgeranylbromide (GG-Br) gave 4 in 88%
overall yield from (ꢀ)-2 as a mixture of three diastereoiso-
mers. Swern oxidation of 4 and subsequent elimination of
Figure 1. Structures of sarcodictyenone and its analogues.
* Corresponding author. Tel.: þ81 3 5981 3660; fax: þ81 3 5981 3656.
E-mail address: asaoka-m@fc.jwu.ac.jp (M. Asaoka).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.088

1896
T. Yamazaki et al. / Tetrahedron 64 (2008) 1895e1900
Scheme 1. Synthesis of (þ)-sarcodictyenone.
phenylsulfinic acid by base treatment gave (ꢀ)-5 (78%). Dia-
stereoselective conjugate reduction of (ꢀ)-5 with DIBAH in
the presence of MeCu in THFeHMPT4 gave (þ)-6, whose dia-
stereo homogeneity was confirmed by 13C NMR, in 82%
yield.5 Removal of the trimethylsilyl group was carried out
by CuCl2 treatment9 of the regioselectively formed enol silyl
ether, which was prepared from (þ)-6 by Miller’s method,10
to give (þ)-7 in 86% yield. Introduction of the g-hydroxy
group to (þ)-7 by applying reported methods11 was
unsuccessful.
Oxidative introduction of acetoxy group to a-position of
the carbonyl group via the corresponding trimethylsilyl dienol
ether12 was accomplished by the treatment with lead tetraace-
tate. Since the product 8 was susceptible to silica gel, reduc-
tion of the crude product with sodium borohydride was
carried out to give 9 in 40% overall yield from (þ)-7. Removal
of the acetyl group with methanolic ammonia and mono-
acetylation with acetic anhydride gave 10 whose PCC
oxidation13 gave enone 11 in 30% overall yield from 9. Stereo-
selective reduction of 11 with L-Selectride, removal of the
acetyl group, and sterically controlled partial oxidation of
diol 12 with IBX14 gave (þ)-sarcodictyenone (73% overall
yield from 11) whose specific rotation and spectral data
were in good agreement with those of reported for natural one.
4. Experimental
4.1. General method
Infrared (IR) spectra were measured on a JASCO-FT/
IR-350 spectrometer and recorded in wave number (cmꢀ1).
1H and 13C NMR spectra were recoded in CDCl3 solution
on a JEOL JEM-EX270 or AL-300 or Bruker AM-400 spec-
trometer. Chemical shifts (d) are reported in parts per million
downfield from TMS as internal standard, and coupling con-
stants (J) are reported in hertz. High and low resolution EI
mass spectral data were obtained on a JEOL JMS-SX 102A
and JMS-AX 505W spectrometers. Optical rotations were
measured with a HORIBA SEPA-300 polarimeter. Analytical-
and preparative-thin-layer chromatography (TLC and p-TLC)
were performed on Merck 60 F254 and 60 PF254 pre-coated
silica gel plates, respectively. Visualization was preformed
by ultraviolet light and/or staining with ceric ammonium mo-
lybdate. Flash chromatography was performed on a column
with WAKO C-300 silica gel.
4.2. Materials
All solvents were obtained commercial sources and used
without purification unless otherwise indicated. THF and ether
were distilled over sodium benzophenone ketyl under Ar be-
fore use. CH2Cl2, DIA, DMF, DMPU, DMSO, HMPA, hexane,
NEt3, TMEDA, and toluene were distilled from calcium
hydride or sodium hydride. All non-aqueous reactions were
performed under Ar atmosphere with oven-dried glassware.
3. Conclusion
The first enantioselective total synthesis of (þ)-sarcodicty-
enone has been accomplished [18 steps from (ꢀ)-2, 4.3%
overall yield]. By this synthesis the absolute stereochemistry
of natural (þ)-sarcodictyenone was determined as (4R,5R).

T. Yamazaki et al. / Tetrahedron 64 (2008) 1895e1900
1897
4.2.1. (1R,2R,3R,5S)-5-Benzenesulfonyl-2-methyl-3-
trimethylsilylcyclohexanol (3a) and (1S,2R,3R,5S)-5-
benzenesulfonyl-2-methyl-3-trimethylsilylcyclohexanol (3b)
mixture was gradually warmed to 0 ꢁC over 1 h, then geranyl-
geranylbromide freshly prepared from geranylgeraniol (1.45 g,
5 mmol) was added. After stirring for 30 min at the same tem-
perature, the reaction was quenched with aq NH4Cl. The mix-
ture was extracted twice with AcOEt and the combined
organic layers were dried over anhydrous MgSO4, filtered,
and concentrated. Purification by flash column chromatogra-
phy (hexane/AcOEt,¼5:1) afforded a ca. 30:2:1 mixture of
three diastereomers 4aec (2.77 g, 97%) as a colorless oil.
Separation of the diastereomers was carried out by careful
flash column chromatography (hexane/AcOEt¼7:1).
A
mixture of (ꢀ)-(5R,6R)-6-methyl-5-trimethylsilyl-2-
cyclohexenon (1.97 g, 10.8 mmol), Et3N (1 mL), and benzene-
thiol (1.13 mL, 11.0 mmol) in hexane (10 mL) was stirred at
room temperature for 1 h. The solvent was removed under
reduced pressure to give (2R,3R,5S)-5-benzenesulfanyl-
2-methyl-3-trimethylsilylcyclohexanone as an oil, which was
used in the next step without purification. IR (neat) 1730
1
(C]O) cmꢀ1; H NMR (270 MHz, CDCl3) d 0.02 (s, 9H),
1.13 (d, 3H, J¼6.6 Hz), 1.43 (dt, 1H, J¼10.5 Hz), 1.09e
1.99 (m, 2H), 2.31 (dq, 1H, J¼6.6, 10.5 Hz), 2.53 (dd, 1H,
J¼4.5, 14.4 Hz), 2.69 (dd, 1H, J¼4.5, 14.4 Hz), 3.91 (quintet,
1H, J¼4.5 Hz), 7.21e7.33 (m, 3H), 7.36e7.46 (m, 2H).
To a solution of the crude cyclohexanone derivative in dry
THF (65 mL) was added DIBAL (1.01 M in toluene, 12.8 mL,
13.8 mmol) at ꢀ78 ꢁC under Ar. After 1.5 h stirring, aq NH4Cl
was added to the mixture. The organic layer was separated and
the aqueous layer was extracted with AcOEt. The combined
organic layers were dried over anhydrous MgSO4, filtered,
and concentrated to give a 10:1 mixture of (1R,2R,3R,5S)-
5-benzenesulfanyl-2-methyl-3-trimethylsilylcyclohexanol and
(1S,2R,3R,5S)-5-benzenesulfanyl-2-methyl-3-trimethylsilylcy-
clohexanol as a colorless oil. To a solution of the crude
mixture in CH2Cl2 (100 mL) was added m-CPBA (4.12 g,
23.8 mmol) at 0 ꢁC under Ar. The mixture was stirred for
1.5 h and diluted with ether. After addition of aq NaHCO3,
the organic layer was separated and the aqueous layer was
extracted with AcOEt. The combined organic layers were
washed with Na2S2O3, dried over anhydrous MgSO4, filtered,
and concentrated. Purification by flash column chromatogra-
phy (hexane/AcOEt¼2:1) afforded a mixture of 3a and 3b
(10:1) as a colorless oil [3.22 g, 91% from (ꢀ)-(5R,6R)-
6-methyl-5-trimethylsilyl-2-cyclohexenone]. Analytical sam-
ples were obtained by careful flash column chromatography.
1
4.2.2.1. Compound 4a. IR (neat) 3470 (OH) cmꢀ1; H NMR
(270 MHz, CDCl3) d 0.04 (s, 9H), 1.08 (d, 3H, J¼6.3 Hz),
1.28e1.50 (m, 3H), 1.47 (s, 3H), 1.58 (s, 6H), 1.59 (s, 3H),
1.67 (s, 3H), 1.83e2.24 (m, 14H), 2.17 (t, 2H, J¼6.3 Hz),
2.39 (d, 1H, J¼16.2 Hz), 3.60e3.72 (m, 1H), 4.45 (br d, 1H,
J¼11.9 Hz), 4.94e5.15 (m, 4H), 7.54e7.72 (m, 3H),
7.90e7.95 (m, 2H).
4.2.2.2. Compound 4b. 1H NMR (270 MHz, CDCl3) d 0.03
(s, 9H), 1.23 (s, 3H), 1.10e1.15 (m, 1H), 1.36e1.74 (m, 3H),
1.47 (s, 3H), 1.58 (s, 6H), 1.59 (s, 3H), 1.68 (s, 3H), 1.86e
2.23 (m, 16H), 2.37 (ddd, 1H, J¼3.1, 4.5, 14.7 Hz), 4.06e
4.18 (m, 1H), 4.98e5.15 (m, 4H), 7.53e7.69 (m, 3H),
7.84e7.87 (m, 2H).
4.2.2.3. Compound 4c. 1H NMR (270 MHz, CDCl3) d 0.03
(s, 9H), 0.46e0.56 (m, 1H), 1.04 (d, 3H, J¼6.3 Hz), 1.47e1.84
(m, 4H), 1.58 (s, 6H), 1.60 (s, 6H), 1.68 (s, 3H), 1.92e2.13
(m, 14H), 2.42 (br d, 2H, J¼6.3 Hz), 3.19 (dt, 1H, J¼4.6,
10.2 Hz), 5.04e5.15 (m, 3H), 5.18e5.28 (m, 1H), 7.50e7.66
(m, 3H), 7.82e7.85 (m, 2H).
4.2.3. (5R,6R)-3-Geranylgeranyl-6-methyl-5-trimethylsilyl-
2-cyclohexenone (ꢀ)-5
To a solution of DMSO (680 mL, 9.58 mmol) in dry CH2Cl2
(60 mL) was added oxalyl chloride (414 mL, 4.79 mmol) at
ꢀ60 ꢁC under Ar. After stirring for 5 min at the same temper-
ature, a mixture of 4aec (993 mg, 1.66 mmol) in dry CH2Cl2
(10 mL) was added to the solution. The mixture was stirred for
15 min at the same temperature. NEt3 (1.7 mL, 12.8 mmol)
was added and the reaction mixture was slowly warmed to
a room temperature. After stirring for 40 min, the reaction
was quenched by adding H2O. The organic layer was sepa-
rated and the aqueous layer was extracted with hexane. The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated to give a diastereomeric mixture of
5-benzenesulfonyl-5-geranylgeranyl-2-methyl-3-trimethylsilyl-
cyclohexanone as an oil.
1
4.2.1.1. Compound 3a. IR (neat) 3500 (OH) cmꢀ1; H NMR
(270 MHz, CDCl3) d 0.01 (s, 9H), 1.01 (d, 3H, J¼6.6 Hz),
1.13 (q, 1H, J¼6.6 Hz), 1.60e1.70 (m, 1H), 1.84 (dq, 1H, J¼
2.9, 6.6 Hz), 1.91e2.10 (m, 3H), 2.40e2.64 (m, 1H), 3.03e
3.12 (m, 1H), 3.67e3.73 (m, 1H), 7.55e7.71 (m, 3H),
7.84e7.90 (m, 2H).
1
4.2.1.2. Compound 3b. IR (neat) 3500 (OH) cmꢀ1; H NMR
(270 MHz, CDCl3) d ꢀ0.01 (s, 9H), 0.99e1.08 (m, 1H),
1.07 (d, 3H, J¼6.6 Hz), 1.40e1.58 (m, 2H), 1.62e1.73 (m,
2H), 2.07 (dt, 1H, J¼3.8, 15.8 Hz), 2.34 (dt, 1H, J¼3.8,
14.0 Hz), 3.33 (quintet, 1H, J¼3.8 Hz), 3.90 (dt, 1H, J¼3.8,
8.6 Hz), 7.53e7.68 (m, 3H), 7.84e7.90 (m, 2H); HRMS calcd
for C16H26O3SiS: 326.1372. Found: m/z 326.1382.
To a solution of the crude oil in CH2Cl2 (10 mL) was added
DBU (1.2 mL, 7.96 mmol) at room temperature. After stirring
for 20 min, the mixture was diluted with CH2Cl2, filtered
through a short pad of silica gel and concentrated. Purification
by flash column chromatography (hexane/AcOEt¼20:1) gave
588 mg (78% yield) of (ꢀ)-5 as an oil. [a]D ꢀ35.6 (c 1.3,
4.2.2. 5-Benzenesulfonyl-5-geranylgeranyl-2-methyl-3-
trimethylsilylcyclohexanol (4aec)
To a solution of a mixture (10:1) of 3a and 3b (1.48 g,
4.50 mmol) in dry THF (10 mL) was added n-BuLi (1.57 M
in hexane, 6.1 mL, 9.57 mmol) at ꢀ78 ꢁC under Ar. The
1
CHCl3); IR (neat) 1672 (C]O) cmꢀ1; H NMR (300 MHz,

1898
T. Yamazaki et al. / Tetrahedron 64 (2008) 1895e1900
CDCl3) d 0.045 (s, 9H), 1.19 (d, 3H, J¼6.8 Hz), 1.12 (m, 1H),
1.60e1.63 (m, 12H), 1.68 (s, 3H), 1.98e2.15 (m, 14H), 2.29e
2.35 (m, 1H), 2.87 (d, 2H, J¼6.8 Hz), 5.09e5.12 (m, 4H),
5.82 (s, 1H); 13C NMR (67.5 MHz, CDCl3) d ꢀ1.96, 16.03,
16.12, 16.23, 17.70, 25.71, 26.58, 26.65, 26.79, 29.31,
30.28, 36.23, 39.73, 42.12, 118.72, 123.88, 124.20, 124.42,
124.53, 131.26, 134.97, 135.36, 139.12, 164.20, 202.76;
HRMS calcd for C30H50OSi: 454.3631. Found: m/z 454.3637.
5.11e5.12 (m, 4H), 6.70 (dd, 1H, J¼1.0, 4.7 Hz); 13C NMR
(75 MHz, CDCl3) d 15.78, 15.99, 16.05, 16.21, 17.68, 25.70,
26.56, 26.63, 26.72, 26.77, 32.15, 33.89, 36.32, 39.73,
39.82, 44.37, 121.09, 124.04, 124.20, 124.38, 131.26,
134.93, 135.15, 135.54, 137.32, 144.90, 200.25; HRMS calcd
for C27H42O3: 382.3236. Found: m/z 382.3263.
4.2.6. 2-Acetoxy-5-geranylgeranyl-2-methyl-3-
cyclohexenone 8
4.2.4. (2R,3R,5R)-5-Geranylgeranyl-2-methyl-3-
trimethylsilylcyclohexanone (þ)-6
A solution of dry FeCl3 (20 mg, 0.12 mmol) in dry THF
(2 mL) was cooled to ꢀ20 ꢁC under Ar and a solution of
MeMgBr (2.04 mL, 1.86 mmol, 0.91 M in THF) was added
slowly. The reaction mixture was stirred for 20 min at
ꢀ20 ꢁC and (þ)-7 (100 mg, 0.26 mmol) in dry THF (1 mL)
was added dropwise over a period of 5 min. After stirring
for 20 min at the same temperature, the reaction mixture
was warmed to 0 ꢁC and added TMSCl (252 mL,
1.86 mmol), NEt3 (156 mL, 1.1 mmol), and DMPU (156 mL,
1.24 mmol). The mixture was stirred overnight at room tem-
perature and then aq NaHCO3 was added. The mixture was
extracted three times with ether and the combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated to give 122 mg of the cor-
To a pre-cooled (ꢀ50 ꢁC) solution of CuI (882 mg,
4.61 mmol) in dry THF (21 mL) was added methyllithium
(1.05 M in ether, 4.4 mL, 4.61 mmol) under Ar. After stirring
for 30 min at the same temperature, HMPA (4.2 mL) and
DIBAL (1.01 M in toluene, 4.6 mL, 4.65 mmol) were added.
After 40 min stirring at the same temperature, (ꢀ)-5
(420 mg, 0.92 mmol) in dry THF (10 mL) was added. Then
the mixture was warmed to ꢀ10 ꢁC and stirred for 12 h. The
reaction mixture was treated with hexane and saturated aq
NH4Cl. The resulting mixture was filtered through a short
pad of Celite. After separation of the organic layer, the aque-
ous layer was extracted with AcOEt. The combined organic
layers were dried over anhydrous MgSO4, filtered, and con-
centrated. Purification by flash column chromatography (hex-
ane/AcOEt¼20:1) afforded (þ)-6 (346 mg, 82% yield) as
a colorless oil. [a]D þ32.00 (c 3.0, CHCl3); IR (neat) 1740
1
responding dienol silyl ether as an oil. H NMR (300 MHz,
CDCl3) d 0.21 (s, 9H), 1.61 (s, 12H), 1.69 (s, 3H),
1.63e1.69 (m, 1H), 1.94e2.10 (m, 14H), 2.19 (dd, 1H,
J¼1.5, 8.4 Hz), 2.37e2.45 (m, 1H), 5.12e5.15 (m, 4H),
5.37 (dd, 1H, J¼3.6, 9.3 Hz), 5.71 (dd, 1H, J¼1.8, 9.0 Hz).
The dienol silyl ether was used in the next step immediately.
To a solution of Pb(OAc)4 (340 mg, 0.76 mmol) in CH2Cl2
(30 mL) was added the crude dienol silyl ether (122 mg) in
CH2Cl2 (10 mL) at ꢀ78 ꢁC under Ar. After stirring for
30 min at the same temperature, the reaction was quenched
by adding hexane. The resulting mixture was filtered through
a short pad of silica gel and concentrated to afford 8 (58 mg)
as an oil, which was used in the next step immediately without
further purification, since this compound was found to be rela-
1
(C]O) cmꢀ1; H NMR (300 MHz, CDCl3) d 0.081 (s, 9H),
0.85 (dq, 1H, J¼2.7, 14 Hz), 1.04 (d, 3H, J¼6.6 Hz),
1.20e1.28 (m, 2H), 1.62 (s, 12H), 1.70 (s, 3H), 1.84 (d, 2H,
J¼12 Hz), 1.98e2.06 (m, 14H), 2.25 (m, 1H, J¼6.3,
6.4 Hz), 2.43 (dt, 1H, J¼2.4, 12 Hz), 5.14e5.12 (m, 4H);
HRMS calcd for C30H52OSi: 456.3787. Found: m/z 456.3768.
4.2.5. (5S)-5-Geranylgeranyl-2-methyl-2-cyclohexenone
(þ)-7
To a solution of (þ)-6 (446 mg, 0.98 mmol) in dry CH2Cl2
(10 mL) at room temperature were added hexamethyldisil-
azane (412 mL, 1.96 mmol) and TMSI (172 mL, 1.27 mmol).
After 1 h stirring at the same temperature, the reaction was
quenched with aq NaHCO3. The organic layer was separated
and the aqueous layer was extracted with hexane. The com-
bined organic layers were washed with water, dried over anhy-
drous MgSO4, filtered, and concentrated to give 504 mg of
trimethylsilyl ether as an oil. A solution of the crude oil and
CuCl2 (395 mg, 2.94 mmol) in DMF (5 mL) was stirred at
room temperature under Ar for 2 h and then heated at 60 ꢁC
for 30 min. The reaction was quenched by the addition of
cold H2O. The reaction mixture was extracted twice with hex-
ane, and the combined organic extracts were washed three
times with water, dried over anhydrous MgSO4, filtered, and
concentrated. Purification by p-TLC (hexane/AcOEt¼15:1)
afforded (þ)-7 [322 mg, 86% from (þ)-6] as a colorless oil.
1
tively unstable. H NMR (300 MHz, CDCl3) d 1.45 (s, 3H),
1.60 (s, 12H), 1.69 (s, 3H), 2.03 (s, 3H), 1.98e2.08 (m,
14H), 2.14e2.32 (m, 1H), 2.67 (ddd, 1H, J¼0.9, 4.5,
15 Hz), 2.87 (m, 1H), 5.11e5.14 (m, 4H), 5.54 (dd, 1H,
J¼2.7, 10 Hz), 5.91 (dt, 1H, J¼1.6, 9.7 Hz).
4.2.7. 5-Geranylgeranyl-2-methyl-3-cyclohexene-1,2-diol
2-acetate 9
To a solution of the crude 8 (58 mg) in MeOH (10 mL) was
added NaBH4 (200 mg) at 0 ꢁC under Ar. After stirring over-
night at room temperature, the reaction was quenched by adding
H2O. The mixture was extracted three times with AcOEt and the
combined organic extracts were washed with water, dried over
anhydrous MgSO4, filtered, and concentrated. Purification by
p-TLC (hexane/AcOEt¼5:1) afforded 9 [46 mg, 40% from
1
(þ)-7] as a colorless oil. IR (neat) 1713 (C]O) cmꢀ1; H
[a]D þ23.8 (c 2.0, CHCl3); IR (neat) 1670 (C]O) cmꢀ1; H
NMR (300 MHz, CDCl3) d 1.47 (s, 3H), 1.60 (s, 12H), 1.68
(s, 3H), 1.47e1.68 (s, 3H), 1.68e2.10 (m, 1H), 2.00e2.03
(m, 14H), 2.07 (s, 3H), 2.28 (m, 1H, J¼5.0 Hz), 4.00 (dd, 1H,
J¼3.5, 13 Hz), 4.62 (s, 1H), 5.12 (m, 4H), 5.62 (s, 2H).
1
NMR (300 MHz, CDCl3) d 1.60 (s, 12H), 1.69 (s, 3H),
1.60e1.77 (m, 1H), 1.77 (s, 3H), 1.98e2.17 (m, 16H), 2.38
(dd, 1H, J¼4.5, 17 Hz), 2.53 (dd, 1H, J¼1.7, 12 Hz),

T. Yamazaki et al. / Tetrahedron 64 (2008) 1895e1900
1899
4.2.8. 5-Geranylgeranyl-2-methyl-3-cyclohexene-1,2-diol
1-acetate 10
The crude product was dissolved in MeOH/NH3 (1 mL).
After 3 days at room temperature, the solution was concen-
Compound 9 (44 mg, 0.10 mmol) was dissolved in MeOH/
NH3 (1 mL). After overnight at room temperature, the solution
was concentrated to give (5S)-5-geranylgeranyl-2-methyl-
3-cyclohexene-1,2-diol as a colorless oil. IR (neat) 3400
trated to give 12 as a colorless oil. IR (neat) 3400 (OH) cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.60 (s, 12H), 1.69 (s, 3H),
1.60e1.69 (m, 1H), 1.81 (s, 3H), 1.87e2.14 (m, 16H), 3.97
(t, 1H, J¼3.5 Hz), 4.03 (t, 1H, J¼7.3 Hz), 5.11e5.20
(m, 4H), 5.68 (dd, 1H, J¼1.4, 3.4 Hz); HRMS calcd for
C27H44O2: 400.3341. Found: m/z 400.3344.
(OH) cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.25 (s, 3H),
;
1.60 (s, 12H), 1.68 (s, 3H), 1.59e1.68 (m, 1H), 2.03 (s, 3H),
1.98e2.06 (m, 15H), 2.27e2.38 (m, 1H), 3.79 (dd, 1H, J¼
3.6, 13 Hz), 5.11 (br s, 4H), 5.48 (d, 1H, J¼10 Hz), 5.54
(dd, 1H, J¼2.0, 10 Hz); HRMS calcd for C27H44O2:
400.3341. Found: m/z 400.3340.
4.2.11. (þ)-Sarocdictyenone (þ)-1
To a solution of the crude 12 in THF (0.5 mL) and DMSO
(0.5 mL) was added IBX (100 mg, 0.35 mmol) at room tem-
perature. After 30 min stirring, the reaction was quenched
with H2O. The mixture was extracted twice with AcOEt.
The combined organic extracts were washed twice with water,
dried over anhydrous MgSO4, filtered, and concentrated. Puri-
fication by p-TLC (hexane/AcOEt¼5:1) afforded (þ)-1
(2.4 mg, 73% from 11) as a colorless oil. [a]D þ51.9
(c 0.08, EtOH) [lit.1 [a]D þ52.0 (c 0.17, EtOH)]; IR (neat)
To a solution of the crude diol, NEt3 (61 mL, 0.45 mmol),
and DMAP in dry THF (1 mL) was added acetic acid anhy-
dride (20 mL, 0.22 mmol) at room temperature under Ar. After
20 min stirring, the reaction was quenched by the addition of
MeOH. The resulting mixture was poured into H2O, and the
mixture was extracted twice with AcOEt, and the combined
organic layers were washed with water, dried over anhydrous
MgSO4, filtered, and concentrated to give 10 (42 mg) as an oil,
which was used without further purification. 1H NMR
(300 MHz, CDCl3) d 1.26 (s, 3H), 1.60 (s, 12H), 1.68
(s, 3H), 1.68e1.80 (m, 1H), 1.98e2.09 (m, 15H), 2.12 (s, 3H),
2.35e2.47 (m, 1H), 4.93 (dd, 1H, J¼3.8, 13 Hz), 5.18 (br s,
4H), 5.50 (d, 1H, J¼10 Hz), 5.56 (dd, 1H, J¼1.9, 10 Hz).
3400 (OH), 1682 (C]O) cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 1.60 (s, 12H), 1.68 (s, 3H), 1.80 (s, 3H),
1.98e2.08 (m, 14H), 2.26 (ddd, 1H, J¼6.6, 13.5 Hz), 2.36
(dd, 1H, J¼3.6, 16 Hz), 2.52 (dd, 1H, J¼10, 16 Hz), 4.36
(br s, 1H), 5.08e5.17 (m, 4H), 6.70 (dd, 1H, J¼1.7, 5.2 Hz);
13C NMR (75 MHz, CDCl3) d 15.7, 16.0, 16.1, 16.2, 17.7,
25.7, 26.5, 26.6, 26.8, 29.0, 39.2, 39.7, 39.8, 40.3, 66.4,
121.2, 124.1, 124.2, 124.4, 131.7, 135.3, 135.5, 137.3,
138.1, 143.5, 199.8; HRMS calcd for C27H42O2: 398.3185.
Found: m/z 398.3200.
4.2.9. (6R)-4-Acetoxy-6-geranylgeranyl-3-methyl-
2-cyclohexenone 11
To a solution of 10 (42 mg) in CH2Cl2 (5 mL) was added
PCC (300 mg) at room temperature. The mixture was stirred
overnight and quenched by the addition of hexane. The result-
ing mixture was filtered and concentrated. Purification by
p-TLC (hexane/AcOEt¼10:1) afforded 11 (13 mg, 30% from
Acknowledgements
We are grateful to Dr. K. Takenaka, of Japan Women’s
University, for measurement of MS spectra.
1
9) as an oil. IR (neat) 1747, 1638 (C]O) cmꢀ1; H NMR
(300 MHz, CDCl3) d 1.60 (s, 12H), 1.68 (s, 3H), 1.68e1.72
(m, 1H), 1.90 (s, 3H), 2.13 (s, 3H), 2.29e2.41 (m, 1H),
2.54e2.61 (m, 1H), 5.09e5.11 (m, 4H), 5.70 (m, 1H), 5.92
(s, 1H); HRMS calcd for C29H44O3: 440.3290. Found: m/z
440.3293.
References and notes
1. D’Ambrosio, M.; Guerriero, A.; Fabbri, D.; Pietra, F. Helv. Chim. Acta
1986, 69, 1581e1584.
2. Isolation and the total synthesis of closely related marine natural products,
see: Shin, J.; Fenical, W. Tetrahedron 1993, 49, 9277e9284; Lee, T. W.;
Corey, E. J. J. Am. Chem. Soc. 2001, 123, 1872e1877.
3. Asaoka, M.; Aida, T.; Sonoda, S.; Takei, H. Tetrahedron Lett. 1989, 30,
7075e7078.
4.2.10. (4R,5R)-5-Geranylgeranyl-2-methyl-2-cyclohexene-
1,4-diol 12
To a solution of 11 (6.7 mg, 0.015 mmol) in dry THF
(1 mL) was added L-Selectride (15 mL, 0.015 mmol, 1.0 M
in toluene) at ꢀ78 ꢁC under Ar. After 20 min stirring at the
same temperature, the reaction was quenched by the addition
of MeOH. The resulting mixture was poured into H2O, and the
mixture was extracted three times with AcOEt. The combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated to give a colorless oil. IR (neat) 1740 (C]O),
4. Tsuda, T.; Hayashi, T.; Satomi, H.; Kawamoto, T.; Saegusa, T. J. Org.
Chem. 1986, 51, 537e540.
5. Conjugate reduction of (ꢀ)-5 with Et3SiH6 or [(Ph3P)CuH]6 under
7
reported conditions resulted in recovery of the starting enone. With
Ph2SiH2/ZnCl2 in the presence of cat. Pd(PPh3)4,8 crude (þ)-6 was
obtained in a good yield, however, contaminated unidentified side prod-
ucts could not be removed. The configuration of (þ)-6, (2R,3R,5R),
was assigned by comparison of the spectral data with those of
(2R,3R,5S)-isomer which was obtained in a fair yield via conjugate
addition of geranylgeranyl-MgBr to (ꢀ)-23 in the presence of a catalytic
amount of CuBr$SMe2 at ꢀ100 ꢁC. (2R,3R,5S)-5-Geranylgeranyl-2-
methyl-3-trimethylsilylcyclohexanone: 1H NMR (300 MHz, CDCl3)
d 0.04 (s, 9H), 0.97e1.15 (m, 1H), 1.09 (d, 3H, J¼6.6 Hz), 1.59 (s,
12H), 1.68 (s, 3H), 1.60e1.74 (m, 2H), 1.90e2.48 (m, 18H), 5.03e
5.15 (m, 4H); 13C NMR (75 MHz, CDCl3) d ꢀ1.63, 15.87, 16.00,
3400 (OH) cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.60
(s, 12H), 1.63 (s, 3H), 1.68 (s, 3H), 1.60e1.68 (m, 1H), 2.03e
2.06 (m, 16H), 2.08 (s, 3H), 3.98e3.99 (m, 1H), 5.08e5.19
(m, 4H), 5.29 (t, 1H, J¼8.8 Hz), 5.77 (dt, 1H, J¼1.5,
5.0 Hz); HRMS calcd for C29H46O3: 442.3447. Found: m/z
442.3454.

1900
T. Yamazaki et al. / Tetrahedron 64 (2008) 1895e1900
16.26, 17.67, 25.68, 26.63, 26.70, 26.74, 29.51, 29.83, 32.02, 38.91,
39.71, 39.86, 45.73, 45.99, 122.01, 124.10, 124.22, 124.39, 131.23,
134.90, 135.08, 136.82, 214.86.
9. Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Org. Chem. 1980, 45, 2022e2024;
Asaoka, M.; Shima, K.; Takei, H. J. Chem. Soc., Chem. Commun. 1988,
430e431.
6. Rosen, T.; Heathcock, C. H. J. Am. Chem. Soc. 1985, 107, 3731e
3733.
10. Miller, R. D.; Mckean, D. R. Synthesis 1979, 730e732.
11. Miyasita, M.; Suzuki, T.; Yoshikoshi, A. J. Org. Chem. 1985, 50, 3377e
3380; Rong-Bao, Z.; Yu-Lin, W. Acta Chim. Sin. Engl. Ed. 1989, 86e87.
12. Krafft, M. E.; Holton, R. A. J. Am. Chem. Soc. 1984, 106, 7619e7621.
13. Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682e685.
14. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019e8022.
7. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc.
1988, 110, 291e293; Brestensky, D. M.; Huseland, D. E.; McGettigan,
C.; Stryker, J. M. Tetrahedron Lett. 1988, 29, 3749e3752.
8. Keinan, E.; Greenspoon, N. Tetrahedron Lett. 1985, 26, 1353e1356.