Elucidation of the Sharpless epoxidation of zerumbol

Article abstract of DOI:10.1016/j.tetasy.2006.06.049

The Sharpless asymmetric epoxidation of (+)-zerumbol, itself obtained by the reduction of zerumbone 1 gave only all-erythro bisepoxide 3 which has five stereogenic centers. Chiral monoepoxide 4, which decomposed easily under acidic or high-temperature con

Full text of DOI:10.1016/j.tetasy.2006.06.049

Tetrahedron: Asymmetry 17 (2006) 2311–2316
Elucidation of the Sharpless epoxidation of zerumbol
Takashi Kitayama,a,* Atsushi Furuya,a Chiyuki Moriyama,a Tomomi Masuda,a
Sachiko Fushimi,a Yuji Yonekura,a Haruko Kubo,b Yasushi Kawaib and Seiji Sawadac
aAdvanced Life Science, Graduate School of Agriculture, Kinki University, Nara 631-8505, Japan
bNagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan
cKyoto University of Education, Fushimi, Kyoto 612-0863, Japan
Received 20 June 2006; accepted 21 June 2006
Available online 26 September 2006
Abstract—The Sharpless asymmetric epoxidation of (+)-zerumbol, itself obtained by the reduction of zerumbone 1 gave only all-erythro
bisepoxide 3 which has five stereogenic centers. Chiral monoepoxide 4, which decomposed easily under acidic or high-temperature con-
ditions, could also be obtained. The reaction mechanism was revealed to be diastereoselective but non-enantioselective monoepoxidation
at the 2,3-position, which proceeded quantitatively followed by a second epoxidation at the 10,11-position, and also proceeded extremely
enantioselectively giving an efficient kinetic resolution. Novel asymmetric diepoxydihydroxyzerumbol 6 and triepoxyzerumbol 7 each
with seven stereogenic centers were formed with complete diastereoselectivity by dihydroxylation and epoxidation of bisepoxyzerumbol,
respectively.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
exploit the ready availability and versatility of this sub-
stance as a starting material for conversion to other useful
compounds. Not only does zerumbone show attractive
reactivity, but zerumbone7 and its derivatives6,8 have a
broad array of biological activities.
The concept of diversity oriented synthesis was established
by Schreiber in 2000.1 However, the choice of substrate is
important and moreover, if the substrate is a natural mate-
rial, much chemical development may be needed. Zerum-
bone 1,2 having powerful latent reactivity and containing
three double bonds, two conjugated and one isolated,
and a double conjugated carbonyl group in an 11-mem-
bered ring structure, is a monocyclic sesquiterpene found
as the major component of the essential oil of wild ginger,
Zingiber zerumbet Smith. It is anticipated to be a powerful
tool in the implementation of green chemistry with respect
to the provision of materials followed on from the cultiva-
tion of ginger.
Novel optically active substances as chiral building blocks
derived from zerumbone9,10 can be expected to be of use in
a variety of industrial fields such as medicine, perfumery,
the liquid crystal industry, and the electronics industry,
etc. Moreover, derivatives of zerumbone have potential
as non-natural sugar derivatives and to be incorporated
into new materials such as a chiral auxiliary.
As shown in Scheme 1, Sharpless asymmetric epoxidation
with L-(+)-diethyl tartrate (DET) of racemic zerumbol 2
obtained by reduction of zerumbone gave only the all-ery-
thro bisepoxide (ꢀ)-(1R,2R,3R,10S,11S)-3 which has five
stereogenic centers in moderate yield.9 However, none of
the chiral monoepoxy alcohols nor the chiral zerumbols 4
were isolated. Herein, we report the isolation of another
chiral product obtained by Sharpless epoxidation of
zerumbol and elucidation of the mechanism of this asym-
metric epoxidation. Moreover, two novel optically active
compounds with seven stereogenic carbons were obtained
from bisepoxyzerumbol 3 stereoselectively.
Zerumbone 1 exhibits a variety of interesting reactions,
such as transannular ring contraction and cyclization,3–5
regio- and stereoselective conjugate additions,3 and various
regioselective ring cleavage reactions.4,6 However, much of
its chemistry still remains to be explored in order to fully
*
Corresponding author. Fax: +81 742 43 8976; e-mail: kitayama@
nara.kindai.ac.jp
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.049

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T. Kitayama et al. / Tetrahedron: Asymmetry 17 (2006) 2311–2316
OH
OH
Ti(OPri)4 (1.0 eq)
TBHP (2.0 eq)
L-(+)-DET (1.2 eq)
OH
O
LAH
O
O
O
+
-35 ~ -40 oC
(+)-4
38% yield 89% ee
zerumbone, 1
( )-2
100 %
3
(-)-
40% yield 99% ee
Scheme 1.
2. Results and discussion
form by treatment of ( )-2 with m-chloroperbenzoic acid
(Scheme 2) was not detected by TLC. While the ee of
(+)-4 did not change on purification by silica gel chroma-
tography, the yield was somewhat compromised due to
decomposition.
Careful reexamination of the Sharpless asymmetric epoxi-
dation of racemic zerumbol 2 led to the isolation of bisep-
oxide (ꢀ)-3 (40%) and the monoepoxide (+)-4 (38%)
(Scheme 1). Compound 4, which decomposed above
40 ꢁC in organic solvents or under weakly acidic conditions
As shown in Scheme 3, Sharpless epoxidation of ( )-2
without DET gave racemic all erythro-3 and 4 in 67%
and 28% yield, respectively, without any by-products
although racemic erythro-4 was not completely consumed.
Moreover, the total yield was very high in the absence of
DET. This result suggests that, as expected, the Ti-TBHP
system efficiently controls the diastereoselectivity of these
reactions.
was the chiral monoepoxyzerumbol which had
a
(1S,2S,3S)-configuration. The enantiomeric excess of
(+)-4 was established by GC using a capillary column
[CP-CD (CP-cyclodextrin-B-236-M-19), Inj: 200 ꢁC,
Det: 200 ꢁC, column: 140 ꢁC, retention time (+)-4:
47 min, (ꢀ)-4: 49 min]. Gaseous 4 did not decompose
below 150 ꢁC under GC conditions.
Monitoring the epoxidation of ( )-2 under a variety of
conditions showed that the starting material was com-
pletely consumed after 2 h, and suggested that the first
formed product was racemic ( )-4 which was slowly but
efficiently kinetically resolved in the second epoxidation
step to give (ꢀ)-3. threo-5, which was prepared in racemic
Interestingly, attempted oxidization of (+)-4 (89% ee) using
either L- or D-DET under normal Sharpless reaction condi-
tions failed and no consumption of (+)-4 was observed
even after several hours (Scheme 4). When geraniol
(0.5 equiv) was added to the reaction mixture under the
same conditions, it was completely epoxidized after 1 h to
afford 2,3-epoxygeraniol as confirmed by TLC compared
against an authentic sample. This is consistent with (+)-4
being resistant to epoxidation rather than deactivation of
the Sharpless epoxidation catalyst.
OH
OH
MCPBA (1 eq) / AcOEt
28 %
O
Sharpless epoxidation of ( )-2 with L-DET at ꢀ60 ꢁC gave
(+)-4 with a lower ee of approximately 60%.
As shown in Scheme 5, (ꢀ)-3 reacted with OsO4, AD-mixa
or AD-mixb to afford the 6,7-dihydroxy compound (ꢀ)-
(1R,2R,3R,6S,7S,10S,11S)-6 containing seven stereogenic
racemic threo-5
( )-2
Scheme 2.
OH
OH
OH
Ti(OPri)4 (1.0 ~ 2.0 eq)
TBHP (2.0 ~ 4.0 eq)
O
O
O
+
-35 ~ -40 oC, 24 h
67 %
3
( )-erythro-
28 %
( )-erythro-4
( )-2
Scheme 3.
Ti(OPri)4 (1.0 eq)
TBHP (2.0 eq)
CH3
CH3
O
-(-)-DET or -(+)-DET (1.2 eq)
D
L
Geraniol
[No reaction]
4
(+)-
H3C
OH
-35 ~ -40 oC
Scheme 4.

T. Kitayama et al. / Tetrahedron: Asymmetry 17 (2006) 2311–2316
2313
OH
OH
OH
O
O
O
O
O
O
Dihydroxylation
MCPBA/EtOAc
96 %
Reagent
HO
O
HO
OsO4, NMMO (95%)
AD-mix-α (70%)
AD-mix-β (70%)
6
(-)-
(-)-3
(-)-7
Scheme 5.
centers in over 95% yield. The stereoselectivity of the
dihydroxylation of 3 depends on the configuration of the
substrate rather than on the chiral catalyst. Moreover,
(ꢀ)-3 reacted with MCPBA in ethyl acetate to afford the
novel chiral triepoxide (ꢀ)-(1R,2R,3R,6S,7S,10S,11S)-7 in
96% yield also with seven stereogenic centers.
2.1. Absolute configuration
The relative configuration within (+)-4 was determined by
anomalous dispersion of a heavy atom derivative. For this
purpose, (+)-4 (89%) was converted to the 4-chloro-3,5-
dinitrobenzoate derivative (+)-8 (89% ee) (Scheme 6).
Recrystallization of (+)-8 from EtOH gave triclinic crystals
of racemic ( )-(1SR,2SR,3SR)-8, one of which was sub-
jected to X-ray analysis (Fig. 1). The absolute configura-
tion of (ꢀ)-3 was assigned as (1R,2R,3R,10S,11S) on the
assumption that the usual selectivity observed in the second
Sharpless asymmetric epoxidation with L-DET was operat-
ing. From this, the absolute configuration of (+)-4 was
assigned as (1S,2S,3S).
Figure 1. ORTEP drawing of the crystal structure of diepoxy esters ( )-8.
The relative configurations within (1R,2R,3R,6S,7S,10S,
11S)-6 and (1R,2R,3R,6S,7S,10S,11S)-7 were also deter-
mined by X-ray analysis. Monoclinic crystals were ob-
tained by recrystallization of each from hexane and ethyl
acetate (Figs. 2 and 3). The absolute configurations were
assigned from that of (ꢀ)-3 from which they were derived.
3. Conclusion
The Sharpless asymmetric epoxidation (with L-DET) of
racemic zerumbol ( )-2 gave racemic erythro-2,3-epoxide
( )-4 regioselectively but not enantioselectively. A second
NO2
Cl
NO2
O
O2N
Cl
O2N
OH
O
CO2H
Figure 2. ORTEP drawing of (ꢀ)-6.
O
O
DCC
in situ epoxidation step led to the efficient kinetic resolution
of ( )-4 to generate (ꢀ)-3 on 99% ee. Further diastereo-
selective oxidation of (ꢀ)-3 led to the formation of (ꢀ)-6
and (ꢀ)-7, each with seven stereogenic centers.
(+)-4 (89% ee)
Scheme 6.
(+)-8 (89% ee)

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T. Kitayama et al. / Tetrahedron: Asymmetry 17 (2006) 2311–2316
4.3. (1S,2S,3S)-2,3-Epoxy-2,6,9,9-tetramethyl-6,10-cyclo-
undecadien-1-ol, (+)-4
23:5
½aꢁD ¼ þ19:9 (c 1.16, EtOH) 89% ee, IR (KBr) 3497,
2959, 2927, 1462 cmꢀ1; d 1H NMR (CDCl3): d 1.12 (s,
3H, CH3 at C9), 1.12 (s, 3H, CH3 at C9), 1.32 (s, 3H,
CH3 at C6), 1.40–1.49 (m, 1H, H at C4), 1.54 (s, 3H,
CH3 at C2), 1.91–1.95 (m, 2H, H2 at C8), 2.10–2.26 (m,
3H, H at C4 and 2H at C5), 2.47 (s, 1H, OH at C1), 2.75
(dd, 1H, J = 3.0 and 10.6 Hz, H at C3), 4.21 (d, 1H,
J = 4.3 Hz, H at C1), 4.99 (t, 1H, H at C7), 5.29 (dd, 1H,
J = 4.3 and 16.2 Hz, H at C11), 5.47 (d, 1H, J = 16.2, H
at C10); 13C NMR: d 15.2 (CH3 at C2), 15.6 (CH3 at
C6), 24.0 (C4), 26.7 (CH3 at C9), 27.7 (CH3 at C9), 36.3
(C9), 36.5 (C5), 40.1 (C8), 58.2 (C3), 64.5 (C2), 70.4 (C1),
125.8 (C7), 126.8 (C11), 131.9 (C6), 138.2 (C10). HRMS:
m/z calcd mass for C15H24O2 236.1776, found 236.1780.
Figure 3. ORTEP drawing of (ꢀ)-7.
4.4. (1SR,2RS,3RS)-2,3-Epoxy-2,6,9,9-tetramethyl-6,10-
cycloundecadien-1-ol, ( )-threo-5
4. Experimental
4.1. General methods
A mixture of 2 (300 mg, 1.36 mmol) and MCPBA (259 mg,
1.50 mmol) in ethyl acetate (30 mL) was stirred at 0 ꢁC for
1 h and then at room temperature for 15 h. The progress of
the epoxidation was monitored by TLC. Ethyl acetate
(10 mL) was added to the reaction mixture and washed
with NaHCO3 (5 · 30 mL) and brine (3 · 30 mL), dried
over Na2SO4, and concentrated on a rotary evaporator.
Chromatography on silica gel, eluting with a mixture of
EtOAc and hexane (1/3) afforded diastereomerically pure
(1SR,2RS,3RS)-4 in 28% yield. IR (KBr) 3497, 2959,
1462 cmꢀ1; d 1H NMR (C6D6): d 0.67 (s, 3H, CH3 at
C9), 0.68 (s, 3H, CH3 at C9), 0.99 (s, 3H, CH3 at C6),
0.91–1.03 (m, 1H, H at C4), 1.07 (s, 3H, CH3 at C2),
1.32–1.82 (m, 5H, H at C4, 2H at C5 and 2H at C8),
2.06 (dd, 1H, J = 4.3 and 9.9 Hz, H at C3), 2.73 (s, 1H,
OH at C1), 3.38 (d, 1H, J = 8.6 Hz, H at C1), 4.53 (dd,
1H, J = 3.3 and 10.2 Hz, H at C7), 4.69 (d, 1H,
J = 16.2 Hz, H at C10), 5.04 (dd, 1H, J = 8.6 and
16.2 Hz, H at C11); 13C NMR: d 11.0 (CH3 at C2), 14.8
(CH3 at C6), 24.0 (CH3 at C9), 25.0 (C4), 29.9 (CH3 at
C9), 36.3 (C9), 36.4 (C5), 40.5 (C8), 60.2 (C3), 66.0 (C2),
81.6 (C1), 125.7 (C7), 126.8 (C11), 132.0 (C6), 141.4
(C10). HRMS: m/z calcd mass for C15H24O2 236.1776,
found 236.1793.
NMR spectra were obtained at 270 MHz for protons and
68 MHz for 13C in CDCl3 with tetramethylsilane (TMS)
as the internal standard unless otherwise noted. Chemical
shifts d were reported in parts per million from TMS. Mass
spectra were recorded at 70 eV, and high-resolution mass
spectra (HRMS) were obtained by direct injection. The
X-ray diffraction and CCDC numbers appear in the sec-
tions on compound data. Chemicals were of commercially
available reagent grade and used without further
purification.
4.2. (1R,2R,3R,10S,11S)-2,3-10,11-Diepoxy-2,6,9,9-tetra-
methyl-6-cycloundecen-1-ol, (ꢀ)-3 and (1S,2S,3S)-2,3-
epoxy-2,6,9,9-tetramethyl-6,10-cycloundecadien-1-ol, (+)-4
A mixture of Ti(OPri)4 (644 mg, 2.27 mmol) and L-DET
(560 mg, 2.72 mmol) in dry CH2Cl2 (20 mL) was stirred
at ꢀ30 ꢁC for 10 min before the addition of 2 (500 mg,
2.27 mmol) and finally 5 M TBHP (0.92 mL, 4.60 mmol).
The homogeneous solution was stored in a freezer at
ꢀ26 ꢁC in a reaction vessel with a septum cap. The progress
of the oxidation was monitored by TLC. After 48 h, the
flask was placed in a ꢀ30 ꢁC bath and 10% aqueous tar-
taric acid (11.5 mL) was added to the solution with stirring.
After 10 min, the cooling bath was removed and stirring
continued until the aqueous layer became clear after which
the aqueous solution was immediately extracted with
CH2Cl2 (3 · 30 mL). The combined organic extracts were
washed with water (30 mL) and brine (3 · 30 mL), dried
over Na2SO4, and concentrated on a rotary evaporator
below 10 ꢁC to leave a colorless oil whose odor indicated
contamination by TBHP. The oil was taken up in ether
in an ice bath and stirred with 1 M NaOH (6.8 mL) at
0 ꢁC for 30 min. The ether layer was washed with brine
(3 · 30 mL), dried over Na2SO4, and concentrated on a
rotary evaporator below 10 ꢁC to leave a clear oil. Chroma-
tography on silica gel, eluting with a 4:1 mixture of hexane
and EtOAc, afforded (ꢀ)-3 and (+)-4 in 40% (229 mg) and
38% (204 mg) yield, respectively.
4.5. (1R,2R,3R,6S,7S,10S,11S)-6,7-Dihydroxy-2,3-10,11-
bisepoxy-2,6,9,9-tetramethylcycloundecan-1-ol, (ꢀ)-6
(i) OsO4 method: A mixture of (ꢀ)-bisepoxyzerumbol
(120 mg, 0.476 mmol), OsO4 (242 mg, 0.953 mmol), and
N-methylmorpholineoxide (NMMO: 562 mg, 4.79 mmol)
in acetone/H2O/CH3CN (1/1/1, 6 mL) was stirred at
40 ꢁC for 45 h. The progress of the oxidation was moni-
tored by TLC. OsO4 was removed by filtration and the or-
ganic layer concentrated on a rotary evaporator. The
aqueous solution was extracted with ethyl acetate
(3 · 30 mL). The combined organic extracts were washed
with water (30 mL) and brine (3 · 30 mL), dried over
Na2SO4, and concentrated on a rotary evaporator. Chro-
matography on silica gel, eluting with EtOAc, afforded
enanatiomerically pure (ꢀ)-5 in 95% yield (129.5 mg).

T. Kitayama et al. / Tetrahedron: Asymmetry 17 (2006) 2311–2316
2315
1
(ii) AD-mixb method: A mixture of AD mix-b (1.40 g), tert-
BuOH (5 mL), H2O (5 mL), and MeSO2NH2 (0.095 g) was
cooled to 0 ꢁC, where upon some of the dissolved salts pre-
cipitated. Bisepoxyzerumbol, (ꢀ)-3 (0.25 g, 1 mmol) was
added and the reaction mixture was stirred with a mechan-
ical stirrer for 24 h at 0 ꢁC, after which time TLC analysis
indicated a lack of starting alkene. Sodium sulfite (1.5 g)
was added and the mixture stirred for 1 h while it came
to room temperature. EtOAc (10 mL) was added and after
separation of the layers, the aqueous layer was re-extracted
with more EtOAc (3 · 5 mL). The combined extracts were
washed with 2 M KOH (15 mL), dried (MgSO4), and the
IR (KBr) 3447, 2978, 2959, 2934, 1396 cmꢀ1; H NMR; d
0.91 (s, 3H, CH3 at C9), 1.14 (s, 3H, CH3 at C9), 1.35 (s,
3H, CH3 at C6), 1.43 (s, 3H, CH3 at C2), 1.60 (s, 2H, H2
at C4), 1.66 (s, 2H, H2 at C8), 2.22 (s, 1H, H at C5), 2.30
(t, 1H, J = 5.3 Hz, H at C5), 2.60 (d, 1H, J = 2.6 Hz, H
at C7), 2.88 (s, 1H, H at C10), 2.98 (dd, 1H, J = 5.3 and
10.6 Hz, H at C3), 3.11 (s, 1H, H at C11), 4.19 (s, 1H, H
at C10) 13C NMR; 15.5 (CH3 at C2), 16.7 (CH3 at C6),
18.0 (CH3 at C9), 25.1 (C4), 29.2 (CH3 at C9), 33.1 (C9),
35.0 (C5), 37.8 (C8), 55.4 (C3), 55.5 (C11), 58.8 (C10),
60.1 (C6), 60.3 (C2), 61.6 (C7), 68.0 (C1). HRMS: m/z
calcd mass for C15H24O4 268.1675, found 268.1684.
solvent was removed on a rotary evaporator to afford 5
23:5
in 70% yield (198 mg). Mp 148–150 ꢁC, ½aꢁD ¼ ꢀ2:6 (c
4.8. X-ray crystallographic study of (ꢀ)-7
1.07, EtOH), IR (KBr) 3481, 2976, 2932, 1479 cmꢀ1; H
1
NMR: d 0.89 (s, 3H, CH3 at C6), 1.10 (s, 6H, CH3 at C9
and CH3 at C9), 1.26–1.41 (m, 2H, H2 at C8), 1.45 (s,
3H, CH3 at C2), 1.63–1.66 (m, 2H, H2 at C5), 1.87 (d,
2H, J = 3.9 Hz, H2 at C4), 2.35 (s, 1H, OH at C6), 2.54
(s, 1H, OH at C7), 2.72 (dd, 1H, J = 1.2 and 15.8 Hz, H
at C10), 2.8d, 1H, J = 3.6 Hz, H at C3), 3.23 (s, 1H, H at
C11), 3.52 (dd, 1H, J = 3.3 and 8.6 Hz, H at C1), 4.25 (s,
1H, H at C7); 13C NMR: d 15.5 (CH3 at C2), 18.4 (CH3
at C6), 20.0 (C4), 22.9 (CH3 at C9), 29.9 (CH3 at C9),
33.1 (C9), 34.6 (C5), 42.1 (C8), 55.1 (C11), 59.2 (C3
and C10), 62.6 (C2), 66.5 (C7), 70.4 (C1), 74.2 (C6).
HRMS: m/z calcd mass for C15H26O5 286.1780, found
268.1793.
A colorless prism crystal, crystal size 0.40 · 0.50 ·
0.18 mm3, monoclinic, space group P21 (no. 4), a =
˚
9.301(8), b = 5.724(5), c = 13.932(12) A, b = 104.845(9)ꢁ,
3
V = 716.9(10) A , Z = 2, Dcalcd = 1.243 g/cm3, l(Mo-
˚
Ka) = 0.88 cmꢀ1, was used for data collection. The inten-
sity data were measured on a Rigaku Mercury CCD detec-
tor using Mo-Ka radiation at a temperature of ꢀ180
1 ꢁC. The structure was solved by direct methods (SIR97)11
and expanded using Fourier techniques (DIRDIF99).12
All calculations were performed using the Crystal Structure
crystallographic software package. The final cycle of
full-matrix least-squares refinement on F2 was based on
3164 reflections (all data) and 268 variable parameters
and gave R1 = 0.032 (I > 2.0r(I)) and wR2 = 0.083 (all
data). The value of the goodness of fit indicator was 1.02
(Summary of Data CCDC 285435).
4.6. X-ray crystallographic study of (ꢀ)-6
A
colorless prism crystal, crystal size 0.20 · 0.10 ·
0.10 mm3, monoclinic, space group Cc (no. 9), a =
4.9. (1SR,2SR,3SR)-2,3-Epoxy-2,6,9,9-tetramethyl-6,10-
cycloundecadienyl 4-chloro-3,5-dinitrobenzoate, ( )-8
˚
16.73(2), b = 8.518(10), c = 11.051(12) A, b = 105.004(13)ꢁ,
V = 1520.8(30) A , Z = 4, Dcalcd = 1.251 g/cm3, l(Mo-Ka) =
3
˚
0.92 cmꢀ1, was used for data collection. The intensity
data were measured on a Rigaku Mercury CCD detector
using Mo-Ka radiation at a temperature of ꢀ180 1 ꢁC.
The structure was solved by direct methods (SIR97)11
and expanded using Fourier techniques (DIRDIF99).12 All
calculations were performed using the Crystal Structure
crystallographic software package. The final cycle of
full-matrix least-squares refinement on F2 was based on
3017 reflections (all data) and 285 variable parameters
and gave R1 = 0.043 (I > 2.0r(I)) and wR2 = 0.090 (all
data). The value of the goodness of fit indicator was 1.26
(Summary of Data CCDC 285434).
Under an atmosphere of N2, the mixture of (+)-4 (40.3 mg,
0.17 mmol), 4-dimethylaminopyridine (4.6 mg, 0.04 mmol),
4-chloro-3,5-dinitrobenzoic acid (43.6 mg, 0.18 mmol), and
N,N0-dicyclohexylcarbodiimide (54.3 mg, 0.26 mmol) in
5 mL anhydrous CH2Cl2 was stirred at 0 ꢁC for 5 min
and then at room temperature for 3 h. Water (15 mL)
was then added to the solution and the reaction stirred
for 20 min. The precipitated urea was filtered off and the
filtrate extracted with CH2Cl2 (2 · 20 mL). The combined
organic solutions were washed with 0.5 M HCl and satu-
rated aq NaHCO3, and then dried over Na2SO4, and con-
centrated on a rotary evaporator to afford a colorless solid
residue. Chromatography on silica gel, eluting with a 4:1
mixture of hexane and EtOAc afforded 8 in 40% yield.
mp 128.0–129.5 ꢁC; IR (KBr) 1278.6, 1349.0, 1549.5,
4.7. (1R,2R,3R,6S,7S,10S,11S)-2,3-6,7-10,11-Triepoxy-
2,6,9,9-tetramethylcycloundecan-1-ol, (ꢀ)-7
1731.8 cmꢀ1 1H NMR: d 1.17 (s, 6H, 2 · CH3 at C9),
;
A mixture of (ꢀ)-bisepoxyzerumbol (300 mg, 1.19 mmol)
and MCPBA (247 mg, 1.43 mmol) in ethyl acetate
(30 mL) was stirred at 0 ꢁC for 1 h and then at room tem-
perature for 21 h. The progress of the epoxidation was
monitored by TLC. Ethyl acetate (10 mL) was added to
the reaction mixture and washed with NaHCO3
(5 · 30 mL) and brine (3 · 30 mL), dried over Na2SO4,
and concentrated on a rotary evaporator. Chromatography
on silica gel, eluting with a mixture of EtOAc and hexane
1.40 (s, 3H, CH3 at C2), 1.41–1.49 (m, 1H, H at C4),
1.55 (s, 3H, CH3 at C6), 1.91 (dd, 1H, J = 4.4, 13.9 Hz,
H at C8), 1.96–2.03 (m, 1H, H at C4), 2.09 (dd, 1H,
J = 9.9 and 13.9 Hz, H at C8), 2.22 (m, 2H, H2 at C5),
2.66 (dd, 1H, J = 2.9 and 10.6 Hz, H at C3), 5.11 (dd,
1H, J = 4.4, 9.9 Hz, H at C7), 5.42 (dd, 1H, J = 5.5 and
16.5 Hz, H at C11), 5.48 (d, 1H, J = 5.5 Hz, H at C1),
5.50 (d, 1H, J = 16.5 Hz, H at C10), 8.54 (s, 2H, H at
C20); 13C NMR: d 15.6 (CH3 at C6), 16.6 (CH3 at C2),
24.1 (C4), 25.2 (CH3 at C9), 29.3 (CH3 at C9), 36.8 (C9),
36.9 (C5), 40.3 (C8), 59.5 (C3), 62.7 (C2), 76.2 (C1),
(1/1), afforded enantiomerically pure (ꢀ)-7 in 96% yield
23:5
(307 mg). Mp 107–109 ꢁC, ½aꢁD ¼ ꢀ4:5 (c 0.101, EtOH),

2316
T. Kitayama et al. / Tetrahedron: Asymmetry 17 (2006) 2311–2316
123.8 (C11), 124.5 (C10), 124.9 (C7), 128.1 (C20), 131.0
supported by the Ministry of Education, Science, Sports,
and Culture, Grant-in-Aid for Scientific Research (B),
17406003, 2005.
(C6), 132.8 (C40), 140.0 (C10), 149.5 (C30), 160.9 (C@O).
4.10. Crystallographic studies of ( )-8
References
A colorless prism, 0.60 · 0.20 · 0.10 mm, triclinic, space
group P ꢀ 1 (no. 2), a = 10.158(4), b = 12.081(5),
3
˚
˚
1. Schreiber, S. L. Science 2000, 287, 1964–1969.
2. Dev, S. Tetrahedron 1960, 8, 171–180.
c = 19.656(6) A, V = 2149.5(13) A , Z = 4, Dc = 1.437 g/
cm3, l(Mo-Ka) = 2.25 cmꢀ1 was used for data collection.
The intensity data were measured on a Rigaku RAPID
detector using Mo-Ka radiation at a temperature of
ꢀ180 + 1 ꢁC. The structure was solved by direct methods
(SIR97)11 and expanded using Fourier techniques (DIR-
DIF99).12 All the calculations were performed using the
Crystal Structure crystallographic software package. The
final cycle of full-matrix least-squares refinement was based
on 9635 observed reflections and 777 variable parameters
and gave R1 = 0.039 and wR2 = 0.096. The value of the
goodness of fit indicator was 1.01. (Summary of Data
CCDC 611417.)
3. Kitayama, T.; Okamoto, T.; Hill, R. K.; Kawai, Y.;
Takahashi, S.; Yonemori, S.; Yamamoto, Y.; Ohe, K.;
Uemura, S.; Sawada, S. J. Org. Chem. 1999, 64, 2667–2672.
4. Kitayama, T.; Yokoi, T.; Kawai, Y.; Hill, R. K.; Morita, M.;
Okamoto, T.; Yamamoto, Y.; Fokin Valery, V.; Sharpless,
K. Barry; Sawada, S. Tetrahedron 2003, 59, 4857–4866.
5. Ohe, K.; Miki, K.; Yanagi, S.; Tanaka, T.; Sawada, S.;
Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 3627–3634.
6. Kitayama, T.; Takatani, M.; Yamamoto, K.; Utsumi, R.;
Okamoto, T.; Hill, R. K.; Kawai, Y.; Sawada, S. Biosci.
Biotechnol. Biochem. 2001, 65, 2193–2199.
7. Murakami, A.; Takahashi, M.; Jiwajinda, M. S.; Koshimizu,
K.; Ohigashi, H. Biosci. Biotechnol. Biochem. 1999, 63, 1811–
1812.
8. Yamamoto, K.; Kitayama, T.; Minagawa, S.; Watanabe, T.;
Sawada, S.; Okamoto, T.; Utsumi, R. Biosci. Biotechnol.
Biochem. 2001, 65, 2306–2310.
9. Kitayama, T.; Masuda, T.; Kawai, Y.; Hill, R. K.; Takatani,
M.; Sawada, S.; Okamoto, T. Tetrahedron: Asymmetry 2001,
12, 2805–2810.
10. Kitayama, T.; Nagao, R.; Masuda, T.; Hill, R. K.; Morita,
M.; Takatani, M.; Sawada, S.; Okamoto, T. J. Mol. Catal. B:
Enzym. 2002, 17, 75–79.
11. Altomare, A.; Burla, M.; Camalli, M.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A.; Polidori, G.;
Spagna, R. J. Appl. Crystallogr. 1999, 32, 115–119.
12. Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W.
P.; de Gelder, R.; Israel, R.; Smits, J. M. M. The DIRDIF-99
program system, Technical Report of the Crystallography
Laboratory; University of Nijmegen: The Netherlands, 1999.
Acknowledgments
Rhizomes of Zingiber zerumbet Smith and zerumbone were
supplied by Taiyo Corporation. We wish to express our
sincerest gratitude to Professor Tadashi Okamoto for his
valuable suggestions and discussions. We thank Dr.
Hikaru Takaya for advice and helpful discussions. We
are also grateful to Dr. Masanori Morita for the measure-
ment of HRMS. We are indebted to Dr. Masahiro Taka-
tani for his assistance. This work is supported by the
Program for Promoting the Advancement of Academic
Research at Private Universities, by a grant from Taiyo
Corporation, and by SUNBOR Grant from Suntory Insti-
tute for Bioorganic Research. This research was partially