Enzymatic resolution of the 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane (1,8-cineole) system

Article abstract of DOI:10.1016/S0957-4166(02)00313-0

Regioselective oxidation of 1,8-cineole 1 with chromyl acetate according to a literature procedure gave the bicyclic 2-ketocineole 8 as the major product along with the symmetrical diketocineole 9. The bicyclic monoketone was reduced with lithium aluminum hydride followed by exposure to acetyl chloride/DMAP to afford the exo-acetate (±)-4b. Pig liver esterase (PLE)-mediated hydrolysis of the racemic acetate provided the alcohol (-)-2b (45%) together with its antipodal acetate (+)-4b (43%) in greater than 99% enantiomeric purity, as determined by analysis of the Mosher's ester derivatives. Iodination of the alcohol exo-(+)-2b, obtained by hydrolysis of the resolved actetate with iodine/triphenylphosphine/imidazole, provided the corresponding endo iodide (-)-12a, which was easily dehydrohalogenated with DBU under solvent-free conditions to provide the corresponding cineolene (-)-6 in an overall yield of 6 and 99% e.e.

Full text of DOI:10.1016/S0957-4166(02)00313-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1173–1180
Enzymatic resolution of the
1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane (1,8-cineole) system
Frederick A. Luzzio* and Damien Y. Duveau
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY 40292, USA
Received 1 April 2002; accepted 3 June 2002
Abstract—Regioselective oxidation of 1,8-cineole 1 with chromyl acetate according to a literature procedure gave the bicyclic
2-ketocineole 8 as the major product along with the symmetrical diketocineole 9. The bicyclic monoketone was reduced with
lithium aluminum hydride followed by exposure to acetyl chloride/DMAP to afford the exo-acetate ( )-4b. Pig liver esterase
(PLE)-mediated hydrolysis of the racemic acetate provided the alcohol (−)-2b (45%) together with its antipodal acetate (+)-4b
(43%) in greater than 99% enantiomeric purity, as determined by analysis of the Mosher’s ester derivatives. Iodination of the
alcohol exo-(+)-2b, obtained by hydrolysis of the resolved actetate with iodine/triphenylphosphine/imidazole, provided the
corresponding endo iodide (−)-12a, which was easily dehydrohalogenated with DBU under solvent-free conditions to provide the
corresponding cineolene (−)-6 in an overall yield of 6 and 99% e.e. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
excretia of the brushtail opossum Trichosurus vulpecula
when the animals were maintained on a diet of 0.5% 1.3
The individual enantiomeric 2- and 3-acetoxy deriva-
tives 4a/4b and 5a/5b have been detected as the odifer-
ous principles contained in the rhizomes of the galangal
Alpinia galanga.4 The rare cineolene (2,3-didehydro-1,8-
cineole) 6 has been isolated by gas chromatography,
along with 1 as a major constituent, from the essential
oils of Laurus nobilus (Lauraceae). The biosynthesis of
6 in Lauraceae was presumed to involve either dehydro-
genation of 1 or dehydration of 2a/2b or 3a/3b, all of
The 2- and 3-hydroxy and corresponding acetoxy
derivatives of 1,8-cineole (eucalyptol) 1 are biologically
significant congeners of the monoterpenoid 1,3,3-
trimethyl-2-oxabicyclo[2.2.2]octane system.1 The 2-exo-
hydroxy derivative 2b has recently been detected as the
sole metabolic product when 1 was incubated with
human liver microsomes under various concentrations
and P450 levels.2 In contrast, both the 2- and 3-hydroxy-
lated products 2a/2b and 3a/3b were detected in the
O
O
O
R2
OH
R1
7
1
6
2a, R1=endo OH, R2=H
2b, R1=exo OH, R2=H
3a, R1=H, R2=endo OH
3b, R1=H, R2=exo OH
4a, R1=endo OAc, R2=H
4b, R1=exo OAc, R2=H
5a, R1=H, R2=endo OAc
5b, R1=H, R2=exo OAc
* Corresponding author. Tel.: (001) 502 852 7323; fax: (001) 502 852 8149; e-mail: faluzz01@athena.louisville.edu
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00313-0

1174
F. A. Luzzio, D. Y. Du6eau / Tetrahedron: Asymmetry 13 (2002) 1173–1180
which are biosynthetic cyclization products of a-terpi-
neol.5 Although the chiral a-terpineol system 7 has
served as a starting point for the synthesis of several of
the corresponding cineole derivatives,6 we are currently
interested in the 1,8-cineole system as a synthon for
chiral monoterpenoid synthetic intermediates.
Slow addition of a freshly-prepared solution of chromyl
acetate in acetic anhydride to a solution of 1 in glacial
acetic acid effected oxidation at C-2 to provide 8 as the
major product. Isolation of 8 entailed extractive
workup to remove reduced chromium by-products fol-
lowed by neutralization of the excess acetic anhydride
and spinning band distillation. Flash column chro-
matography after distillation afforded ketone 8 (50%)
and diketone 9 (8%).9 The racemic ketone 8 was
reduced with lithium aluminum hydride in diethyl ether
to provide the racemic exo-alcohol 2b7 as the sole
product in quantitative yield after purification by flash
column chromatography. Treatment of the alcohol ( )-
2b with acetyl chloride in the presence of 4-dimethyl-
aminopyridine (DMAP) in dichloromethane at 0°C
provided the racemic acetate ( )-4b in 70% yield after
purification by flash column chromatography.
Our interest in the synthetic potential of 1 was further
driven by its relatively low cost and ready availability
together with the ease at which 1 may be functionalized
by oxidation at C-2 to afford both symmetrical and
chemically resolvable products. Moreover, functional-
ization of such chiral intermediates at either C-2 or C-3
(or both) followed by regioselective opening of the
1,8-ether bridge will allow an entry into the series of
extended menthane derivatives with control of the
absolute stereochemistry. Herein, we report the highly
efficient resolution of the 1,8-cineole system through the
employment of porcine liver esterase (PLE) in conjunc-
tion with the racemic 3-acetoxy derivative as the sub-
strate. The resolved compounds were then used as
intermediates for the preparation of the naturally
occuring cineolene derivative (−)-6 through mild, selec-
tive halogenation followed by elimination.
Based on our experience with the PLE-mediated desym-
metrization of meso-spirocyclic diacetates, we elected to
conduct the initial enzymatic hydrolysis studies under
strictly aqueous conditions.10 Incubation of the acetate
( )-4b with a commercially available preparation of
porcine liver esterase (PLE) for 12 h at 37°C afforded a
chromatographically-separable mixture of the alcohol
(−)-2b (45, 90% of theoretical) and the acetate (+)-4b
(43, 86% of theoretical). Despite the inherent hydro-
phobicity of terpene esters such as ( )-4b, the enzymatic
reaction mixture formed a uniform suspension which
was easily sampled and this could be monitored by
thin-layer chromatography. Furthermore, only a single
enzyme run was required to provide alcohol and acetate
of high enantiomeric purity.11 The (+)-acetate which
was isolated from the lipase hydrolysis was saponified
with lithium hydroxide in tetrahydrofuran/methanol/
water at room temperature and thus provided the alco-
hol (+)-2b (80%) after silica gel column chromato-
2. Results and discussion
The synthetic scheme commences with the chromyl
acetate-mediated oxidation of commercially available
1,8-cineole 1 to the corresponding racemic 2-keto
derivative 8 (Scheme 1). Although the transformation
was first described by Catalan,7 the requirements of a
useful reaction scale, high degree of purity and the
necessary safety precautions connected with the prepa-
ration and use of oxochromium(VI) reagents8 prompted
us to develop an improved procedure (see Section 4).
Scheme 1. Reagents and conditions: (a) CrO3/Ac2O/AcOH/0–5°C/20 h (50%); (b) LiAlH4/Et2O/reflux/1.5 h (99%); (c) CH3COCl/
DMAP/CH2Cl2/0°C–rt (70%); (d) pig liver esterase/H2O/pH 7.00/37°C/12 h, (+)-4b (86.4%), (−)-2b (89.4%); (e) p-toluenesulfonyl
chloride/DMAP/CH2Cl2/0°C/24 h (81%).

F. A. Luzzio, D. Y. Du6eau / Tetrahedron: Asymmetry 13 (2002) 1173–1180
1175
graphy. To confirm the enantiomeric purity, Mosher
esters (+)-10a and (−)-10b12 were prepared from each of
the resolved (+)- and (−)-alcohols, respectively, using
freshly-prepared (R)-(+)-a-methoxy-a-(trifluoromethyl)-
phenylacetyl (MTPA) chloride and DMAP in
dichloromethane. 19F NMR analysis of each ester
revealed >99% enantiomeric purity for both derivatives
at a concentration of 10 mg/mL in CDCl3. The abso-
lute configuration of the alcohol (−)-2b, generated from
the enzymatic reaction, was determined to be 1R,4S,5R
homogenous product, obtained in 45% isolated yield,
consisted of a mixture of endo- and exo-iodides (endo/
exo, 2.5:1).
The lengthy purification steps required to remove both
unreacted triphenylphosphine and triphenylphosphine
oxide contributed to a considerable reduction in the
yield of isolated purified product. A related iodination
was examined in conjunction with the racemic series.15
Iodine/chlorodiphenylphosphine/imidazole
was
1
by comparative H and 13C NMR analysis of its (S)-
employed with ( )-2b as the substrate and thereby
afforded the endo- and exo-iodides in a similar ratio in
48% isolated yield albeit with simpler purification steps.
The exclusive formation of the endo-iodide ( )-12a
through the p-toluenesulfonyl ester ( )-13 was also
pursued. The p-toluenesulfonyl ester ( )-13 was pre-
pared in 81% yield by treating of the exo-alcohol ( )-2b
with p-toluenesulfonyl chloride in the presence of 4-
dimethylaminopyridine (DMAP). Interestingly, treat-
ment of ( )-13 with 5 equiv. of sodium iodide in
refluxing acetone for 20 h resulted in a 36% isolated
yield of endo- and exo-iodides with a reversed ratio of
1:2 (endo–exo) (Scheme 4). In general, dehydrohalo-
genation of the mixture of endo- and exo- (2.5:1, endo/
exo) iodides (−)-12a and (−)-12b by heating with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provided
cineolene (−)-6 (Scheme 3).16 The initial dehydrohalo-
genation experiments in the (−)-12a/12b series
employed toluene as a reaction solvent and 2 equiv. of
DBU. Although elimination commenced at 100–102°C,
as evidenced by a brown precipitate of DBU·HI, the
iodides 12a/12b were never completely consumed in the
presence of the solvent. Moreover, monitoring the
(+)-O-methyl mandelate ester (+)-11 (Scheme 2).4b The
spectral values were in agreement with those reported
by Kubota for the O-methyl mandelate derivatives of
the naturally-occuring acetoxycineoles.
Halogenation of the cineole nucleus and its derived
alcohols en route to unsaturated cineole derivatives has
been problematic due to a lack of selectivity together
with the sensitivity of the 1,3,3-trimethyl-2-oxabicy-
clo[2.2.2]octane nucleus to cleavage and rearrange-
ment.13 The Garegg–Samuelsson iodination appeared
to be particularly attractive since it has been employed
successfully in the carbohydrate series to convert both
primary and secondary hydroxyl groups to the corre-
sponding iodides (Scheme 3).14 Exposure of the alcohol
(+)-2b to a mixture of iodine/triphenylphosphine/imida-
zole in benzene/acetonitrile at 78°C effected complete
consumption of (+)-2b thereby forming the less polar
(chromatographically more mobile) iodinated product,
1
as indicated by monitoring the reaction by TLC. H
NMR analysis indicated that the chromatographically-
Scheme 2. Reagents and conditions: (a) (R)-C6H5COMeCF3COCl/DMAP/CH2Cl2/16 h/rt; (b) (S)-C6H5COMeCOCl/DMAP/
CH2Cl2/16 h/rt.
O
O
a
b
(+)-2b
R2
(-)-6
R1
(-)-12a, R1=I, R2=H
(-)-12b, R1=H, R2=I
Scheme 3. Reagents and conditions: (a) I2/PPh3/imidazole/benzene/CH3CN/75°C/6 h (45%) or I2/ClPPh2/imidazole/toluene/rt/2 h
(48%); (b) DBU/100°C/15 min then 115°C/20 min (99%).

1176
F. A. Luzzio, D. Y. Du6eau / Tetrahedron: Asymmetry 13 (2002) 1173–1180
O
O
a
b
(+)-12a/12b
OR1
(+)-13, R1=p-toluenesulfonyl
(+)-6
Scheme 4. Reagents and conditions: (a) NaI/acetone/reflux/20 h (36%); (b) DBU/115–120°C/20 h (61%).
DBU-promoted elimination of 12a/12b by 1H NMR
revealed that the endo-iodide 12a was consumed faster
than exo-12b. The most efficient dehydrohalogenation
conditions entailed heating the mixture of 12a/12b with
1.3 equiv. of DBU without a solvent which resulted in
complete consumption of the iodides and a quantitative
yield of cineolene (−)-6. Preliminary elimination experi-
ments in the racemic series also employed p-toluenesul-
fonyl ester ( )-13 as a substrate. The treatment of
p-toluenesulfonyl ester ( )-13 with DBU at 115–120°C
for 20 h resulted in a 61% isolated yield of racemic
cineolene ( )-6 (Scheme 4).
gel 60 (E. Merck 7734, 70–230 mesh). Celite filtrations
employed Celite 521. Analytical thin-layer chromato-
graphic (TLC) separations utilized 0.25 mm glass-
backed silica gel plates (E. Merck 5715, silica gel 60
F254). The TLC chromatograms were developed by
dipping in 2% anisaldehyde in ethanol or 2.5% phos-
phomolybdic acid in ethanol followed by heating (hot
plate). Solutions, reaction mixtures and chromato-
graphic fractions were concentrated under vacuum
using a standard rotary evaporator. Enzymatic reac-
tions were conducted in a Lab-Line Model 3525 Incu-
bator-Shaker. High-resolution mass spectroscopic
analyses (HRMS) were performed by the Nebraska
Center for Mass Spectrometry, University of Nebraska,
Lincoln and the University of California Riverside
Mass Spectrometry Facility.
3. Conclusion
Pig liver esterase (PLE) is effective for the enantioselec-
tive hydrolysis of a racemic mixture of cineolyl acetates.
The enzyme was employed under strictly aqueous con-
ditions and provided the products with high enan-
4.2. ( )-1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-5-one,
8
tiomeric
excess
and
chemical
yield.
The
To a mechanically stirred solution of glacial acetic acid
(90 mL, 1.57 mol) and acetic anhydride (18 mL, 1.98
mol) was added (Caution!) anhydrous chromium triox-
ide (37.5 g, 0.37 mol, technical flake) while cooling in
an ice/water bath. The red–brown solution was stirred
under an atmosphere of nitrogen for 1 h while cooling
was continued. The flask was then fitted with a steel
canula and a solution of chromyl acetate was added
dropwise through the canula under nitrogen pressure to
a stirred, cooled (ice/water bath) solution of 1,8-cineole
1 (18.4 g, 0.12 mol) and glacial acetic acid (30 mL).
After the transfer of the chromyl acetate solution was
complete, some residual chromium trioxide remained.
The residual material was dissolved, while cooling, in
additional acetic acid/acetic anhydride solution (20–30
mL) and then transferred via canula to the 1,8-cineole
solution. After addition of the oxidant was complete,
the resultant dark-green 1,8-cineole/oxidant solution
was stored at 4°C for 20 h. A crushed ice/water mixture
(1 L) was then added followed by extraction of the
dark-green solution with diethyl ether (5×200 mL). The
combined ether extracts containing the products along
with residual acetic acid/acetic anhydride were neutral-
ized by cautious addition of anhydrous sodium carbon-
ate while stirring vigorously. The salts resulting from
the neutralization were removed by vacuum filtration
while washing with ether and the filtrate was dried over
anhydrous sodium sulfate. Removal of the solvent fol-
lowed by flash column chromatography (hexane/ether,
9:1) of the residual oil provided the racemic ketone 8
(10.08 g, 50%) along with diketone 9 (1.74 g, 8%) and
unreacted 1,8-cineole (1.84 g, 10%). For 8: Rf 0.23
enzyme-mediated reaction was found to be selective for
the (R)-ester, a result which is consistent with PLE
selectivity for many similar types of substrates.17 Both
the iodination–dehydroiodination scheme in the chiral
series and the p-toluenesulfonate elimination in the
racemic series were found to be superior to both the
previously reported xanthate pyrolysis and Bamford–
Stevens protocols in yielding the desired cineolenes.
4. Experimental
4.1. General
NMR spectra were recorded on a Varian INOVA 500
instrument using CDCl3 as solvent and internal stan-
dard unless otherwise indicated. Carbon signals marked
with an asterisk represent methyl and methyne carbons
as determined by APT experiments. Proton coupling
constants (J) are reported in hertz (Hz). 19F NMR
spectra were recorded using trifluromethybenzene as an
external standard. FTIR spectra were recorded with a
Mattson Galaxy Series 5000 FT instrument. Optical
rotation values were recorded with a Jasco DIP 360
polarimeter. Dichloromethane was distilled from CaH2
and pyridine was distilled from barium oxide. All other
reagents and solvents were ACS reagent grade and used
as commercially available. Flash column chromatogra-
phy was carried out using silica gel 60 (E. Merck 9385,
230–400 mesh).18 Silica gel filtrations employed silica

F. A. Luzzio, D. Y. Du6eau / Tetrahedron: Asymmetry 13 (2002) 1173–1180
1177
1
(hexane/ether, 9:1); H NMR (500 MHz, CDCl3)19 l:
1.06 (s, 3H), 1.15 (s, 3H), 1.23 (s, 3H), 1.55 (m, 1H),
1.67 (m, 1H), 1.79 (m, 1H), 2.08 (dd, J=2.0, 3.8, 1H),
2.16 (m, 2H), 2.30 (dd, J=3, 18.8, 1H); 13C NMR (125
MHz, CDCl3) l: 18.3, 26.5, 27.2, 30.9, 49.2, 52.0, 73.8.
IR (CHCl3) 3437, 3033, 2456 cm−1, 1725. HRMS (EI)
m/z (M+) calcd for C10H16O2 168.1150, found 168.1156.
4.5. Enzymatic resolution of ( )-exo-1,3,3-trimethyl-2-
oxabicyclo[2.2.2]octane-5-yl acetate: (−)-exo-1,3,3-
trimethyl-2-oxabicyclo[2.2.2]octane-5-ol, (−)-2b and
(+)-exo-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane-5-yl
acetate, (+)-4b
Racemic ester ( )-4b (0.85 g, 4.71 mmol) was ground to
a fine powder and added in one portion to phosphate
buffer solution (pH 7.00, 15 mL). A suspension of
porcine liver esterase (EC 3.1.1.1. Sigma Lotc
29F8055, 2530 units) was added to the buffer/substrate
suspension and the reaction mixture was swirled in an
incubator at 37°C for 12 h. The suspension was then
saturated with brine (5.0 mL) followed by the addition
of dichloromethane (5 mL). The suspension was vac-
uum-filtered through a Celite pad to remove proteina-
ceous material followed by extraction of the filtrate
with dichloromethane (3×20 mL). The combined
extracts containing the crude ester/alcohol mixture were
dried over sodium sulfate and concentrated. Flash
column chromatography (hexane/ether, 5:1) of the
residual oil provided the ester (+)-4b (368 mg, 43%) and
the alcohol (−)-2b (305 mg, 45%). For ester (+)-4b: mp
41–43°C; Rf 0.52 (hexane/ether, 1:1); [h]2D5 +55.8 (c=
4.3. ( )-exo-1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-
5-ol, ( )-2b
A suspension of lithium tetrahydroaluminate (0.64 g,
16.8 mmol) in ether (25 mL) was prepared in a 300 mL
round-bottom flask fitted with a dry-ice cold finger
condenser, mechanical stirrer and argon inlet. To the
stirred suspension was added a solution of ( )-ketone 8
(1.13 g, 6.73 mmol) in dry ether (5.0 mL) under a
stream of argon while cooling in an ice/water bath.
After the addition of 8 was complete, the reaction
mixture was refluxed (1.5 h) followed by cooling the
reaction mixture (ice/water) prior to quenching. The
vigorously stirred reaction mixture was then quenched
by the addition of saturated aqueous sodium sulfate (20
mL) followed by extraction of the resultant white sus-
pension with diethyl ether (3×25 mL). The ethereal
extracts were combined, dried over anhydrous sodium
sulfate, filtered and concentrated to provide ( )-2b as a
chromatographically homogeneous oil (1.18 g, 99%)
which was of sufficient purity to use in the acetylation
1
1.25, CHCl3). H NMR (500 MHz, CDCl3) l: 1.12 (s,
3H), 1.24 (s, 3H), 1.36 (s, 3H), 1.47 (m, 2H), 1.62 (m,
1H), 1.74 (m, 2H), 2.06 (s, 3H), 2.10 (m, 2H), 4.98 (ddd,
J=2.13, 4.57, 5.9, 1H); 13C NMR (125 MHz, CDCl3)
l: 21.25, 21.71, 27.07, 30.34, 30.40, 30.63, 37.55, 40.48,
70.19, 73.02, 73.34. IR (CHCl3) 3434, 2974, 2461, 1725
cm−1. HRMS (EI) m/z (M+) calcd for C12H20O3
212.1412, found 212.1412. For alcohol (−)-2b: mp 90–
92°C; Rf 10.21 (hexane/ether, 1:1); [h]2D5 −45.3 (c=1.24,
CHCl3). H NMR (500 MHz, CDCl3) l: 1.11 (s, 3H),
1.24 (s, 3H), 1.38 (m, 2H), 1.43 (s, 3H), 1.57 (m, 2H),
1.69 (ddd, J=3.25, 6.11, 13.81, 1H), 4.15 (ddd, J=2.1,
4.23, 6.11, 1H); 13C NMR (125 MHz, CDCl3) l: 21.66,
27.11, 27.38, 30.37, 31.03, 40.99, 43.45, 70.43, 71.09. IR
(CHCl3) 2461, 1725, 1464, 1368 cm−1. HRMS (EI) m/z
(M+) calcd for C10H18O2 170.1306, found 170.1301.
1
step. Rf 0.16 (hexane/ether, 2:1); H NMR (500 MHz,
CDCl3)19 l: 1.11 (s, 3H), 1.23 (s, 3H), 1.37 (m, 2H),
1.43 (s, 3H), 1.53 (m, 1H), 1.58 (m, 1H), 1.68 (ddd,
J=3.18, 6.06, 13.79, 1H), 2.04 (m, 2H), 4.14 (ddd,
J=2.01, 6.08, 10.27, 1H); 13C NMR (125 MHz, CDCl3)
l: 21.66, 27.08, 30.34, 30.74, 31.03, 40.97, 43.43, 70.46,
71.06, 73.69. IR (CHCl3) 3613, 2957, 2462, 1623 cm−1;
HRMS (EI) m/z (M+) calcd for C10H18O2 170.1306,
found 170.1300.
4.4. ( )-exo-1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-
5-yl acetate, ( )-4b
4.6. (+)-exo-1,3,3-Trimethyl-2-oxabicyclo[2.2.2]octane-
5-ol, (+)-2b
To a stirred solution of ( )-alcohol 2b (1.0 g, 5.87
mmol) and 4-dimethylaminopyridine (1.08 g, 8.81
mmol) dissolved in dichloromethane (10.0 mL) was
added acetyl chloride (1.38 g, 17.6 mmol) while cooling
at 0–5°C. The reaction mixture was warmed to room
exo-Acetate (+)-4b (315 mg, 1.48 mmol) was added to a
solution of 1N aqueous lithium hydroxide (15 mL) in
water/methanol/THF (4:3:5). The reaction mixture was
stirred at room temperature (3 h) while monitoring by
TLC. Brine (15 mL) was then added followed by
extraction with THF (3×10 mL). The extracts were then
combined and dried over anhydrous sodium sulfate (16
h). The drying agent was removed by filtration followed
by removal of the solvent, reconstitution of the residue
in dichloromethane (20 mL) and drying over anhydrous
sodium sulfate. Removal of the drying agent and sol-
vent followed by filtration through a short pad of silica
gel provided the pure exo-alcohol (+)-2b (203 mg,
temperature
followed
by
removal
of
the
dichloromethane and excess acetyl chloride under vac-
uum. The residue was dissolved in diethyl ether, directly
applied to a flash silica column and eluted with pen-
tane/ether (9:1). Evaporation of the solvents provided
the ( )-acetate 4b as white crystals (0.88 g, 70%). Mp
41–43°C. Rf 0.42 (hexane/ether, 2:1). 1H NMR (500
MHz, CDCl3) l: 1.13 (s, 3H), 1.24 (s, 3H), 1.36 (s, 3H),
1.47 (m, 2H), 1.63 (m, 1H), 1.75 (m, 2H), 2.06 (s, 3H),
2.11 (m, 2H), 4.99 (ddd, J=2.15, 4.55, 5.76, 1H); 13C
NMR (125 MHz, CDCl3) l: 21.24, 21.71, 26.97, 30.34,
30.39, 30.62, 37.60, 40.47, 70.21, 73.01, 73.36. IR
(CHCl3) 3432, 3038, 1725, 1369 cm−1. HRMS (EI) m/z
(M+) calcd for C12H20O3 212.1412, found 212.1416.
1
80%). Mp 90–92°C; [h]2D5 +49.8 (c=1.04, CHCl3). H
NMR (500 MHz, CDCl3) l: 1.11 (s, 3H), 1.24 (s, 3H),
1.38 (m, 2H), 1.44 (s, 3H), 1.58 (m, 2H), 1.69 (ddd,
J=3.25, 6.11, 13.84, 1H), 2.05 (m, 2H), 4.15 (ddd,
J=2.12, 4.25, 6.08, 1H); 13C NMR (125 MHz, CDCl3)
l: 21.67, 27.11, 30.34, 31.07, 40.93, 43.44, 70.45, 71.05,

1178
F. A. Luzzio, D. Y. Du6eau / Tetrahedron: Asymmetry 13 (2002) 1173–1180
73.67. IR (CHCl3) 2974, 1462, 1365 cm−1. HRMS (EI)
residual oil provided ( )-12 as an endo/exo mixture
(79.5 mg, 48%; endo/exo, 2.5:1) which exhibited the
same spectral characteristics as (−)-12.
m/z (M+) calcd for C10H18O2 170.1306, found 170.1309.
4.7. (−)-endo-/exo-5-Iodo-1,3,3-trimethyl-2-oxabicyclo-
[2.2.2]octane, (−)-12
4.7.2. Preparation of ( )-12. Sodium iodide/exo-p-tolue-
nesulfonate method. A solution of freshly ground dry
exo-p-toluenesulfonate 13 (250 mg, 0.77 mmol) in dry
acetone (2.0 mL) was added to a solution containing
vacuum dried sodium iodide (578 mg, 3.85 mmol) in
acetone (2.0 mL). The reaction mixture was heated
under reflux under nitrogen for 20 h, during which time
the reaction mixture became dark brown. The reaction
mixture was filtered through a plug of glass wool
followed by removal of the acetone. The residue was
dissolved in dichloromethane (25 mL), washed with 5%
aqueous sodium bicarbonate solution (25 mL) and then
washed with a 5% aqueous sodium thiosulfate solution
(2×25 mL). The organic layer was then dried over
anhydrous sodium sulfate. Removal of the drying agent
followed by flash column chromatography of the resid-
ual oil (hexane/ether, 20:1) afforded ( )-12 as an endo/
exo mixture (78.7 mg, 37%; endo/exo, 1:2) which
exhibited the same spectral characteristics as ( )-12
prepared by the arylphosphine/iodine methods
described above.
Iodine (700 mg, 2.76 mmol) was added to a stirred
solution of imidazole (376 mg, 5.52 mmol) and ben-
zene/acetonitrile (2:1, 20 mL). To the brown–black
solution, under a nitrogen atmosphere, was added
triphenylphosphine (724 mg, 2.76 mmol) to give a
yellow-white suspension. Alcohol (+)-2b, dissolved in
benzene/acetonitrile (2:1, 1 mL) was then added to the
reagent mixture which turned the suspension white. The
reaction mixture was heated at 75°C for 6 h, during
which time the mixture changed colour back to yellow.
At the end of the reaction, the mixture was concen-
trated under vacuum and the residue was directly
applied to a flash chromatography column eluting with
hexane/ether (6:1). Concentration of the eluent gave the
product (−)-12a/12b as a colorless oil along with
triphenylphosphine. Addition of ether (1–5 mL) and
iodomethane (1 mL, 16.1 mmol) precipitated the
triphenylphosphine as the methiodide which was
removed by filtration. Removal of the solvent furnished
the endo- and exo-iodides (−)-12a and (−)-12b (173 mg,
45%) as an oily liquid which yellows on standing at
room temperature. Rf 0.65 (hexane/ether, 1:1); [h]2D5 −30
(c=1.23, CHCl3). FTIR (CHCl3) 3045, 2976, 1437,
1176 cm−1. For endo-(−)-12a: 1H NMR (500 MHz,
CDCl3) l: 1.07 (s, 3H), 1.28 (s, 3H), 1.34 (s, 3H), 1.62
(m, 1H), 1.70 (m, 1H), 1.73 (m, 1H), 2.08 (m, 1H), 2.10
(m, 1H), 2.26 (m, 1H), 2.46 (m, 1H), 5.04 (m, 1H); 13C
NMR (125 MHz, CDCl3) l: 20.6, 26.57, 28.28, 28.85,
30.05, 31.45, 42.72, 46.87, 71.19, 74.44. For exo-(−)-
4.8. ( )-5-exo-(p-Toluenesulfonyloxy)-1,3,3-trimethyl-2-
oxabicyclo[2.2.2]-octane, 13
Racemic alcohol 2b (579 mg, 3.4 mmol) and 4-di-
methylaminopyridine (1.66 g, 13.6 mmol) was dissolved
in dichloromethane (4 mL). The solution was then
cooled to 0°C under nitrogen and p-toluenesulfonyl
chloride (1.3 g, 6.8 mmol) dissolved in dichloromethane
(2.0 mL) was added dropwise by syringe while stirring.
Stirring was continued at room temperature for 24 h.
The reaction mixture was then poured into a separatory
funnel, washed with brine (3×25 mL) and dried over
sodium sulfate. Removal of the drying agent and sol-
vent followed by flash chromatography provided the
exo-p-toluenesulfonate 13 (0.89 g, 81%). Mp 92–93°C;
1H NMR (500 MHz, CDCl3) l: 1.17 (s, 3H), 1.21 (s,
3H), 1.34 (m, 3H), 1.37 (s, 3H), 1.59 (m, 1H), 1.87 (ddd,
J=3.16, 6.02, 14.4 Hz, 1H), 1.97 (dd, J=10.5, 14.4 Hz,
2H), 2.07 (m, 1H), 2.46 (s, 3H), 4.81 (ddd, J=2.10,
2.24, 4.41 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.80 (d,
J=8.19 Hz, 2H); 13C NMR (125 MHz, CDCl3) l:
21.30, 26.81, 30.00, 30.67, 38.50, 38.65, 40.59, 70.18,
73.22, 80.55, 80.93, 127.75, 127.98, 129.64, 130.55,
134.59, 144.89. IR (CHCl3) 2974, 2457, 1599, 1359
1
12b: H NMR (500 MHz, CDCl3) l: 1.10 (s, 3H), 1.28
(s, 3H), 1.53 (m, 1H), 1.63 (m, 1H), 1.69 (s, 3H), 1.75
(m, 1H), 1.96 (m, 1H), 2.10 (m, 1H), 2.29 (m, 1H), 2.42
(m, 1H), 4.50 (dd, J=9.63, 9.99 Hz); 13C NMR (125
MHz, CDCl3) l: 21.36, 25.32, 26.88, 29.72, 29.98,
30.84, 42.12, 46.23, 72.09, 74.87. IR (CHCl3) 3061,
2976, 1437, 1176 cm−1.
4.7.1. ( )-endo-/exo-5-Iodo-1,3,3-trimethyl-2-oxabicy-
clo[2.2.2]octane, ( )-12: chlorodiphenylphosphine method.
To a solution of imidazole (160 mg, 2.35 mmol) in dry
toluene (1.0 mL) was added chlorodiphenylphosphine
(0.21 mL, 1.17 mmol) by syringe under an atmosphere
of nitrogen. ( )-exo-Alcohol 2b (100 mg, 0.59 mmol)
dissolved in dry toluene (1.0 mL) was then added by
syringe while stirring. A solution of iodine (298 mg,
1.17 mmol) was then added while stirring and the
resultant brown solution was stirred at room tempera-
ture under nitrogen (2 h). When the reaction was
complete the mixture was transferred to a separatory
funnel and then washed with saturated sodium bicar-
bonate (5 mL). Ground iodine was added to the separa-
tory funnel and shaken until the organic phase was
colored with unreacted iodine. The organic layer was
then separated, washed with 5% aqueous sodium thio-
sulfate (3×15 mL) and dried over anhydrous sodium
sulfate. Removal of the solvent followed by flash
column chromatography (hexane/ether, 6:1) of the
cm−1. HRMS (CI) m/z (MNH4 ) calcd for C17H28NO4S
+
342.1753, found 342.1753.
4.9. (−)-1,3,3-Trimethyl-2-oxabicyclo[2.2.2]oct-5-ene,
(−)-6
A mixture of endo-iodide (−)-12 (115 mg, 0.41 mmol)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (68 mg, 0.45
mmol) were mixed in a 5 mL round-bottomed flask
connected directly to a 10 mL vacuum trap cooled to
−78°C. The mixture was heated (oil bath) while stirring
under nitrogen at 100°C for 15 min and then at 115°C
for 20 min. During the heating the reaction mixture

F. A. Luzzio, D. Y. Du6eau / Tetrahedron: Asymmetry 13 (2002) 1173–1180
1179
became green-brown and viscous. The flask was cooled
then vacuum (1.0 Torr) was applied to the apparatus
followed by gentle warming of the flask (80–90°C). The
olefin (−)-6 (62 mg, 99%) was collected in the vacuum
trap at −78°C as a clear colorless liquid: [h]2D5 −39.8
(−)-exo-Mosher ester, (−)-10b: [h]2D5 −7.00 (c=2.8,
1
CHCl3). H NMR (500 MHz, CDCl3) l: 1.10 (s, 3H),
1.13 (s, 3H), 1.22 (s, 3H), 1.28 (m, 1H), 1.46 (m, 1H),
1.55 (m, 1H), 1.64 (m, 1H), 1.74 (m, 1H), 1.68 (ddd,
J=3.16, 6.29, 14.3), 2.13 (m, 1H), 2.21 (dd, J=10.59,
14.11, 1H), 3.54 (s, 3H), 5.25 (m, 1H), 7.41 (m, 3H),
7.54 (m, 2H); 13C NMR (125 MHz, CDCl3) l: 21.38,
26.88, 30.16, 30.22, 37.88, 40.17, 70.14, 73.11, 75.37,
74.44, 122.46, 124.75, 127.44, 128.64, 129.80, 132.53;
19F NMR (470 MHz, CDCl3) l: −72.68 (s, 3F) 1%,
−72.7 (s, 3F) 99%. HRMS (EI) m/z (MH+) calcd for
C20H25O4F3 386.1705, found 386.1718.
1
(c=1.00, CHCl3); H NMR (500 MHz, CDCl3) l: 0.99
(s, 3H), 1.28 (s, 3H), 1.33 (s, 3H), 1.73 (m, 1H), 2.01 (m,
1H), 2.28 (m, 1H), 6.09 (d, J=8.14, 1H), 6.46 (dt,
J=1.39, 8.08, 1H). 13C NMR (125 MHz, CDCl3) l:
20.59, 28.30, 29.29, 31.48, 36.65, 71.28, 74.47, 135.38,
135.6. IR (CHCl3) 3611, 2462, 1461, 1378 cm−1. HRMS
(EI) m/z (M+) calcd for C10H16O 152.1201, found
152.1195.
4.11. (+)-exo-1,3,3-Trimethyl-2-oxabicyclo[2.2.2]oct-5-
yl-S-a-methoxyphenyl-acetate, (+)-(11)
4.9.1. Preparation of ( )-6 by DBU-promoted elimina-
tion of exo-p-toluenesulfonate, ( )-13. A mixture of the
racemic 5-exo-tosylate ( )-13 (671 mg, 2.07 mmol) and
DBU (0.37 mL, 2.48 mmol) was placed in a 25 mL
round-bottom flask fitted with a water-cooled cold-
finger condenser. The mixture was heated (oil bath,
115–120°C) for 20 h while stirring, during which time
the color of the mixture became dark brown. At the
end of the reaction period the condenser was removed
and the flask was fitted with a 10 mL vacumm trap
cooled with dry ice. The product was then distilled into
the trap under vacuum (1 Torr). The yield of pure
( )-cineolene 6 was 193.4 mg (61%) which had the same
spectral properties as detailed for (−)-6.
(S)-(+)-a-Methoxyphenylacetic acid (60 mg, 0.36 mmol)
was added to oxalyl chloride (1.0 mL, 11.3 mmol). The
solution was stirred at room temperature (20 h) then
heated under reflux (3 h). The excess oxalyl chloride
was removed by short-path distillation at atmospheric
pressure followed by application of vacuum (0.5 Torr)
at 0°C. The product acid chloride was then dissolved in
dichloromethane (1.0 mL) and slowly added to a solu-
tion of exo-alcohol (−)-2b (61.3 mg, 0.36 mmol) and
DMAP (132 mg, 1.08 mmol) in dichloromethane (1.0
mL) under a nitrogen atmosphere. The reaction mix-
ture was stirred at room temperature (16 h) followed by
removal of the reaction solvent and direct flash column
chromatography (hexane/ether, 2:1) of the residue. The
yield of the oily colorless mandelic acid ester (+)-11 was
4.10. (+)- and (−)-exo-1,3,3-Trimethyl-2-oxabicyclo-
[2.2.2]oct-5-yl-R-a-methoxy-a-(trifluoromethyl)-
phenylacetate. Mosher esters, (+)-10a and (−)-10b
1
44 mg (38%). [h]2D5 +6.2 (c=1.7, CHCl3). H NMR (500
MHz, CDCl3) l: 1.05 (s, 3H), 1.18 (s, 3H), 1.20 (s, 3H),
1.38 (m, 1H), 1.48 (m, 2H), 1.58 (m, 1H), 1.1 (dd,
J=1.97, 3.89, 1H), 2.03 (dd, J=10.36, 14.07, 2H), 4.72
(s, 3H), 5.03 (ddd, J=2.15, 4.51, 10.5, 1H), 7.35 (m,
3H), 7.42 (m, 2H); 13C NMR (125 MHz, CDCl3) l:
21.24, 30.26, 30.66, 37.73, 40.21, 70.11, 73.19, 73.85,
83.01, 127.42, 128.84, 136.30. HRMS (EI) m/z (MH+)
calcd for C19H27O4 319.1901, found 319.1909.
Thionyl chloride (1.0 mL, 13.7 mmol) was added to
(R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid
(134 mg, 0.57 mmol). Finely ground sodium chloride
(166 mg, 2.85 mmol) was added and the mixture was
refluxed for 48 h. At the end of the reflux period, excess
thionyl chloride was removed by short-path distillation
at atmospheric pressure, which left a yellow residual
oily acid chloride. The crude product was placed under
vacuum (0.5 Torr) at 0°C (0.5 h). The oily acid chloride
was then dissolved in dichloromethane (4.0 mL). Half
the solution of the Mosher acid chloride (2.0 mL) was
added to a stirred solution of the exo-alcohol (+)-2b
(0.25 mmol) and 4-dimethylaminopyridine (0.76 mmol)
in dichloromethane (0.5 mL). The other half of the acid
chloride solution was added to the exo-alcohol (−)-2b
under identical conditions. The esterification reactions
were both stirred (16 h) followed by solvent removal
under vacuum and direct flash column chromatography
(hexane/ether, 2:1). (+)-exo-Mosher ester, (+)-10a: [h]D25
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