Synthesis of bridgehead hydroxy bicyclo[2.2.2]octane derivatives

Article abstract of DOI:10.1021/jo051284e

Two independent synthetic routes, starting from 1,3-cyclohexadione, toward the 4-hydroxy bicyclo[2.2.2]octane-2,6-dione derivative 3 are described.

Full text of DOI:10.1021/jo051284e

ment reactions, including the homoallyl-homoallyl radi-
Synthesis of Bridgehead Hydroxy
Bicyclo[2.2.2]octane Derivatives1
cal rearrangement.12,13
Viveca Thornqvist, Sophie Manner,
Magnus Wingstrand, and Torbjo¨rn Frejd*
Division of Organic Chemistry, Kemicentrum, Lund
University, P.O. Box 124, SE-221 00 Lund, Sweden
Torbjorn.Frejd@organic.lu.se
Received June 23, 2005
Our group has been particularly interested in bicyclo-
[2.2.2]octane-2,6-dione 1, which we have employed in
synthesis14 and as ligands for asymmetric catalysis.4,15
For these purposes, we needed easy access to bridgehead
hydroxyl derivatives based on 2. Since 2 was difficult to
isolate because of its high water solubility, we chose the
protected derivative 3 as more suitable for further
manipulations. Two independent methods for the syn-
thesis of 3 are presented in this report.
Our first route based on the aldol addition as a key
reaction (7 f 8) is shown in Scheme 1 and starts with
monoacetal 4, which was synthesized from commercially
available 1,3-cyclohexadione.16
Hong and Chin17 previously reported a synthetic
method for the preparation of 7a, which included ally-
lation of 4. In our hands, however, allylation of 4 to give
5a with allyl Grignard reagent in THF led to the
formation of a complex product mixture. More successful
was the application of the corresponding indium re-
agent.18 By reacting 4 with allyl bromide and indium in
3 Å MS-dried methanol at 0 °C, 5a was obtained in 90%
yield.
The initial plan for the continued synthesis was to
prepare compound 8a in a “one-flask operation” (i.e.,
ozonolysis of 5a) to give the corresponding aldehyde 9
(Scheme 2), followed by acid-catalyzed deprotection of the
ketal and in situ acid-catalyzed intramolecular aldol
addition. This methodology has been applied earlier in
the synthesis of other bicyclo[2.2.2]octane derivatives.10,19
However, this operation failed, instead resulting in
compound 10.
Two independent synthetic routes, starting from 1,3-cyclo-
hexadione, toward the 4-hydroxy bicyclo[2.2.2]octane-2,6-
dione derivative 3 are described.
Multifunctionalized bicyclo[2.2.2]octanes are of interest
due to their occurrence as subunits in natural products,2
in natural product synthesis,3 and as ligands for asym-
metric catalysis.4,5 Four general methods are available
in the literature for the synthesis of these systems:
double Michael addition,6 Diels-Alder reaction,7,8 in-
tramolecular condensation reactions,9-11 and rearrange-
(1) Parts of this work were presented at the 15th International
Conference on Organic Synthesis, IUPAC ICOS-15, August 2004,
Nagoya, Japan.
(2) Gonzalez Gonzalez, J.; Martinez Olivares, E.; Delle Monache,
F. Phytochemistry 1995, 38, 485-489.
(3) (a) Paquette, L. A.; Poupart, M. A. J. Org. Chem. 1993, 58, 4245-
4253. (b) Mori, K.; Matsushima, Y. Synthesis 1993, 406-410. (c)
Paquette, L. A.; Oplinger, J. A. Tetrahedron 1989, 45, 107-124.
(4) (a) Sarvary, I.; Almqvist, F.; Frejd, T. Chem.-Eur. J. 2001, 7,
2158-2166. (b) Sarvary, I.; Wan, Y.; Frejd, T. J. Chem. Soc., Perkin
Trans. 1 2002, 645-651.
(5) (a) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org.
Chem. 2005, 70, 2503-2508. (b) Defieber, C.; Paquin, J.-F.; Serna, S.;
Carreira, E. M. Org. Lett. 2004, 6, 3873-3876.
It seemed reasonable that the cyclic ketal had to be
removed before ozonolysis, but to minimize the risk of
water elimination, the tertiary alcohol was protected
prior to the ketal cleavage. After several attempts with
(11) Ranu, B. C.; Guchhait, S. K.; Ghosh, K.; Patra, A. Green Chem.
2000, 2, 5-6.
(12) Finet, L.; Lena, J. I. C.; Kaoudi, T.; Birlirakis, N.; Arseniyadis,
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(13) (a) Hrnciar, P.; Liptay, T.; Sraga, J. Collect. Czech. Chem.
Commun. 1990, 55, 1208-1215. (b) Arseniyadis, S.; Yashunsky, D. V.;
de Freitas, R. P.; Dorado, M. M.; Potier, P.; Toupet, L. Tetrahedron
1996, 52, 12443-12458. (c) Toyota, M.; Yokota, M.; Ihara, M. Tetra-
hedron Lett. 1999, 40, 1551-1554.
(14) (a) Almqvist, F.; Frejd, T. Tetrahedron: Asymmetry 1995, 6,
957-960. (b) Almqvist, F.; Ekman, N.; Frejd, T. J. Org. Chem. 1996,
61, 3794-3798. (c) Almqvist, F.; Frejd, T. J. Org. Chem. 1996, 61,
6947-6951. (d) Almqvist, F.; Manner, S.; Thornqvist, V.; Berg, U.;
Wallin, M.; Frejd, T. Org. Biomol. Chem. 2004, 2, 3085-3090.
(15) (a) Almqvist, F.; Torstensson, L.; Gudmundsson, A.; Frejd, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 376-377. (b) Sarvary, I.;
Norrby, P.-O.; Frejd, T. Chem.-Eur. J. 2004, 10, 182-189.
(16) Takagi, H.; Hayashi, T.; Mizutani, T.; Masuda, H.; Ogoshi, H.
J. Chem. Soc., Perkin Trans. 1 1999, 1885-1892.
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(18) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831-
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1998, 81, 2375-2387.
10.1021/jo051284e CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/10/2005
J. Org. Chem. 2005, 70, 8609-8612
8609

SCHEME 1a
temperature had to be lowered to -15 °C in the latter
case. Subsequently, oxidative cleavage of the allyl deriva-
tives 6a-c was affected by ozone in CH2Cl2 at -78 °C,
followed by reductive workup using DMS.
Since the TBDMS-protected derivatives seemed most
suitable to work with, we chose to continue the synthesis
by using the crude oxidation product 6b, which, as
indicated by 1H NMR, contained the aldehyde 7b. Thus,
the aldol reaction conditions were tested on this crude
aldehyde. First, base-catalyzed aldol reactions were
examined. However, neither K2CO3 nor Cs2CO3 in dif-
ferent concentrations in methanol could avoid formation
of complex reaction mixtures. This prompted us to look
for alternative reagents, and at an early stage our
attention was drawn to Al2O3, which had been found to
efficiently catalyze intramolecular aldolizations of both
a keto aldehyde24 and a diketone.11 To our satisfaction,
when passing crude 7b through a column containing
basic Al2O3, the desired bicyclic compound 8b was col-
lected almost pure as a mixture of endo- and exo-alcohols
in 47% combined yield (starting from 6b). With the aim
to improve the reaction conditions for the cyclization, we
examined the influence of different solvents and solid
reagents. Three conventional solvents of different polarity
(EtOAc, toluene, and heptane) were tested together with
Al2O3 and high surface SiO2 (450 m2/g), respectively. It
was found that the highest reaction rates and yields were
obtained by using heptane as solvent in combination with
Al2O3. No product could be isolated in the attempts with
SiO2. However, we found that Kubota et al.25 had
employed mesoporous SiO2 in combination with amine
bases to enhance base-catalyzed aldolizations between
different derivatives of benzaldehyde and acetone. This
study inspired us to further investigate the potential of
high surface SiO2, this time together with amine bases.
Accordingly, a suspension of crude 7b and high surface
SiO2 in heptane was subjected to primary (pentylamine
and propylamine) and secondary (piperidine) amines, but
these were unable to promote the reaction. The tertiary
amines tributylamine, diisopropylethylamine, and tri-
ethylamine, on the other hand, were quite effective,
yielding endo-8b in an isolated yield of 55, 70, and 78%,
respectively. Different qualities of Al2O3 were also tested
but SiO2 was superior, in contrast to the reactions
performed in the absence of base, as mentioned. Since
SiO2 did not promote any reaction in the absence of base,
we checked if TEA alone could be responsible for the
aldolization, but only traces of 8b were obtained in this
experiment; the unreacted aldehyde was recovered in
56% yield.
a Reagents and conditions: (a) In powder (2 equiv), allyl bromide
(3 equiv), MeOH (dried), rt, 90%; (b) TBDMSOTf (1.9 equiv), 2,6-
lutidine (3.1 equiv), CH2Cl2, 0 °C, 95%; (c) BnBr (3 equiv), Ag2O
(3 equiv), EtOAc, rt, 37%; (d) PdCl2(CH3CN)2 (5 mol %), acetone:
formation of 6a: -15 °C, 85-90%; formation of 6b: 0 °C, 90%;
formation of 6c: 0 °C, 86%; (e) O3, -78 °C, heptane (7b) or CH2Cl2
(7c); (f) SiO2, TEA, rt, formation of 8b: heptane, 67% (endo
isomer), 16% (exo isomer); formation of 8c: heptane/toluene 2:1,
50% (endo isomer), 14% (exo isomer); (g) KMnO4‚CuSO4‚5H2O (2:1
w/w), toluene, 80 °C, 90%.
SCHEME 2a
a Reagents and conditions: (a) O3, CH2Cl2, -78 °C, Et3N, 55%;
(b) acetone/2 M HCl (100:1 or 200:1), rt then reflux, 35%.
a number of benzyl protection methodologies, 5c was
obtained in 37% yield, at best, using BnBr/Ag2O in
EtOAc.20 Because of this quite modest result, we decided
to test silyl protection. The combination of TBDMSOTf
and 2,6-lutidine21 proved to be very successful, providing
5b exclusively in 95% yield.
The cleavage of the cyclic ketal by trans-acetalization
was examined next. Since we expected that acidic hy-
drolysis would be difficult considering the problems we
had in producing 8a through acidic deprotection/cycliza-
tion, we instead turned our attention to PdCl2(CH3CN)2,
a soft Lewis acid.22 Thus, on treating 5b with a catalytic
amount of the palladium catalyst at room temperature,
in acetone and darkness, 6b was obtained in 90% yield.
By applying the same conditions to 5c, 6c was produced
in 86% yield and 5a gave 6a in 85% yield, although the
Since TEA can be used as a reducing agent in ozonoly-
sis reactions, the possibility to develop a tandem reaction
appeared logical. To test this idea, a solution of 6b in
heptane was purged with ozone at -78 °C. After the
reaction reached room temperature, TEA and SiO2 were
added. The dual role of TEA was evident since 8b was
obtained as a diastereomeric mixture of endo- and exo-
alcohols, which were separated by column chromatogra-
(22) (a) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H.
Tetrahedron Lett. 1985, 26, 705-708. (b) Kharasch, M. S.; Seyler, R.
C.; Mayo, F. R. J. Am. Chem. Soc. 1938, 60, 882-884.
(23) Pandolfi, E.; Comas, H. Tetrahedron Lett. 2003, 44, 4631-4633.
(24) Ogawa, T.; Mori, K.; Matsui, M.; Sumiki, Y. Tetrahedron Lett.
1968, 2551-2555.
(20) (a) Kuhn, R.; Low, I.; Trischmann, H. Chem. Ber. 1957, 90, 203-
218. (b) Van Hijfte, L.; Little, R. D. J. Org. Chem. 1985, 50, 3940-
3942.
(21) Corey, E. J.; Cho, H.; Ruecker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455-3458.
(25) Kubota, Y.; Goto, K.; Miyata, S.; Goto, Y.; Fukushima, Y.; Sugi,
Y. Chem. Lett. 2003, 32, 234-235.
8610 J. Org. Chem., Vol. 70, No. 21, 2005

SCHEME 3a
SCHEME 4a
a Reagents and conditions: (a) isopropenyl acetate (10 equiv),
maleic anhydride (1.3 equiv), p-TsOH (cat.), reflux, 12 h; (b) H2O,
80 °C, 12 h; (c) pyridine/H2O/TEA (10:10:1), electrolysis, 24 h, 55%
over three steps; (d) trimethylorthoformate (1.5 equiv), p-TsOH
(cat.), MeOH, rt, 24 h, quant.; (e) TBDMSCl (5 equiv), 60% NaH
(5 equiv), THF, 0 °C f rt, 12 h, 52% over two steps; (f) i. BH3‚THF,
THF, 0 °C f rt, ii. 2 M NaOH, 30% H2O2, 15: 0%, 16: 39%.
a Reagents and conditions: (a) i. TBDMSOTf (1.5 equiv), 2,6-
lutidine (2.6 equiv), CH2Cl2, 0 °C ii. 1 M HCl, THF, rt, 1 h, 70%;
(b) i. hydroboration reagent (see text), THF, 0 °C, 3 h, ii. 2 M
NaOH, 30% H2O2, rt, 12 h; (c) Jones’ oxidation, 64% of 3; (d) i.
BH3‚THF, THF, 0 °C, 3 h, ii. TPAP, NMO, CH2Cl2, rt, 4 h, 42%.
phy to afford endo-8b and exo-8b in 67 and 16% yield,
respectively (starting from 6b).
Motivated by the ease of the improved preparation of
8b from 6b, the same methodology was planned for 6a
and 6c, but these compounds were not soluble in heptane
and instead the two-step procedure had to be employed,
in which CH2Cl2 was used as solvent in the ozonolysis
reaction. Furthermore, to enhance the solubility of the
substrates during the aldolization, toluene was used as
cosolvent in combination with heptane. In this way, 8c
was formed as a diastereomeric mixture of endo- and exo-
alcohols, which after separation were obtained in 50 and
14% yield, respectively. In the case of 6a, the cyclization
reaction was very sluggish and irreproducible, and 8a
(45%) was not obtained in a pure state due to the high
water solubility and instability of the product. Addition-
ally, the diastereoisomers were difficult to separate by
column chromatography. No further efforts were made
to optimize the synthesis of 8a. meso-Diketone 3 was then
conveniently obtained in 90% yield by oxidation of 8b by
KMnO4/CuSO4‚5H2O.26
the hydroboration was preceded by two protection steps:
acetalization of ketone 12 produced 13 quantitatively,
which was then TBDMS-protected under the same condi-
tions as for 5a. Surprisingly, two products were formed.
Apart from the expected 14, deacetalization occurred
giving TBDMS-protected 17 (Scheme 4). Due to separa-
tion problems of 14 and 17, TBDMSCl in combination
with NaH in THF, which gave 14 as the only product,
was used instead, even though full conversion of 13 could
not be achieved.
In the first hydroboration-oxidation attempts of 14,
BH3‚THF was chosen. However, several products were
formed where only the exo-isomer of 16 could be isolated
as an impure sample. At first, we anticipated one of the
MeO groups of the acetal in 14 to coordinate BH3,
directing it toward C2-attack, which would form the
desired regioisomer 15 after oxidation. However, to our
surprise, formation of 16 was favored. Apparently, the
acetal group was not as small or directing as we antici-
pated. It is possible that the borane was coordinated by
the acetal group in a way remote from the C-2 position,
preventing borane addition via a C-2 directive effect. The
absence of formation of the endo-isomer of 16 might be
explained by steric hindrance from the acetal-BH3
complex, forcing the borane toward exo attack.
Our second route toward 3 was based on the Diels-
Alder product 12 (from dienol bisacetate of 11 + maleic
anhydride) (Scheme 3). Compound 12 was obtained in
an overall yield of 55%, starting from 11, according to a
modified literature procedure8 in which the lead tetra-
acetate-induced bisdecarboxylation was replaced with a
more environmentally friendly Kolbe-like electrolytic
bisdecarboxylation.27
For the hydration of 12, hydroboration-oxidation was
chosen since varying the size of the borane reagent, in
combination with a large protection group at the bridge-
head hydroxyl, was thought to increase the probability
to obtain the desired regioisomer 15. In our first attempt,
Due to the difficulties to synthesize 14 selectively in
high yield in combination with several protection and
deprotection steps followed by selectivity problems in the
hydroboration step, we changed our approach (Scheme
4). Thus, 12 was TBDMS-protected to give 17 and bis-
silylated enol ether 22, which was easily cleaved by acidic
hydrolysis, resulting in a 70% total yield of 17.
(26) (a) Paquette, L. A.; Tsui, H.-C. J. Org. Chem. 1996, 61, 142-
145. (b) Menger, F. M.; Lee, C. J. Org. Chem. 1979, 44, 3446-3448.
(27) Lightner, D. A.; Paquette, L. A.; Chayangkoon, P.; Lin, H. S.;
Peterson, J. R. J. Org. Chem. 1988, 53, 1969-1973.
Starting from 17, compound 3 could in principle be
obtained either via a stepwise hydroboration followed by
J. Org. Chem, Vol. 70, No. 21, 2005 8611

purified by column chromatography (SiO2, pentane/ether 1:1)
to give endo-8b (673 mg, 67%) and exo-8b (166 mg, 16%) as
white solids.
oxidation sequence via 18 or via direct one-pot in situ
hydroboration-oxidation.
The stepwise approach was tested first by employing
a series of borane reagents (BH3‚THF, disiamyl borane,
thexyl borane, catechole borane, 9-BBN, and BBr2H‚
SMe2). A large excess of the borane reagent was used to
ensure full conversion of both the carbonyl and the olefin
unit. Complex mixtures containing all four alcohols 18/
19/20/21 in different ratios were obtained together with
several byproducts when more bulky boranes were ap-
plied. Complete conversion of 17 into 18 and 19 (49:51)
was only observed with BH3‚THF. Next, 18 and 19 were
oxidized separately under Jones’ conditions where 18
gave 3 (64%). Surprisingly, 23 (the oxidation product of
19) was not detected. Worth noticing is that the acid-
sensitive TBDMS group was resistant toward Jones’
conditions.
endo-8b: Rf 0.14; mp 80.5-81.7 °C; IR (KBr) 3408, 2961, 2856,
1
1717, 1252, 1132, 835, 773 cm-1; H NMR (400 MHz, benzene-
d6) δ 3.50-3.45 (m, 1H), 2.51 (br dAB, JAB ) 17.9 Hz, 1H), 2.22
(ddAB, J ) 3.3 Hz, JAB ) 17.9 Hz, 1H), 2.12-2.11 (m, 1H), 1.85
(dddAB, J ) 3.3, 9.2 Hz, JAB ) 13.5 Hz, 1H), 1.57 (dAB, JAB
)
13.5 Hz, 1H), 1.28 (d, J ) 2.8 Hz, 1H), 1.25-1.19 (m, 3H), 1.06-
0.98 (m, 1H), 0.91 (s, 9H), -0.03 (s, 6H); 13C NMR (100 MHz,
benzene-d6) δ 209.5, 72.1, 67.8, 52.4, 50.0, 44.7, 32.5, 25.8, 18.4,
18.0, -2.0; HRMS (FAB+) calcd for C14H27O3Si (M + H):
271.1729. Found: 271.1736. Anal. Calcd for C14H26O3Si: C,
62.18; H, 9.69. Found: C, 62.23; H, 9.64.
exo-8b: Rf 0.25; mp 45.5-47.6 °C; IR (KBr) 3408, 2949, 2856,
1
1715, 1252, 1142, 835, 773 cm-1; H NMR (400 MHz, benzene-
d6) δ 3.61-3.59 (m, 1H), 2.18-2.02 (m, 4H), 1.79-1.73 (m, 1H),
1.65-1.63 (m, 1H), 1.49 (tdAB, J ) 3.3 Hz, JAB ) 13.5 Hz, 1H),
1.34-1.32 (m, 1H), 1.20-1.19 (m, 1H), 0.91 (br s, 9H), 0.73 (br
s, 1H), -0.03 (s, 6H); 13C NMR (100 MHz, benzene-d6) δ 209.4,
72.6, 64.9, 51.6, 50.8, 45.5, 33.2, 25.8, 18.0, 16.4, -1.99; HRMS
(FAB+) calcd for C14H27O3Si (M + H): 271.1729. Found:
271.1725. Anal. Calcd for C14H26O3Si: C, 62.18; H, 9.69.
Found: C, 62.14; H, 9.78.
Attempts were also made to synthesize 3 in a one-step
procedure starting from 17. The most common and
frequently used method for this kind of operation was
found in the literature to be hydroboration followed by
chromic acid oxidation of the organoborane.28 Since the
yields were rather low using this oxidation and seemed
to drop on scaling up, hydroboration followed by either
PCC oxidation in CH2Cl229 or TPAP/NMO oxidation were
tried.30 Oxidation with TPAP/NMO was found to be the
most promising method for the following reasons: (a) no
decrease in yield on scaleup, (b) use of a catalytic amount
of TPAP instead of a stoichiometric excess of the chro-
mium reagents, and (c) simple workup by filtration
through a pad of SiO2. This resulted in an overall 42%
yield of 3.
Deprotection of 3 to give 2 was performed in BF3‚Et2O/
CH3CN at 0 °C,31 which proceeded nicely, but 2 proved
to be very difficult to isolate due to its high water
solubility. Thus, the silyl-protecting group positioned at
the bridgehead hydroxyl in 3 should preferentially be
kept in place prior to further transformations.
4-(tert-Butyldimethylsilanyloxy)-bicyclo[2.2.2]octan-2,6-
dione (3). (a) Oxidation of 8b: A solution of endo/exo-8b (100
mg, 0.37 mmol) in toluene (1.5 mL) was stirred with KMnO4/
CuSO4‚5H2O (440 mg, 2:1 w/w) at 80 °C for 12 h. After cooling
the mixture, we removed the solid by filtration through a pad
of silica gel, which was rinsed thoroughly with ether. The solvent
was removed at reduced pressure to leave 3 (90 mg, 90%), which
was obtained as white crystals upon recrystallization from
pentane. Rf 0.38 (heptane/EtOAc 7:3); mp 88.6-89.2 °C; IR (KBr)
2957, 2351, 1734, 1710 cm-1; 1H NMR (400 MHz, benzene-d6) δ
3.04 (t, J ) 2.8 Hz, 1H), 2.16 (br dAB, JAB ) 15.6 Hz, 2H), 2.01
(dAB, JAB ) 15.2 Hz, 2H), 1.26-1.15 (m, 4H), 0.85 (s, 9H), -0.16
(s, 6H); 13C NMR (100 MHz, benzene-d6) δ 202.2, 71.8, 63.1, 52.1,
32.5, 25.7, 20.0, 17.9, -2.3; HRMS (FAB+) calcd for C14H25O3Si
(M + H): 269.1573. Found: 269.1569. Anal. Calcd for C14H24O3-
Si: C, 62.64; H, 9.01. Found: C, 62.49; H, 9.11.
(b) Hydroboration of 17, Followed by Oxidation. At 0
°C, 2 M BH3‚SMe2 (4.0 mL, 8.0 mmol) was added to a solution
of 17 (518 mg, 2.0 mmol) in ether (6 mL). After 4.5 h at room
temperature, H2O (8 mL) was added, followed by saturation of
the aqueous phase with NaCl (s) and extraction with EtOAc (5
× 15 mL). The organic phase was washed with brine (60 mL)
and dried (Na2SO4) before removal of solvent at reduced pres-
sure. The residue was dissolved in CH2Cl2 (7 mL), followed by
addition of powdered 4 Å MS, NMO (1.64 g, 14.0 mmol), and
TPAP (50 mg, 0.14 mmol). After 12 h at room temperature, the
reaction mixture was filtrated through a pad of SiO2 and eluted
with EtOAc. The residue was purified by column chromatogra-
phy (SiO2, heptane/EtOAc 9:1) to give 3 (223 mg, 40%) as white
crystals. This reaction was repeated several times in different
scales (0.5-2 mmol), which gave reproducible yields (40%). See
Table 1 in Supporting Information for further details.
In conclusion, two independent synthetic routes toward
the bridgehead TBDMS-protected 4-hydroxy bicyclo-
[2.2.2]octane-2,6-dione 3 have been developed starting
from 11. Compound 3 and a number of the intermediate
compounds presented here may be interesting starting
materials for the preparation of more complex organic
molecules.
Experimental Section
(()-endo/exo-4-(tert-Butyldimethylsilanyloxy)-6-hydroxy-
bicyclo[2.2.2]octan-2-one (8b). Ozone was bubbled through
a solution of 6b (1.0 g, 3.73 mmol) in heptane (75 mL) at -78
°C until it turned light blue (ca. 30 min). Excess ozone was then
driven off by flushing with argon, and then TEA (14 mL) was
added and the reaction mixture was allowed to reach room
temperature. Under intense stirring, SiO2 (450 m2/g) (17 g) was
added, and after a couple of minutes the color had turned deep
red. After completion of reaction (TLC), the silica gel was filtered
off and washed with EtOAc. The filtrate was collected, the
solvent was removed at reduced pressure, and the residue was
Acknowledgment. We thank the Swedish Science
Council, The Crafoord Foundation, The Royal Physi-
ographic Society in Lund, The Research School in
Medicinal Sciences at Lund University, and The Knut
and Alice Wallenberg Foundation for economic support.
We also thank Karl-Erik Bergqvist for help with NMR
spectral data and Einar Nilsson for obtaining mass
spectral data.
(28) (a) Brown, H. C.; Garg, C. P. Tetrahedron 1986, 42, 5511-5514.
(b) Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1961, 83, 2951-2952.
(29) (a) Parish, E. J.; Parish, S.; Honda, H. Synth. Commun. 1990,
20, 3265-3271. (b) Rao, V. V. R.; Devaprabhakara, D.; Chandraseka-
ran, S. J. Organomet. Chem. 1978, 162, C9-C10. (c) Brown, H. C.;
Kulkarni, S. U.; Rao, C. G.; Patil, V. D. Tetrahedron 1986, 42, 5515-
5522.
(30) Yates, M. H. Tetrahedron Lett. 1997, 38, 2813-2816.
(31) King, S. A.; Pipik, B.; Thompson, A. S.; DeCamp, A.; Verhoeven,
T. R. Tetrahedron Lett. 1995, 36, 4563-4566.
Supporting Information Available: Experimental pro-
1
cedures and other detailed results; H and 13C NMR spectra
for compounds 9, 10, 14, 16, 18, and 19; COSY, HMQC, and
HMBC spectra for compound 16; COSY and NOESY spectra
for compounds endo-8b and exo-8b. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO051284E
8612 J. Org. Chem., Vol. 70, No. 21, 2005