Synthesis of optically active tetrahydrozerumbone

Article abstract of DOI:10.1016/j.tetasy.2009.11.030

Tetrahydrozerumbone 2, which has a powerful balmy fragrance, has a stereogenic carbon at C2 and can be easily prepared from zerumbone 1, which is one of the most important materials that displays an NMRDOS character. Reduction of 2 gave two diastereomers 3 and 4; their optically active (>99% ee) alcohols were obtained by lipase-catalyzed stereoselective transesterification of each racemic alcohol. The enantioselectivity of tetrahydrozerumbol does not entirely depend on the hydroxyl position but on the 2-methyl position. Compounds (R)-2 and (S)-2 were obtained by Dess-Martin oxidation of the corresponding alcohols. Interestingly, (R)-2 showed a strong balmy fragrance while (S)-2 had hardly any fragrance.

Full text of DOI:10.1016/j.tetasy.2009.11.030

Tetrahedron: Asymmetry 21 (2010) 11–15
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of optically active tetrahydrozerumbone
a
b
a
a
Takashi Kitayama a, , Sayo Ohta , Yasushi Kawai , Tomoyasu Nakayama , Masataka Awata
*
a Department of Advanced Bioscience, Graduate School of Agriculture, Kinki University, Nara 631-8505, Japan
b Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetrahydrozerumbone 2, which has a powerful balmy fragrance, has a stereogenic carbon at C2 and can
be easily prepared from zerumbone 1, which is one of the most important materials that displays an
NMRDOS character. Reduction of 2 gave two diastereomers 3 and 4; their optically active (>99% ee) alco-
hols were obtained by lipase-catalyzed stereoselective transesterification of each racemic alcohol. The
enantioselectivity of tetrahydrozerumbol does not entirely depend on the hydroxyl position but on the
2-methyl position. Compounds (R)-2 and (S)-2 were obtained by Dess–Martin oxidation of the corre-
sponding alcohols. Interestingly, (R)-2 showed a strong balmy fragrance while (S)-2 had hardly any
fragrance.
Received 26 September 2009
Revised 25 November 2009
Accepted 26 November 2009
Available online 11 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
Zerumbone 11,2 has the potential to become one of the most
important compounds displaying NMRDOS3 character and contains
three double bonds; an isolated one at C6, and two at C2 and C10,
which are part of a cross-conjugated dienone system. Zerumbone 1
is a monocyclic sesquiterpene found as the major component of
the essential oil of wild ginger, Zingiber zerumbet Smith. It is antic-
ipated to be a powerful tool in the implementation of green chem-
istry with respect to the provision of materials following on from
the cultivation of ginger, therefore, the chemistry of zerumbone
plays an important role in material sciences.
*
Tetrahydrozerumbone 2
Zerumbone 1
Balmy fragrance
Scheme 1.
An X-ray structure4 reveals that the dienone system lies in a
slightly distorted plane which is perpendicular to that of the iso-
lated double bond. Therefore, zerumbone 1 and its derivatives ex-
hibit a variety of interesting reactions, for example, transannular
ring contraction and cyclization,2 regioselective conjugate addi-
tions;2,5 various regiospecific ring cleavage reactions,5,6 ring
expansion,3 unique asymmetric epoxidation,7 and lipase-catalyzed
transesterification.8,9 Moreover, it was found that some of the no-
vel zerumbone derivatives possessed intriguing bioactivities.5,10–12
In particular, tetrahydrozerumbone 2 with a powerful balmy fra-
grance has a stereogenic carbon at C2 and is prepared easily from
zerumbone 111,12 in spite of the distinctly characteristic odor of
zerumbone 1 (Scheme 1).
Herein we report that two optically active compounds of 2 were
synthesized to elucidate the effect of the fragrance. We have devel-
oped a kinetic resolution by lipase-catalyzed transesterification
against some zerumbone diastereomers with a comparatively long
distance between the two stereogenic centers.9 Two types of alco-
hol, 3 and 4, which were obtained by the reduction of 2 have two
stereogenic centers in which the distance is shortest. The kinetic
resolution of 3 and 4 was studied using lipase-catalyzed transeste-
rification and it was found that their stereoselectivity was different
from those of other zerumbone derivatives. Two optically active
compounds 2 were obtained after their oxidation, and finally the
main fragrance component was confirmed.
It is expected that there is a difference in odor between the two
optically active compounds of tetrahydrozerumbone 2. It is very
attractive scientifically to elucidate the difference, which would
enable its wide use as a source of a new fragrance.
2. Results and discussion
As shown in Scheme 2 and Table 1, zerumbone 1 was hydroge-
nated using a 5%Pd/C system to afford racemic tetrahydrozerum-
bone 2, with a balmy fragrance, in high yield (77–94%). Although
* Corresponding author. Fax: +81 742 43 8976.
E-mail address: kitayama@nara.kindai.ac.jp (T. Kitayama).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.030

12
T. Kitayama et al. / Tetrahedron: Asymmetry 21 (2010) 11–15
O
O
*
2H2, 5%Pd/C, solvent
r.t., 100 min
1
2
Scheme 2.
Table 1
Hydrogenation of zerumbone with 5%Pd/C
Solvent
5%Pd/C (mol %)
Yield (%)
EtOH
EtOH
IPA
Acetone
Acetone
AcOEt
CHCl3
Hexane
Hexane
0.8
0.3
0.3
0.5
0.2
0.4
0.5
0.5
0.2
88
89
93
89
82
80
77
89
94
Figure 1. ORTEP drawing of the crystal structure of racemic tetrahydrozerumbol 3.
by GC using a capillary column (CP-CD; CP-cyclodextrin-B-236-
M-19). Predictably, all lipases, especially for Alcaligenes sp., pro-
duced the corresponding acetate in good yield. Moreover, the E
value14 of the lipase-catalyzed reaction was far greater than that
of other zerumbone derivatives as substrates. The remaining chi-
ral alcohols 7 and 8 were oxidized with the Dess–Martin reagent
to afford the corresponding chiral ketones 2. Each ketone
showed a minus sign for its specific rotation, therefore, the
enantioselectivity of the threo-form at the hydroxyl position
was different from that of the erythro-form.
the hydrogenation of an isolated olefin is typically easier than that
of a conjugated olefin, zerumbone showed the opposite selectivity
during hydrogenation, which might affect the reaction selectivity
may be because the planar surface made from the sp2 hybridized
orbital of the conjugated olefin is distorted.
As shown in Scheme 3, racemic tetrahydrozerumbone 2 was re-
acted with LiAlH4 (LAH) in dry Et2O at 0 °C for 30 min and the dia-
stereomeric mixture was separated by silica gel chromatography
to afford racemic threo tetrahydrozerumbol 3 and the erythro-form
4 in 34% and 39% yields, respectively. The chemical shifts and cou-
pling constants of 1H NMR (400 MHz) spectra showed almost the
same value but the states of the substances were quite different.
Racemic 3 was obtained as a solid state and racemic 4 in a liquid
state.
Monoclinic single crystals of racemic 3 were obtained by recrys-
tallization from CH2Cl2/hexane and subjected to X-ray analysis.
The X-ray structure of 3 showed the relative configuration of
(1SR,2SR), as shown in Figure 1.
As shown in Scheme 4, the lipase-catalyzed kinetic transesteri-
fications of 3 and 4 were studied after which we attempted to oxi-
dize the chiral alcohols 7 and 8 using the Dess–Martin agent to give
target ketone 2 and confirm the fragrance.
As shown in Scheme 5 and Figure 2, the absolute configuration
of the remaining alcohol 7 via lipase-catalyzed transesterification
was determined by anomalous dispersion of heavy atom deriva-
tives. For this purpose, 7 was converted to its 4-chloro-3,5-dinitro-
benzoate 9. An orthorhombic crystal of
9 was obtained by
recrystallization from hexane, and was subjected to X-ray analysis.
It was determined that the absolute configuration of 7 was the
(1R,2R)-form and the Flack parameter was 0.05.15 Finally, (ꢀ)-
(R)-2 was obtained from 7 upon treatment with the Dess–Martin
reagent, and (+)-(S)-2 was obtained by the same treatment after
hydrolysis of 6 with NaOH.
The difference of the fragrance between the optically active
compounds (R)-2 and (S)-2 was verified. It was elucidated that
(ꢀ)-(R)-2 was the main component with the balmy fragrance
and not (+)-(S)-2. We believe that if the balmy fragrance can
be produced inexpensively and in large quantities, zerumbone
chemistry will achieve great developments from the viewpoint
of using natural products. Moreover, optically active tetra-
hydrozerumbone with attractive properties suggests the new
possibility of biological activity. Consequently, the efficient syn-
thesis of optically active 2 should be studied for the development
of this field.
Table 2 shows the detailed results from the transesterification
of 3 and 4 with isopropenyl acetate in THF at 35 °C in the pres-
ence of some lipases that were compatible with several zerum-
bone derivatives, as found in our previous work.8,9,13 The
lipase-catalyzed reaction was monitored by GC using a normal
column (DB-5) and the enantiomeric excess (ee) was checked
O
OH
OH
threo
LAH / abs Et2O
0ºC, 30 min
OH
quant
erythro
racemic threo 3: solid
racemic erythro 4: oil
racemic-2
Scheme 3.

T. Kitayama et al. / Tetrahedron: Asymmetry 21 (2010) 11–15
13
OH
OAc
OH
O
*
*
*
*
*
Lipase,
THF, 35ºC
oxidation
OAc
+
racemic
3 (threo), 4 (erythro)
chiral
5 (threo), 6 (erythro)
chiral
7 (threo), 8 (erythro)
chiral 2
Scheme 4.
Table 2
Transesterification of 3 and 4 using various lipases in THF
Lipase
Substrate: 3
Substrate: 4
Time
(d)
Conversion
(%)
E value
Time
(d)
Conversion
(%)
E value
MeitoQL
MeitoQLM
Amano PS
Amano AK
Amano R
Meito TL
CAL-B
8
24
18
14
18
15
15
11
52
8
6
0.4
2
230
150
220
210
200
200
200
23
30
23
23
7
31
52
4
15
3
160
120
200
160
200
0
25
15
6
1
1
200
3. Conclusion
Racemic tetrahydrozerumbone with a balmy fragrance was sep-
arated into two optically active compounds (R)-2 and (S)-2 ob-
tained by oxidation of the corresponding chiral alcohols via
lipase-catalyzed enantioselective transesterification of the racemic
form. We found that the lipase recognizes the difference in stereo-
chemistry not at the hydroxyl position, but at the 2-methyl posi-
tion. It was elucidated that (ꢀ)-(R)-2 was the main component
with a balmy fragrance.
Figure 2. ORTEP drawing of the crystal structure of 9.
by direct injection. Optical rotations were measured on a JASCO
DIP-140 polarimeter. The X-ray diffraction and CCDC numbers ap-
pear in the section on compound data. Melting points were re-
corded on a Yanako MP-J3. Chemicals were of commercially
available reagent grade, and used without further purification.
4. Experimental
4.1. General methods
Column chromatography was performed on silica gel (70–230
mesh). TLC was performed on Merck 60 F254 silica gel plates. The
enantiomeric excess (ee) values were determined by chiral GC
(CHROMPACK, CP-CD; CP-cyclodextrin-B-236-M-19). NMR spectra
were recorded on a Bruker instrument at 400 MHz for protons, and
100 MHz for 13C in CDCl3 with tetramethylsilane (TMS) as the
internal standard. Chemical shifts d were reported in parts per mil-
lion (ppm) from TMS. Infrared spectra were recorded on a Shima-
dzu FRIR-8200D spectrophotometer. Mass spectra were recorded
at 70 eV, and high-resolution mass spectra (HRMS) were obtained
4.1.1. 2,6,9,9-Tetramethylcycloundec-6-enone (tetrahydrozerum-
bone) 2
Under an atmosphere of H2, 5%Pd/C (0.2 mol %) was added to a
solution of zerumbone 1 (100 mg, 0.46 mmol) in hexane (20 mL)
and stirred for 100 min at room temperature. The reaction mixture
was filtered on Celite and the filtrate was concentrated. The resi-
due was subjected to silica gel column chromatography using ethyl
acetate and hexane (1:50) as an eluent to afford racemic 2,6,9,9-
tetramethylcycloundec-6-enone (tetrahydrozerumbone) 2 in 94%
OR
O
*
*
*
NO2
Cl
O
O
R
R
NO2
NO2
Cl
NO2
1) hydrolysis
2
6 (R: Ac)
(+)-(S)-
*
*
*
*
HO2C
2) Dess-Martin
DCC, DMAP,
7
(R: H)
(-)-(R)-2
Dess-Martin
9
Scheme 5.

14
T. Kitayama et al. / Tetrahedron: Asymmetry 21 (2010) 11–15
(96.2 mg) yield. Colorless oil. IR (NaCl film) 2930, 1711, 1458 cmꢀ1
.
K
a
) = 0.624 cmꢀ1 was used for data collection. The intensity data
were measured on a Rigaku Mercury CCD detector using Mo K
1H NMR (CDCl3): d 0.97 (s, 6H, 2CH3 at C9), 0.99 (d, 3H, J = 6.9 Hz,
CH3 at C2), 1.41–1.54 (3H at C3, C4 and C10), 1.55 (s, 3H, CH3 at
C6), 1.58–1.76 (m, 3H, H at C3, C4 and C10), 1.93 (d, 2H,
J = 7.3 Hz, H at C8), 2.00–2.02 (m, 2H, H at C5), 2.41–2.45 (m, 2H,
H at C11), 2.57–2.61 (m, 1H, H at C2), 5.24 (t, 1H, J = 7.3 Hz, H at
C7), 13C NMR d 16.1 (CH3 at C6), 16.1 (CH3 at C2), 21.8 (CH2 at
C4), 29.3 (CH3 at C9), 29.7 (CH3 at C9), 32.4 (CH2 at C3), 33.6
(C9), 33.7 (CH2 at C10), 35.3 (CH2 at C11), 39.7 (CH2 at C5), 40.7
(CH2 at C8), 44.5 (CH at C2), 123.6 (CH at C7), 134.8 (C6), 213.6
(C1). HRMS (M+H+): m/z calcd mass for C15H27O 223.2062, found
223.2096.
a
radiation at a temperature of ꢀ180 1 °C. The structure was solved
by direct methods (SIR97)16 and expanded using Fourier techniques
(
DIRDIF99).17 All the calculations were performed using the Crystal-
Structure crystallographic software package. The final cycle of
full-matrix least-squares refinement was based on 5131 observed
reflections (I > 2.00
R1 = 0.1024 and wR2 = 0.2274. The value of the goodness of fit indi-
cator was 1.392. (Summary of Data CCDC 746556).
r (I)) and 345 variable parameters and gave
4.4. General procedure of lipase-catalyzed transesterification of
racemic 3
4.2. Reduction of 2
A mixture of racemic 3 (or 4) (10 mg, 4.5 ꢁ 10ꢀ2 mmol), isopro-
penyl acetate (1.0 mL, 9.2 mmol), and the lipase (dry MeitoQLM,
50 mg) in THF (2 mL: water content <1.0% v/v) was stirred for 24
d at 35 °C. The conversion was 52%. The reaction was followed by
gas chromatography using a column of DB-5 (detector and injec-
tion temperature, 220 °C; column temperature, 180 °C; carrier
gas, He; linear velocity: 30 cm/s, FID detector). Under these condi-
tions, the retention time of racemic 3 (or 4) and its corresponding
acetate were 6.7 min and 8.4 min (6.6 min and 8.2 min), respec-
tively. The reaction mixture was filtered and the filtrate was con-
centrated. Chromatography on silica gel, eluting with a 50:1
mixture of hexane and EtOAc, afforded 7 and acetate 5 in 99.8%
and 91.3% ee (8 and acetate 6 in 99.4% and 91.2% ee), respectively,
as determined by gas chromatography using a column of CPCD
(detector and injection temperature, 180 °C; column temperature,
130 °C (5 and 7) and 120 °C (6 and 8); carrier gas He; linear veloc-
ity: 30 cm/s, FID detector). Under these conditions the retention
times of 5, 7, 6, and 8 were 68, 72, 111, and 118 min, respectively.
Under an N2 atmosphere, tetrahydrozerumbone
2 (0.81 g,
3.7 mmol) in absolute Et2O (7 mL) was added dropwise to a sus-
pension of LiAlH4 (0.10 g, 3.1 mmol) in absolute Et2O (2 mL) at
0 °C, which was stirred for 30 min in ice salt bath. Next, H2O
(50 mL) and 2 M H2SO4 (10 mL) were added, and Et2O was re-
moved by rotary evaporator; the mixture was extracted with
EtOAc (3 ꢁ 30 ml). The combined organic solutions were washed
with brine (3 ꢁ 30 mL), dried over Na2SO4, and concentrated on a
rotary evaporator. The residue was subjected to silica gel column
chromatography using AcOEt and hexane (1:12) as an eluent to af-
ford (1RS,2RS)-threo-2,6,9,9-tetramethylcycloundec-6-enol 3 and
(1RS,2SR)-erythro-2,6,9,9-tetramethylcycloundec-6-enol 4 in 34%
(0.28 g) and 39% (0.32 g) yield, respectively.
4.2.1. (1RS,2RS)-threo-2,6,9,9-Tetramethylcycloundec-6-enol 3
Mp 60.5–71.0 °C. IR (KBr) 3452, 2947, 1460 cmꢀ1 1H NMR: d
.
0.91 (d, 3H, J = 6.6 Hz, CH3 at C2), 0.93 (s, 3H, CH3 at C9), 0.98 (s,
3H, CH3 at C9), 1,09–1.21 (m, 2H, H at C3 and 10), 1.32 (dd, 1H,
J = 12.1 and 12.6 Hz, H at C10), 1.44–1.70 (m, 6H, 2H at C4 and
C11 and H at C2 and C3), 1.58 (s, 3H, CH3 at C6), 1.93 (d, 2H,
J = 6.9 Hz, H at C8), 2.06–2.12 (m, 2H, H at C5), 3.24 (q, 1H,
J = 5.6, 4.1 and 6.2 Hz, H at C1), 5.27 (t, 1H, J = 6.9 Hz, H at C7),
13CNMR: d 15.3 (CH3 at C6), 16.1 (CH3 at C2), 21.4 (CH2 at C3),
26.3 (CH2 at C11), 27.2 (CH3 at C9), 32.1 (CH2 at C4), 32.3 (CH2 at
C10), 32.7 (CH at C2), 32.8 (CH3 at C9), 33.0 (C9), 38.8 (CH2 at
C5), 40.0 (CH2 at C8), 75.9 (CH at C1), 124.6 (CH at C7), 133.6
(C6). HRMS (M+H+): m/z calcd mass for C15H29O 225.2218, found
225.2219. Anal. Calcd for C15H28O: C, 80.29; H, 12.58. Found: C,
79.99; H, 12.62.
4.4.1. (1S,2S)-1-Acetoxy-2,6,9,9-tetramethyl-6-cycloundecene, 5
Colorless oil. ½a D23:5
ꢂ
¼ þ33:9 (c 1.01, CHCl3), 91.2% ee. IR(NaCl
film) 2952, 1736, 1468 cmꢀ1
.
1H NMR (CDCl3): d 0.80 (d, 3H,
J = 6.6 Hz, CH3 at C2), 0.90 (s, 3H, CH3 at C9), 0.96–1.05 (m, 2H, H
at C3 and C10), 0.97 (s, 3H, CH3 at C9), 1.16 (t, 1H, J = 11.4 and
11.8 Hz, H at C3), 1.33 (t, 1H, J = 11.2 and 13.4 Hz, H at C10),
1.47–1.58 (m, 3H, 2H at C4 and H at C11), 1.60 (s, 3H, CH3 at C6),
1.68–1.77 (m, 2H, H at C2 and C11), 1.91–1.93 (br, 2H, H at C8),
2.02 (s, 3H, CH3 at CH3CO), 2.10–2.17 (m, 2H, H at C5), 4.46 (ddd,
1H, J = 5.5, 5.4 and 4.5 Hz, H at C1), 5.29 (dd, 1H, J = 7.0 and
6.7 Hz, H at C7), 13C NMR: d 15.3 (CH3 at C6), 16.0 (CH3 at C2),
21.0 (CH3 at OCOCH3), 21.3 (CH2 at C4), 23.7 (CH2 at C11), 27.1
(CH3 at C9), 31.2 (CH at C2), 31.7 (CH2 at C3), 32.2 (CH3 at C9),
32.8 (CH2 at C10), 32.9 (C9), 39.0 (CH2 at C5), 40.1 (CH2 at C8),
78.1 (CH at C1), 124.6 (CH at C7), 133.7 (C6), 170.7 (CO). HRMS
(M+Na+): m/z calcd mass for C17H30O2Na 289.2143, found
289.2090.
4.2.2. (1RS,2SR)-erythro-2,6,9,9-Tetramethylcycloundec-6-enol 4
Colorless oil. IR (NaCl film) 3375, 2952, 1460 cmꢀ1 1H NMR: d
.
0.94 (s, 3H, CH3 at C9), 0.94 (s, 3H, CH3 at C9), 0.95 (d, 3H,
J = 7.1 Hz, CH3 at C2), 0.85–1.01 (m, 2H, H at C10 and C11), 1.17–
1.33 (m, 3H, H at C3, C10 and 11), 1.47–1.68 (m, 4H, 2H at C4
and H at C2 and C3), 1.60 (s, 3H, CH3 at C6), 1.90 (d, 2H,
J = 6.8 Hz, H at C8), 2.11–2.14 (m, 2H, H at C5), 3.28 (d, 1H,
J = 10.9 Hz, H at C1), 5.25 (t, 1H, J = 6.8 Hz, H at C7), 13CNMR: d
15.3 (CH3 at C6), 18.1 (CH3 at C2), 21.1 (CH2 at C4), 22.6 (CH2 at
C11), 26.7 (CH3 at C9), 29.3 (CH2 at C3), 31.6 (CH at C2), 32.5
(CH3 at C9), 33.2 (C9), 36.1 (CH2 at C10), 39.0 (CH2 at C5), 39.9
(CH2 at C8), 77.4 (CH at C1), 124.6 (CH at C7), 133.5 (C6). HRMS
(M+H+): m/z calcd mass for C15H29O 225.2218, found 225.2229.
Anal. Calcd for C15H28O: C, 80.29; H, 12.58. Found: C, 79.87; H,
12.65.
4.4.2. (1R,2S)-1-Acetoxy-2,6,9,9-tetramethyl-6-cycloundecene, 6
Colorless oil. ½a D23:5
ꢂ
¼ ꢀ33:8 (c 1.05, CHCl3), 91.1% ee IR (NaCl
film) 2932, 1790, 1460 cmꢀ1
.
1H NMR (CDCl3): d 0.86 (d, 3H,
J = 6.9 Hz, CH3 at C2), 0.92 (s, 3H, CH3 at C9), 0.94 (s, 3H, CH3 at
C9), 0.89–1.10 (m, 2H, H at C3 and C10), 1.26–1.32 (m, 2H, H at
C10 and C11), 1.34–1.49 (m, 2H, H at C3 and C4), 1.62 (s, 3H,
CH3 at C6), 1.65–1.67 (m, 3H, H at C2, C4 and C11), 1.89–1.93
(br, 2H, H at C8), 1.99 (s, 3H, CH3 at CH3CO), 2.04–2.15 (m, 2H,
H2 at C5), 4.48 (d, 1H, J = 10.4 Hz, H at C1), 5.28 (t, 1H, J = 6.7 Hz,
H at C7), 13C NMR d 15.3 (CH3 at C6), 17.9 (CH3 at C2), 21.2 (CH3
at OCOCH3), 23.3 (CH2 at C4), 25.9 (CH2 at C11), 26.2 (CH3 at C9),
28.1 (CH2 at C3), 30.5 (CH at C2), 32.6 (CH3 at C9), 33.3 (C9), 35.7
(CH2 at C10), 39.2 (CH2 at C5), 40.1 (CH2 at C8), 79.6 (CH at C1),
124.6 (CH at C7), 133.7 (C6), 171.0 (CO). HRMS (M+Na+): m/z calcd
mass for C17H30O2Na 289.2143, found 289.2221.
4.3. Crystallographic study of racemic 3
A colorless prism, 0.40 ꢁ 0.10 ꢁ 0.10 mm, monoclinic, space
group P21/a (no.14), a = 10.877(5), b = 10.406(4), c = 25.754(12) Å,
b = 102.231(16)°, V = 2848.7(20) Å3, Z = 8, Dc = 1.046 g/cm3,
l(Mo

T. Kitayama et al. / Tetrahedron: Asymmetry 21 (2010) 11–15
15
4.4.3. (1R,2R)-2,6,9,9-Tetramethylcycloundeca-6-enol, 7
for 1 h. Next, CH2Cl2 (30 mL) and 1 M NaOH aq (30 mL) were added
into the solution after which the aqueous solution was extracted
with CH2Cl2 (3 ꢁ 30 mL). The combined organic extracts were
washed with brine (3 ꢁ 30 mL), dried over Na2SO4, and concen-
trated on a rotary evaporator. The residue was subjected to silica
gel column chromatography using hexane and AcOEt (20/1) as an
eluent to afford (2R)-2,6,9,9-tetramethyl-6-cycloundecen-1-one,
Colorless oil. ½a D23:5
¼ þ10:0 (c 1.00, CHCl3), 99.8% ee. NMR spec-
ꢂ
tra were the same data with 3.
4.4.4. (1S,2R)-2,6,9,9-Tetramethylcycloundeca-6-enol, 8
Colorless oil. ½a D23:5
¼ þ32:8 (c 1.05, CHCl3), 99.4% ee. NMR spec-
ꢂ
tra were the same data with 4.
(ꢀ)-(R)-2 in 71% yield. ½a D23:5
¼ ꢀ53:6 (c 0.85, CHCl3), 99.8% ee.
ꢂ
4.4.5. (1R,2R)-2,6,9,9-Tetramethyl-6-cycloundecenyl 4-chloro-
3,5-dinitrobenzoate 9
NMR spectra were the same data with racemic 2.
Under an N2 atmosphere, a mixture of 7 (50.0 mg, 0.22 mmol),
4-dimethylaminopyridine (7.4 mg, 0.06 mmol), 4-chloro-3,5-dini-
trobenzoic acid (62.0 mg, 0.25 mmol), and N,N’-dicyclohexylcarbo-
diimide (66.0 mg, 0.32 mmol) in 3 mL of anhydrous CH2Cl2 was
stirred at 0 °C for 5 min and then at room temperature for 1.5 h.
Water (20 mL) was then added to the solution and the reaction
was stirred for 20 min. The precipitated urea was filtered off and
the filtrate extracted with CH2Cl2 (3 ꢁ 20 mL). The combined or-
ganic solutions were washed with 0.5 M HCl and saturated aq
NaHCO3, and then dried over Na2SO4, and concentrated on a rotary
evaporator to afford a light yellow solid residue. Chromatography
on silica gel, eluting with a 4:1 mixture of hexane and EtOAc affor-
4.5.2. (2S)-2,6,9,9-Tetramethyl-6-cycloundecen-1-one, (+)-(S)-2
A solution of aqueous NaOH (2.0 mL, 6.0 equiv) was added into
a solution of 6 (31.0 mg, 0.12 mmol) in MeOH (3 mL) at room tem-
perature and stirred at the same temperature for 2.5 h. Next, H2O
(20 mL) was added to the mixture at room temperature and the
aqueous solution was extracted with AcOEt (3 ꢁ 30 mL). The com-
bined organic extracts were washed with brine (3 ꢁ 30 mL), dried
over Na2SO4, and concentrated on a rotary evaporator. The residue
was subjected to silica gel column chromatography using hexane
and AcOEt (20/1) as an eluent to afford single diastereomer of
(1R,2S)-2,6,9,9-tetramethylcycloundeca-6-enol, 2, in 97% yield
(25.2 mg, 91.0% ee, ½a D23:5
¼ ꢀ22:9 (c 1.25, CHCl3)). The procedure
ꢂ
ded 9 in 73% yield. ½a D23:5
ꢂ
¼ ꢀ13:8 (c 0.85, CHCl3), 99.8% ee Mp
of the Dess–Martin oxidation of the (1R,2S)-form was the same
method as mentioned above. (2S)-2,6,9,9-Tetramethyl-6-cycloun-
decen-1-one, (+)-(S)-2 was obtained in 68% (17.7 mg, 91.0% ee).
102.0–107.0 °C. IR (KBr) 2951, 1722, 1547 cmꢀ1
.
1H NMR (CDCl3):
d 0.85 (d, 3H, J = 6.6 Hz, CH3 at C2), 0.91 (s, 3H, CH3 at C9), 0.98
(s, 3H, CH3 at C9), 1.05–1.11 (m, 1H, H at C3), 1.23–1.30 (m, 2H,
H at C3 and C10) 1.44 (dd, 1H, J = 11.1 and 12.1 Hz, H at C10),
1.59–1.77 (m, 3H, H at C4 and C11), 1.65 (s, 3H, CH3 at C6),
1.84–2.00 (m, 2H, H at C2 and C11), 1.96 (dd, 2H, J = 7.2 and
6.1 Hz, H at C8), 2.15 (t, 2H, J = 5.3 and 7.4 Hz, H2 at C5), 4.78 (q,
1H, J = 4.1 and 6.9 and 4.1 Hz, H at C1), 5.34 (t, 1H, J = 6.7 and
6.5 Hz, H at C7), 8.53 (s, 2H, H at C2’). 13C NMR d 15.5 (CH3 at
C6), 16.2 (CH3 at C2), 21.3 (CH2 at C4), 24.3 (CH2 at C11), 27.2
(CH3 at C9), 31.2 (CH at C2), 31.9 (CH2 at C9), 32.0 (CH3 at C3),
33.2 (CH2 at C10), 35.0 (C9), 39.1 (CH2 at C5), 40.3 (CH2 at C8),
81.9 (CH at C1), 124.4 (C1’), 124.6 (CH at C7), 127.9 (CH at C2’),
131.9 (C1’), 134.0 (C6), 149.86 (C3’), 161.5 (CO). Anal. Calcd for
C22H29ClN2O6: C, 58.34; H, 6.82; N, 6.18. Found: C, 58.07; H,
6.82; N, 6.31.
½
a 2D3:5
ꢂ
¼ þ31:9 (c 0.95, CHCl3), 91.0% ee NMR spectra were the same
data with racemic 2.
Acknowledgments
We wish to express our sincerest gratitude to Professor Seiji
Sawada for his valuable suggestions and discussions. We are also
grateful to Mr. Kenji Kondo for the measurement of HRMS. Rhi-
zomes of Zingiber zerumbet Smith and zerumbone were supplied
by Taiyo Corporation. Lipases were supplied by Meito Sangyo
Corporation.
References
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2. 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.
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Tetrahedron 2006, 62, 10859–10864.
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Thirasasana, N.; White, A. H. Aust. J. Chem. 1981, 34, 2243–2247.
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Asymmetry 2007, 18, 1676–1681.
4.5. Crystallographic study of 9
A colorless prism crystal, crystal size 0.60 ꢁ 0.20 ꢁ 0.08 mm3,
orthorhombic, space group P212121 (no. 19), a = 10.142(3),
b = 11.723(3), c = 38.126(9) Å, V = 4532.7(21) Å3, Z = 8, Dcalcd
=
1.327 g/cm3,
l(MoKa
) = 2.085 cmꢀ1, was used for data collection.
The intensity data were measured on a Rigaku R-AXIS RAPID using
Mo Ka
radiation at a temperature of ꢀ180 1 °C. The structure was
solved by direct methods (SIR97)16 and expanded using Fourier
techniques (DIRDIF99).17 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 8158
reflections (all data) and 618 variable parameters and gave
9. Kitayama, T.; Awata, Y.; Kawai, Y.; Tsuji, A.; Yoshida, Y. Tetrahedron: Asymmetry
2008, 19, 2367–2373.
R1 = 0.0861 (I > 2.0r (I)) and wR2 = 0.2258 (all data). The value of
10. Yamamoto, K.; Kitayama, T.; Minagawa, S.; Watanabe, T.; Sawada, S.; Okamoto,
T.; Utsumi, R. Biosci., Biotechnol., Biochem. 2001, 65, 2306–2310.
11. Sawada, S.; Yokoi, T.; Kitayama, T. Aroma Res. 2002, 3, 34–39.
12. Sawada, S.; Kitayama, T.; Yokoi, T.; Kato, M. JP2002155001.
13. Kitayama, T.; Nagao, R.; Masuda, T.; Hill, R. K.; Morita, M.; Takatani, M.;
Okamoto, T. J. Mol. Catal. B: Enzym. 2002, 17, 75–79.
the goodness of fit indicator was 1.041. Flack parameter was
0.05(12).14 (Summary of Data CCDC 746557).
4.5.1. (2R)-2,6,9,9-Tetramethyl-6-cycloundecen-1-one, (ꢀ)-
(R)-2
14. Chen, C.-S.; Fujimoto, T.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.
Under an N2 atmosphere, Dess–Martin periodinane (56.8 mg,
0.13 mmol) was added into CH2Cl2 (1.5 mL) at room temperature
and stirred until the mixture was dissolved completely. Compound
7, 30.0 mg (0.13 mmol), in CH2Cl2 (0.5 mL) was dropped into the
Dess–Martin solution and then stirred at the same temperature
15. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876–881.
16. 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.
17. 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.