Asymmetric syntheses of highly functionalized bicyclo [2.2.2] octene derivatives

Article abstract of DOI:10.3987/COM-10-S(E)22

Highly functionalized bicyclo[2.2.2]octene derivatives bearing two quaternary carbon centers were synthesized in an asymmetric fashion. The key transformations were the regioselective Diels-Alder reaction between 3,6-dimethyl-o-quinone monoacetal and 1,1-diethoxyethylene and the subsequent enzymatic resolution. The optically active bicyclo[2.2.2]octene derivatives obtained should serve as versatile chiral building blocks for highly functionalized natural products such as ryanodine. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)22

HETEROCYCLES, Vol. 82, No. 1, 2010
491
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 491 - 504. © The Japan Institute of Heterocyclic Chemistry
Received, 21st April, 2010, Accepted, 31st May, 2010, Published online, 2nd June, 2010
DOI: 10.3987/COM-10-S(E)22
ASYMMETRIC SYNTHESES OF HIGHLY FUNCTIONALIZED
BICYCLO[2.2.2]OCTENE DERIVATIVES
Masafumi Iwatsu, Daisuke Urabe, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, inoue@mol.f.u-tokyo.ac.jp.
Abstract – Highly functionalized bicyclo[2.2.2]octene derivatives bearing two
quaternary carbon centers were synthesized in an asymmetric fashion. The key
transformations were the regioselective Diels-Alder reaction between
3,6-dimethyl-o-quinone monoacetal and 1,1-diethoxyethylene and the subsequent
enzymatic resolution. The optically active bicyclo[2.2.2]octene derivatives
obtained should serve as versatile chiral building blocks for highly functionalized
natural products such as ryanodine.
Dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday.
INTRODUCTION
Many natural terpenoids possess complex carbocycles decorated by various oxygen functionalities and
alkyl appendages. Among the diverse structural units found in terpenoids, quaternary carbon centers
pose a particular challenge to synthetic organic chemists. The challenge is exacerbated further when
multiple quaternary stereocenters are present within the complex carbocycles.1 Recently, we reported
the synthesis of racemic C2-symmetric bicyclo[2.2.2]octene (±)-1, which bears two quaternary
stereocenters (Scheme 1).2 The diketone functionalities of (±)-1 were then utilized as the chemical
handles for its derivatization into (±)-2, which directly corresponds to the tricyclic skeleton of the
3
pentacyclic sesquiterpenoid, ryanodine.
This synthesis demonstrated the utility of the
bicyclo[2.2.2]octene (±)-1 as an intermediate for construction of complex carboskeletons with multiple
quaternary carbons.

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HETEROCYCLES, Vol. 82, No. 1, 2010
OH
HO
HO
H
OH
syn
HO
8 steps (ref. 2)
O
O
O
O
O
O
O
EtS
SEt
OH
ryanodine
N
H
(±)-1
(±)-2
Scheme 1. Synthesis of the tricyclic core of ryanodine from the C2-symmetric bicyclo[2.2.2]octene
Aside from the ryanodine structure, the 1,4-syn-oriented dimethyl groups of (±)-1 at the quaternary
centers are structural units of various terpenoids, such as 3-hydroxy-15-rippertene,4 cyanthiwigin F,5 and
correolide (Figure 1).6 Therefore, compound 1 and related highly functionalized bicyclo[2.2.2]octene
derivatives should act as versatile building blocks for diverse polycyclic natural products. In this
context, we decided to establish an asymmetric synthetic route to 1 and its analogous structures.
syn
H
H
O
H
H
CO2Me
H
H
OH
H
OAc
O
HO
OAc
O
OAc
O
syn
cyanthiwigin F
syn
OAc
AcO
3-hydroxy-15-rippertene
correolide
Figure 1. Natural terpenoids containing 1,4-syn-oriented dimethyl groups
RESULTS AND DISCUSSION
Enantiopure (+)-1 was planned to be synthesized through enzymatic resolution of racemic compounds
(Scheme 2).7 To do so, the secondary hydroxy and acetoxy groups were retrosynthetically introduced to
the bicyclo[2.2.2]octene structure for the enzymatic acetylation and deacetylation, respectively. In the
synthetic direction, the resolution of the racemic compounds (±)-3, (±)-4, (±)-5 or (±)-6 would generate
the corresponding enantiomerically pure acetate or alcohol, which were to be converted into (+)-1. The
two quaternary stereocenters of bicycles (±)-3-6 would be in turn constructed using the regioselective
Diels-Alder reaction in a single step. Specifically, the ketene equivalent and 3,6-dimethyl-o-quinone
monoacetal 7 were used as the dienophile and diene, respectively, to establish the bicyclic structure.8
Compound 7 with two sp2-connected methyl groups would be synthesized from 2,5-dimethylphenol 8 via
oxidative dearomatization.9

HETEROCYCLES, Vol. 82, No. 1, 2010
493
EtO
O
X
O
EtO
OR
O
O
O
O
H
OH
3:
(±)- R = H, X = (OCH2)2
1
(+)-
7
8
4:
(±)- R = H, X = O
(±)-5: R = Ac, X = (OCH2)2
(±)-6: R = Ac, X = O
Scheme 2. Plan for asymmetric syntheses of the bicyclo[2.2.2]octene derivatives
As shown in Scheme 3, 3,6-dimethyl-o-quinone monoacetal 7 was synthesized from 2,5-dimethylphenol
8 in four steps. Ortho-selective formylation of 810 and subsequent Dakin reaction afforded catechol 911
in 99% yield. Monoetherification of 9 with ethylene carbonate in the presence of n-Bu4NI,12 followed
by oxidative intramolecular acetalization of 10 using PhI(OAc)2, furnished cyclic acetal 7 in 42% yield
(two steps).
O
O
OH
O
1. MgCl2, Et3N;
(HCHO)n, reflux
2. H2O2, NaOH
PhI(OAc)2
(CF3)2CHOH
OH
OH
-Bu NI, 150 °C
O
n
4
99% (2 steps)
57%
72%
OH
OH
10
8
9
O
OR
O
H
1N HCl, THF
O
77% (2 steps)
OEt
NOE
DIBAL-H
CH2Cl2
-90 to -78 °C
H
OEt
O
Ac2O, Py.
O
-3
-5
(±) (R = H)
(±) (R = OAc)
toluene, 150 °C
EtO
EtO
DMAP
100%
O
O
O
95%
O
O
7
11
(±)-
H2SO4, THF
H2O, 50 °C
OR
O
H
73% (2 steps)
Ac2O, Py.
DMAP
97%
(±)-4 (R = H)
(±)-6 (R = OAc)
Scheme 3. Syntheses of the racemic bicyclo[2.2.2]octene derivatives
Despite the general tendency toward facile dimerization through self Diels-Alder reaction of o-quinone
monoacetals,8 3,6-dimethyl-o-quinone monoacetal 7 was remarkably stable even above 100 °C. Most
importantly, diene 7 smoothly underwent Diels-Alder reaction with the electron-rich ketene equivalent,
1,1-ethoxyethylene, at 150 °C to introduce the two quaternary stereocenters. The reaction resulted in

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HETEROCYCLES, Vol. 82, No. 1, 2010
formation of bicyclo[2.2.2]octene (±)-11 as the sole product in 95% yield.
Both the exceptional stability and the exclusive regioselectivity in the cycloaddition should arise from the
unique structural features of 7 (Figure 2). The bulky ketal and the two methyl groups prevent the
dimerization pathway via TS-A, while the serious steric repulsion between the ketal and the ethoxy group
of 1,1-diethoxyethylene inhibits the Diels-Alder reaction via the transition state TS-C. Consequently,
TS-B is favored over the other two transition states, leading to predominant formation of (±)-11.
EtO
OEt
O
O
O
EtO
OEt
O
O
O
O
O
O
O
O
O
TS-C
TS-B
TS-A
O
O
O
EtO
EtO
O
EtO
EtO
O
O
O
O
O
O
O
O
12
11
(±)-
13
(±)-
(±)-
Figure 2. Possible Diels-Alder reactions of 7
Thus obtained (±)-11 was converted to the four substrates (±)-3, (±)-4, (±)-5 and (±)-6 for the enzymatic
resolution (Scheme 3). Reduction of (±)-11 with DIBAL-H, followed by treatment with aqueous 1M
HCl, gave rise to (±)-3 in 77% yield (two steps) through chemoselective removal of the diethyl acetal.
The stereochemistry of the resultant alcohol of (±)-3 was determined by NOE experiments.
Alternatively, stepwise reaction with DIBAL-H then aqueous sulfuric acid transformed bis-acetal (±)-11
into diketone (±)-4 in 73% yield over two steps. Further one-step conversion from (±)-3 and (±)-4 gave
acetylated derivatives (±)-5 (100%) and (±)-6 (97%), respectively.
Next, the four racemic bicyclo[2.2.2]octene derivatives were subjected to either enzymatic acetylation or
deacetylation in order to deliver the corresponding enantiopure compounds.13 Both alcohols (±)-3 and
(±)-4 failed to react with acetylation agents under the various enzymatic conditions, presumably because
the hydroxy groups of (±)-3 and (±)-4 were hindered by the sterically cumbersome bicyclic structures.
In fact, the acetates (±)-5 and (±)-6, the reacting carbonyls of which are more distant from the bicycles
than the hydroxys, had higher reactivity toward the enzymes. Compounds (±)-5 and (±)-6 were
smoothly hydrolyzed into alcohols (+)-4 (13% ee, entry 1) and (+)-3 (58% ee, entry 2), respectively, by
the action of pig liver esterase (PLE) in pH 7 buffer.14 To improve the enantioselectivity, the co-organic
solvent was screened by employing the more promising substrate (±)-5 (entries 3-5). Consequently,

HETEROCYCLES, Vol. 82, No. 1, 2010
495
addition of isopropyl ether (entry 5) to the reaction media was demonstrated to have beneficial effect in
comparison to dimethyl sulfoxide (entry 3) or tert-butanol (entry 4), resulting in formation of (+)-3 of
93% ee in 26% yield.15 After further optimization of temperature and pH, we found the resolution of
(±)-5 was best performed in a mixture of pH 8 buffer and isopropyl ether at 30 °C to afford optically
active (+)-3 (41% yield and 84% ee, entry 6) and (–)-5 (52% yield and 82% ee).16 Recrystallization of
(+)-3 from hexane and ethyl acetate increased its optical purity to 96% ee (78% yield). As shown in
Figure 3, the absolute structure of (+)-3 was unambiguously determined by X-ray crystallographic
analysis of the (R)-MTPA ester derivative 14.
Table 1. Enzymatic resolution
PLE (100 wt%)
phosphate buffer
OAc
H
X
X
O
OAc
OH
+
O
O
X
H
H
see Table 1
5:
3:
5:
(–)- X = (OCH2)2
6:
(–)- X = O
(±)- X = (OCH2)2
(+)- X = (OCH2)2
6:
4:
(±)- X = O
(+)- X = O
yields (enantiomeric excess)b
co-solventa
entry substrate pH
temp. time
3
5
(–)-
(+)-
38% (13% ee)c
29% (58% ee)
29% (67% ee)
13% (84% ee)
26% (93% ee)
41% (84% ee)f
d
6
1
2
3
4
5
6
(±)-
7
7
7
7
7
8
rt
rt
rt
rt
rt
20 min
7 h
–
–
–
d
5
(±)-
–
(±)-5
7 h
DMSO
65%e
86%e
5
(±)-
72 h
24 h
-BuOH
t
(±)-5
-Pr O
i
i
70%e
2
5
(±)-
30 °C 24 h
-Pr O
52% (82% ee)
2
b
1
a20% of cosolvent was used. Optical purity was determined from integration of H
NMR spectra of the corresponding MTPA ester. Product was (+)- . dYield and optical
purity were not determined. eOptical purity was not determined. fThe optical purity was
increased to 96% ee after recrystallyzation from AcOEt/hexane.
c
4
Ph
O
MeO
CF3
CF3
Ph OMe
O
Cl
O
O
O
OH
O
H
O
H
DMAP, pyridine
CH2Cl2
O
O
3
(+)-
14
76%
Figure 3. Synthesis of (R)-MTPA ester 14 and its X-ray crystallographic structure

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HETEROCYCLES, Vol. 82, No. 1, 2010
The enantioselectivity of the enzymatic reaction from (±)-5 was remarkably higher than that from (±)-6
(see entries 1 and 2, Table 1). These distinct outcomes should originate from the steric difference
between the C2’-cyclic acetal and the C2’-ketone of 5 and 6, respectively (Figure 4). Namely, the
reactivities of (+)-5 and (–)-5 toward the enzyme were effectively discriminated by the steric effect of the
bulky C2’-substituted acetal, and consequently hydrolysis of (+)-5 was favored over that of (–)-5. On
the other hand, the same enzyme hydrolyzed both (+)-6 and (–)-6 non-selectively, due to the similar sizes
of the pseudo-equatorially oriented ketone and methyl groups, leading to lower enantiomeric excess of the
generated (+)-4.
enantiomeric
enantiomeric
O
O
O
O
O
O
2
2
2
2'
O
O
2'
2
2' O
O 2'
1
1
1
1
O
O
O
O
5
(+)-
5
6
6
(–)-
(–)-
(+)-
O
O
O
O
PLE
PLE
PLE
O
O
O
O
O
O
O
O
O
(+)-4
O
OH
OH
OH
OH
(+)-3
(–)-3
(–)-4
Figure 4. Significant role of the cyclic acetal in the enzymatic resolution
The obtained enantiopure (+)-3 was successfully converted to the optically active C2-symmetric
bicyclo[2.2.2]octene 1, the intermediate for the synthetic study of ryanodine (Scheme 4). Hydrolysis of
the ketal in alcohol (+)-3 (96% ee) under acidic conditions provided diketone (+)-4 in 95% yield.
Dehydroxylation of diketone (+)-4 was accomplished by a two-step sequence. Chloromesylation of the
hydroxy group converted (+)-4 into (+)-15 in 94% yield. Finally, treatment of -chloromesylated
ketone (+)-15 with NaI17 in the presence of TsOH gave rise to C2-symmetric bicyclo[2.2.2]octene 1 (62%
yield) through -iodoketone formation and subsequent reductive cleavage of the carbon-iodine bond by
nucleophilic attack of iodide.18

HETEROCYCLES, Vol. 82, No. 1, 2010
497
1N H2SO4
THF, 50 °C
NaI, TsOH·H2O
acetone, 50 °C
O
OH
O
O
OR
O
H
O
O
H
O
96%
62%
3
4
(+)- (96% ee)
(+)- : R = H
15
1
(+)-
ClCH2SO2Cl
Et3N, rt
(+)- : R = SO2CH2Cl
94%
Scheme 4. Synthesis of C2-symmetric bicyclo[2.2.2]octene (+)-1
In summary, we established an asymmetric synthetic route to highly functinalized bicyclo[2.2.2]octene
derivatives bearing two quaternary carbon centers. The regioselective Diels-Alder reaction of the
3,6-dimethyl-o-quinone monoacetal to install the 1,4-syn-oriented methyl groups, and the subsequent
enzymatic resolution were the two key reactions to produce bicyclo[2.2.2]octene derivatives (+)-3 and
(–)-5 in a highly enantioselective fashion.
Additionally, the optically active C2-symmetric
bicyclo[2.2.2]octene (+)-1, an intermediate for our synthetic study of ryanodine, was obtained from (+)-3
in three steps. Studies toward an asymmetric total synthesis of ryanodine and other complex natural
products from these bicyclo[2.2.2]octene derivatives are currently underway in our laboratory.
EXPERIMENTAL
All reactions sensitive to air or moisture were carried out under argon or atmosphere in dry or freshly
distilled solvents under anhydrous conditions, unless otherwise noted. All other reagents were used as
supplied unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed using E.
Merck Silica gel 60 F254 pre-coated plates. Column chromatography was performed using 100-210 μm
Silica Gel 60N (Kanto Chemical Co., Inc.) and flash column chromatography was 50-60 μm Silica Gel 60
(Kanto Chemical Co., Inc.). 1H and 13C NMR spectra were recorded on a JEOL JNM-ECX-500,
JNM-ECA-500, or a JNM-ECS-400 spectrometer. Chemical shifts were reported in ppm on the δ scale
1
13
relative to residual CHCl3 (δ = 7.26 for H NMR and δ = 77.0 for C NMR) as an internal reference.
Signal patterns are indicated as s, singlet; d, doublet; m, multiple. Infrared (IR) spectra were recorded
on a Perkin Elmer Spectrum BX FT-IR spectrometer, or a JASCO FT/IR-4100 spectrometer. High
resolution mass spectra were measured on a BRUKER DALTONICS APEX III (ESI), a BRUKER
DALTONICS BioTOF-Q (ESI), a Shimadzu Biotec Axima-TOF2 (MALDI), or a JEOL JMS-700
Mstation (FAB). Optical rotations were recorded on a JASCO DIP-370 Polarimeter or a JASCO
DIP-1000 Digital Polarimeter. Melting points were measured on a Yanaco MP-S3 micro melting point
apparatus or a Yanaco MP-J3 micro melting point apparatus, and are uncorrected.
Cathecol 9.11 A mixture of 2,5-dimethyl phenol 8 (5.00 g, 40.9 mmol), anhydrous MgCl2 (5.85 g, 61.4

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HETEROCYCLES, Vol. 82, No. 1, 2010
mmol), and Et3N (17 mL, 0.12 mol) in MeCN (27 mL) was stirred for 15 min at room temperature, and
then paraformaldehyde (3.69 g, 0.12 mol) was added to the mixture. After being stirred for 2.5 h at
100 °C, the mixture was cooled to room temperature, and diluted with Et2O (40 mL) and 1M HCl (40
mL). After the resulting organic layer was separated, the aqueous layer was extracted with Et2O (40 mL
x 2). Combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the
crude aldehyde, which was used to the next reaction without further purification.
To a solution of the crude aldehyde in THF (17 mL) and H2O (3 mL) was added 5M aqueous NaOH
solution (8.1 mL) and 30% aqueous H2O2 solution (4.2 mL) at 0 °C. After being stirred at room
temperature for 20 min, the reaction mixture was diluted with Et2O (20 mL) and 2N HCl (40 mL). After
the resulting organic layer was separated, the aqueous layer was extracted with Et2O (20 mL x 3).
Combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by column chromatography (silica gel 50 g, hexane/AcOEt 50:1 to 10:1) to afford cathecol 9
(5.58 g, 40.4 mmol) in 99% yield over 2 steps.
Alcohol 10. A mixture of cathecol 9 (1.27 g, 9.19 mmol), ethylene carbonate (850 mg, 9.65 mmol), and
n-Bu4NI (167 mg, 0.45 mmol) was stirred for 7.5 h at 150 °C. Additional ethylene carbonate (81 mg,
0.92 mmol) and n-Bu4NI (167 mg, 0.45 mmol) were added to the solution. After 2.5 h at 150 °C,
additional ethylene carbonate (40 mg, 0.45 mmol) and n-Bu4NI (83 mg, 0.22 mmol) were added to the
solution. After being stirred for 2 h at 150 °C, the reaction mixture was cooled to room temperature, and
diluted with AcOEt (10 mL). The resulting mixture was directly subjected to column chromatography
(silica gel 20 g, hexane/AcOEt 25:1 to 10:1) to afford alcohol 10 (953 mg, 5.23 mmol) in 57% yield: dark
1
red oil; IR (neat)  3447, 2995, 1770, 1759, 1374, 1246, 1059, 913, 744 cm–1; H NMR (500 MHz,
CDCl3) 2.22 (3H, s, CH3), 2.26 (3H, s, CH3), 3.95-3.99 (2H, m, OCH2CH2O), 4.01-4.04 (2H, m,
OCH2CH2O), 6.57 (1H, d, J = 7.8 Hz, CHA=CHB), 6.79 (1H, d, J = 7.8 Hz, CHA=CHB), 7.46 (1H, s, OH);
13C NMR (125 MHz, CDCl3) 15.6, 15.8, 61.9, 74.1, 120.7, 123.90, 126.1, 128.4, 144.3, 147.7; HRMS
(MALDI) calcd for C10H14O3 182.0937 (M+), found 182.0944.
3,6-Dimethyl-o-quinone monoacetal 7. To a solution of alcohol 10 (1.43 g, 7.85 mmol) in
(CF3)2CHOH (5.2 mL) was added PhI(OAc)2 (2.65 g, 8.23 mmol) at room temperature. After being
stirred for 20 min at room temperature, the reaction mixture was concentrated. The residue was purified
by column chromatography (silica gel 35 g, hexane/AcOEt 1:0 to 30:1) to afford 3,6-dimethyl-o-quinone
monoacetal 7 (1.02 g, 5.66 mmol) in 72% yield: yellow oil; IR (neat)  2974, 2898, 1675, 1657, 1450,
1
1382, 1180, 1066, 1021, 980, 951 cm–1; H NMR (500 MHz, CDCl3) 1.80 (3H, s, CH3), 1.83 (3H, s,
CH3), 4.13-4.18 (2H, m, OCH2CH2O), 4.36-4.40 (2H, m, OCH2CH2O), 5.95 (1H, d, J = 6.4 Hz,
CHA=CHB), 6.58 (1H, d, J = 6.3 Hz, CHA=CHB); 13C NMR (125 MHz, CDCl3) 14.5, 16.5, 55.4, 66.0,

HETEROCYCLES, Vol. 82, No. 1, 2010
499
98.8, 123.2, 130.3, 137.1, 144.7, 200.3; HRMS (ESI) calcd for C10H13O3 181.0859 (M+H+), found
181.0858.
Diels-Alder adduct (±)-11. A solution of 3,6-dimethyl-o-quinone monoacetal 7 (1.02 g, 5.66 mmol)
and ketene diethyl acetal (1.5 mL, 11 mmol) in toluene (1.1 mL) was stirred at 150 °C for 17 h. The
reaction mixture was cooled to room temperature, and concentrated. The residue was purified by
column chromatography (silica gel 25 g, hexane/AcOEt 50:1 to 10:1) to afford ketone (±)-11 (1.60 g,
5.40 mmol) in 95% yield: colorless oil; IR (neat) 2977, 2936, 2896, 1741, 1453, 1133, 1074, 1046,
1025, 951; 1H NMR (500 MHz, CDCl3) 1.11-1.16 (6H, m, OCH2CH3 x 2), 1.14 (3H, s, CH3), 1.34 (3H,
s, CH3), 1.70 (1H, d, J = 13.7 Hz, C-CHAHB), 2.27 (1H, d, J = 13.7 Hz, C-CHAHB), 3.49-3.58 (4H, m,
OCH2CH3 x 2), 4.00-4.07 (2H, m, OCH2CH2O), 4.29-4.36 (2H, m, OCH2CH2O), 5.67 (1H, d, J = 8.3 Hz,
CHA=CHB), 6.13 (1H, d, J = 8.3 Hz, CHA=CHB); 13C NMR (125 MHz, CDCl3) 12.2, 15.5, 15.6, 16.3,
41.7, 41.9, 58.2, 58.3, 60.0, 66.5, 66.7, 101.8, 104.8, 132.4, 139.4, 205.5; HRMS (ESI), calcd for
C16H24O5Na 319.1516 (M+Na+), found 319.1514.
Alcohol (±)-3. To a solution of ketone (±)-11 (10.8 g, 36.4 mmol) in CH2Cl2 (37 mL) was added
DIBAL-H (1.0 M in hexane, 66 mL, 66 mmol) at -90 °C. After 20 min, additional DIBAL-H (3.3 mL,
3.3 mmol) was introduced to the mixture. After being stirred at -78 °C for 5 min, the reaction mixture
was diluted with AcOEt (70 mL), sat Rochelle’s salt solution (40 mL) and saturated aqueous NH4Cl
solution (40 mL). After the organic layer was separated, the aqueous layer was extracted with AcOEt
(80 mL x3). Combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to
give the crude alcohol, which was used to the next reaction without further purification.
A solution of the crude alcohol in THF (33 mL) and 1M HCl (3.7 mL) was stirred at room temperature
for 12 h, and the reaction was quenched with saturated aqueous NaHCO3 solution (50 mL). The
resulting solution was extracted with AcOEt (50 mL x 3) and combined organic layers were washed with
brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by
column chromatography (silica gel 50 g, hexane/AcOEt 10:1 to 3:1) to afford alcohol (±)-3 (6.31 g, 28.1
mmol) in 77% yield: colorless crystals; mp 72 °C (recrystallized from hexane/AcOEt); IR (neat)  3481,
1
2969, 2931, 2892, 1727, 1231, 1165, 1114, 1065, 953 cm–1; H NMR (400 MHz, CDCl3) 1.20 (3H, s,
CH3), 1.33 (3H, s, CH3), 1.93 (1H, d, J = 18.8 Hz, C-CHAHB), 2.29 (1H, d, J = 18.8 Hz, C-CHAHB), 3.37
(1H, d, J = 4.6 Hz, OH), 3.38 (1H, d, J = 4.6 Hz, CH-OH), 3.90-4.00 (2H, m, OCH2CH2O), 4.07-4.14 (2H,
m, OCH2CH2O), 5.76 (1H, d, J = 8.2 Hz, CHA=CHB), 6.16 (1H, d, J = 8.2 Hz, CHA=CHB); 13C NMR
(100 MHz, CDCl3) 14.4, 16.5, 41.3, 43.8, 57.1, 64.9, 67.0, 78.7, 110.8, 131.8, 139.9, 209.9; HRMS
(ESI), calcd for C12H16O4Na 247.0941 (M+Na+), found 247.0940.
Acetate (±)-5. A mixture of alcohol (±)-3 (3.01 g, 13.4 mmol), Ac2O (2.3 mL, 24 mmol), pyridine (2.3

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HETEROCYCLES, Vol. 82, No. 1, 2010
mL, 28 mmol), and DMAP (327 mg, 2.68 mmol) in CH2Cl2 (6.7 mL) was stirred at room temperature for
12 h. The reaction was quenched with saturated aqueous NH4Cl solution (10 mL). The resulting
mixture was extracted with AcOEt (10 mL x 2), and combined organic layers were washed with brine (20
mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column
chromatography (silica gel 15 g, hexane/AcOEt 20:1 to 7.5:1) to afford acetate (±)-5 (3.56 g, 13.4 mmol)
in 100% yield: colorless crystals; mp 89 °C (recrystallized from hexane/AcOEt); IR (neat)  2974, 2934,
1
2898, 1733, 1372, 1249, 1225, 1116, 1021, 956 cm–1; H NMR (500 MHz, CDCl3)  1.16 (3H, s, CH3),
1.22 (3H, s, CH3), 1.93 (1H, d, J = 18.9 Hz, C-CHAHB), 2.06 (3H, s, Ac), 2.38 (1H, d, J = 18.9 Hz,
C-CHAHB), 3.78-4.05 (2H, m, OCH2CH2O), 4.00-4.11 (2H, m, OCH2CH2O), 4.54 (1H, s, CH-OAc), 5.74
(1H, d, J = 8.0 Hz, CHA=CHB), 6.20 (1H, d, J = 8.0 Hz, CHA=CHB); 13C NMR (125 MHz, CDCl3) 14.5,
16.3, 20.8, 40.5, 44.6, 54.2, 64.9, 67.5, 78.9, 110.0, 129.9, 141.4, 170.5, 208.3; HRMS(ESI), calcd for
C14H18O5Na 289.1046 (M+Na+), found 289.1045.
Hydroxy ketone (±)-4. To a solution of ketone (±)-11 (423 mg, 1.43 mmol) in CH2Cl2 (2.8 mL) was
added DIBAL-H (1.0 M in hexane, 4.3 mL, 4.3 mmol) at -78 °C. After 1 h at -60 °C, additional
DIBAL-H (1.4 mL, 1.4 mmol) was introduced to the mixture. After being stirred at -60 °C for 1 h,
additional DIBAL-H (0.7 mL, 0.7 mmol) was added to the mixture. After being stirred at -40 °C for 30
min, the reaction mixture was diluted with AcOEt (10 mL), sat Rochelle’s salt solution (10 mL) and
saturated aqueous NH4Cl solution (10 mL). After the organic layer was separated, the aqueous layer
was extracted with AcOEt (10 mL x3). Combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated to give the crude alcohol, which was used to the next reaction without further
purification.
A solution of the crude alcohol in a mixture of THF (0.9 mL), H2SO4 (3.7 mL), and H2O (2.3 mL) was
stirred at 50 °C for 26 h. Then, the mixture was washed with saturated aqueous NaHCO3 solution (10
mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column
chromatography (silica gel 10 g, hexane/AcOEt 10:1 to 5:1 to 1:1) to afford alcohol hydroxy ketone (±)-4
(188 mg, 1.04 mmol) in 73% yield.
Acetate (±)-6. A mixture of hydroxy ketone (±)-4 (75 mg, 0.42 mmol), Ac2O (80 L, 0.83 mmol),
pyridine (34 L, 0.42 mmol) and DMAP (10 mg, 83 mol) in CH2Cl2 (1.0 mL) was stirred at room
temperature for 1.5 h, and saturated aqueous NH4Cl solution (5 mL) was added to the mixture. After
separation, the aqueous layer was extracted with AcOEt (5 mL x 2), and combined organic layers were
washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography (silica gel 5 g, hexane/AcOEt 20:1 to 10:1) to afford acetate (±)-6
(90 mg, 0.40 mmol) in 97% yield: IR (neat)  2978, 2936, 1757, 1735, 1371, 1218, 1121, 1054, 1027

HETEROCYCLES, Vol. 82, No. 1, 2010
501
cm–1; 1H NMR (400 MHz, CDCl3)  1.25 (3H, s, CH3), 1.33 (3H, s, CH3), 2.10 (3H, s, Ac) 2.31 (1H, d, J
= 18.6 Hz, C-CHAHB), 2.36 (1H, d, J = 18.6 Hz, C-CHAHB), 5.13 (1H, s, CH-OAc), 6.08 (1H, d, J = 8.2
13
Hz, CHA=CHB), 6.22 (1H, d, J = 8.2 Hz, CHA=CHB); C NMR (125 MHz, CDCl3) 13.4, 16.2, 20.4,
42.1, 49.5, 55.7, 71.3, 134.5, 137.7, 169.7, 203.1, 205.8; HRMS(FAB), calcd for C12H15O4 223.0970
(M+H+), found 223.0978.
Enzymatic deacetylation of acetate (±)-5. A solution of acetate (±)-5 (5.04 g, 18.9 mmol) and PLE
(5.04 g, 27 units/mg) in i-Pr2O (38 mL) and pH 8 phosphate buffer (0.1 M, 150 mL) was stirred at 30 °C
for 24 h and extracted with Et2O (150 mL x 15). Combined organic layers were dried over anhydrous
Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel 60 g,
hexane/AcOEt 11:1 to 1.5:1) to afford alcohol (+)-3 (1.72 g, 7.67 mmol, 84% ee) and acetate (–)-5 (2.61
22
g, 9.80 mmol, 82% ee, []D –278.8, c 1.05, CHCl3) in 41% and 52% yield, respectively.
Recrystallization of (+)-3 from AcOEt/hexane (2:1, at 35-22 °C) improved its optical purity to 96% ee
(1.35 g, 6.02 mmol, 78% yield): []D22 407 (c 1.00, CHCl3).
(R)-MTPA ester 14. A mixture of alcohol (+)-3 (12 mg, 0.054 mmol), (S)-MTPACl (15 L, 0.082
mmol), and DMAP (3 mg, 0.02 mmol), pyridine (26 L, 0.163 mmol) in CH2Cl2 (0.3 mL) was stirred at
50 °C for 16 h, and additional (S)-MTPACl (15 L, 0.082 mmol) and DMAP (3 mg, 0.02 mmol) was
added to the mixture. The reaction mixture was stirred at 50 °C for 11 h, and then quenched with
saturated aqueous NH4Cl solution (3 mL). The resulting mixture was extracted with Et2O (3 mL x 3),
and combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered,
and concentrated. The residue was purified by flash column chromatography (silica gel 1 g,
hexane/AcOEt 60:1 to 15:1) to afford (R)-MTPA ester 14 (18 mg, 0.041 mmol) in 76% yield: colorless
crystals; mp 139-140 °C; 1H NMR (500 MHz, CDCl3)  1.12 (3H, s, CH3), 1.16 (3H, s, CH3), 1.91 (1H, d,
J = 18.8 Hz, C-CHAHB), 2.30 (1H, d, J = 18.8 Hz, C-CHAHB), 3.46 (3H, s, OCH3), 3.77 (1H, ddd, J =
10.1, 6.9, 6.7 Hz, OCHAHBCH2O), 3.87 (1H, ddd, J = 6.9, 6.4, 2.3 Hz, OCH2CHAHBO), 4.08 (1H, ddd, J
= 8.2, 6.7, 2.3 Hz, OCH2CHAHBO), 4.16 (1H, ddd, J = 10.1, 8.2, 6.4 Hz, OCHAHBCH2O), 4.63 (1H, s,
CH-OCO-), 5.71 (1H, d, J = 8.0 Hz, CHA=CHB), 6.21 (1H, d, J = 8.0 Hz, CHA=CHB), 7.39 (3H, m, Ph),
7.53-7.57 (2H, m, Ph).
Crystallographic data of 14.19
C22H23F3O6, M = 440.414, monoclinic, space group P21, a = 10.891(3) Å, b = 12.273(4) Å, c = 8.517(3)
Å, = 90.00°,  = 110.54(2)°,  = 90.00°, V = 1066.1(6) Å3, density 1.372 g·cm-1, Z = 2, R value = 0.013.
Hydroxy ketone (+)-4. A solution of alcohol (+)-3 (2.74 g, 12.2 mmol) in a mixture of THF (5.5 mL),
H2SO4 (1.1 mL), and H2O (5.5 mL) was stirred at 50 °C for 20 h. Then, AcOEt (10 mL) and saturated
aqueous NaHCO3 solution (10 mL) were added at 0 °C. After the organic layer was separated, the

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HETEROCYCLES, Vol. 82, No. 1, 2010
aqueous layer was extracted with AcOEt (10 mL x 6). Combined organic layers were washed with brine
(70 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column
chromatography (silica gel 25 g, hexane/AcOEt 10:1 to 6:1) to afford hydroxy ketone (+)-4 (2.11 g, 11.7
mmol) in 96% yield: colorless oil; []D25 787 (c 0.98, CHCl3); IR (neat) 3447, 2974, 2934, 1730, 1454,
1
1123, 1064, 1026, 817, 774, 683 cm-1; H NMR (500 MHz, CDCl3) 1.34 (3H, s, CH3), 1.41 (3H, s,
CH3), 2.22 (1H, d, J = 18.5 Hz, C-CHAHB), 2.31 (1H, d, J = 18.5 Hz, C-CHAHB), 2.83 (1H, d, J = 2.0 Hz,
OH), 3.67 (1H, d, J = 2.0 Hz, CH-OH), 6.03 (1H, d, J = 7.9 Hz, CHA=CHB), 6.17 (1H, d, J = 7.9 Hz,
CHA=CHB); 13C NMR (125 MHz, CDCl3) 13.6, 16.1, 42.3, 49.1, 56.7, 72.8, 135.0, 136.9, 206.8, 208.8.;
HRMS(ESI) calcd for C10H12O3Na 203.0679 (M+Na+), found 203.0678.
Chloromesylate (+)-15. To a solution of hydroxy ketone (+)-4 (1.37 g, 7.60 mmol) and Et3N (1.8 mL,
13 mmol) in CH2Cl2 (15 mL) was added ClCH2SO2Cl (1.0 mL, 11 mmol) at 0 °C. After being stirred at
room temperature for 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (20
mL). The resulting mixture was extracted with AcOEt (20 mL x 2). Combined organic layers were
washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was
purified by column chromatography (silica gel 20 g, hexane/AcOEt 10:1 to 4:1) to afford chloromesylate
1
(+)-15 (2.10 g, 7.17 mmol) in 94% yield: H NMR (500 MHz, CDCl3)  1.37 (3H, s, CH3), 1.44 (3H, s,
CH3), 2.32 (1H, d, J = 18.9 Hz, C-CHAHB), 2.41 (1H, d, J = 18.9 Hz, C-CHAHB), 4.71 (1H, s,
CH-OSO2CH2Cl), 4.80 (1H, d, J = 12.6 Hz, CHACHBCl), 4.89 (1H, d, J = 12.6 Hz, CHACHBCl), 6.09
(1H, d, J = 8.0 Hz, CHA=CHB), 6.24 (1H, d, J = 8.0 Hz, CHA=CHB); 13C NMR (125 MHz, CDCl3) 13.4,
16.1, 41.5, 49.3, 55.3, 55.7, 79.7, 134.1, 137.9, 201.3, 203.4.
C2-Symmetric bicyclo[2.2.2]octene (+)-1. A solution of chloromesylate (+)-15 (2.10 g, 7.17 mmol)
and NaI (5.40 g, 35.9 mmol) in acetone (48 mL) was stirred at 50 °C for 12 h, and then TsOH·H2O (1.4 g,
7.5 mmol) was added to the mixture. After being stirred for 1 h at 50 °C, the reaction mixture was
quenched with saturated aqueous Na2S2O3 solution (20 mL). The resulting mixture was extracted with
Et2O (20 mL x 2). Combined organic layers were washed with brine (50 mL), dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel 15 g,
hexane/Et2O 30:1 to 15:1) to afford C2-symmetric bicyclo[2.2.2]octene (+)-1 (731 mg, 4.45 mmol) in
25
62% yield: pale yellow solid; []D 1006 (c 1.01, CHCl3); IR (neat)  2973, 2932, 1726, 1452, 1405,
1383, 1118, 774, 683 cm–1; 1H NMR (500 MHz, CDCl3)  1.30 (6H, s, CH3 x 2), 2.24 (2H, d, J = 18.9 Hz,
13
C-CHAHB x 2), 2.28 (2H, d, J = 18.9 Hz, C-CHAHB x 2), 6.12 (2H, s, CH=C x 2); C NMR (125 MHz,
CDCl3)  16.5, 42.0, 51.1, 137.1, 209.1; HRMS (ESI) calcd for C10H12O2Na 187.0729 (M+Na+), found
187.0736.

HETEROCYCLES, Vol. 82, No. 1, 2010
503
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Young Scientists (S) (JSPS) to M. I. We are grateful to
Prof. Tohru Fukuyama and Dr. Satoshi Yokoshima of the University of Tokyo for performing X-ray
crystallographic analysis.
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18. The deoxygenation from the corresponding mesylate was sluggish.
19. CCDC 764823 contains the supplementary crystallographic data for this paper. These data can be
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