Synthesis of optically active endo,endo bicyclo[2.2.2]octane-2,5-diol, bicyclo[2.2.2]octane-2,5-dione, and related compounds

Article abstract of DOI:10.1021/jo9601167

Optically active C₂-symmetric (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol ((+)-12; 98% ee) and several selectively protected optically active intermediates useful for synthetic transformations were synthesized via a 1,2-carbonyl transposition route starting from the easily available optically active (1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one ((-)-2). The synthetic route also allowed the preparation of optically active (1S,4S)-bicyclo[2.2.2]octane-2,5-dione ((+)-14; 98% ee).

Full text of DOI:10.1021/jo9601167

3794
J . Org. Chem. 1996, 61, 3794-3798
Syn th esis of Op tica lly Active en d o,en d o
Bicyclo[2.2.2]octa n e-2,5-d iol, Bicyclo[2.2.2]octa n e-2,5-d ion e, a n d
Rela ted Com p ou n d s
Fredrik Almqvist, Niklas Ekman, and Torbjo¨rn Frejd*
Organic Chemistry 1, Department of Chemistry, Lund University, P.O. Box 124, S-221 00 Lund, Sweden
Received J anuary 18, 1996X
Optically active C2-symmetric (1S,2S,4S,5S)-bicyclo[2.2.2]octane-2,5-diol ((+)-12; 98% ee) and several
selectively protected optically active intermediates useful for synthetic transformations were
synthesized via a 1,2-carbonyl transposition route starting from the easily available optically active
(1R,4S,6S)-6-hydroxybicyclo[2.2.2]octan-2-one ((-)-2). The synthetic route also allowed the prepara-
tion of optically active (1S,4S)-bicyclo[2.2.2]octane-2,5-dione ((+)-14; 98% ee).
Optically pure derivatives of bicyclo[2.2.2]octane may
cyclohexenone and 2-(N-methylanilino)acrylonitrile10 or
2-((trimethylsilyl)oxy)-1,3-cyclohexadiene and R-acetoxy-
acrylonitrile11 and that (-)-14 of high optical purity (94%)
can be obtained via resolution of the corresponding
olefinic dione 16 as an inclusion complex with (S)-(-)-
10,10′-dihydroxy-9,9′-biphenanthryl, followed by catalytic
hydrogenation of the double bond.12
It should also be noted that even if the resolution of
the racemic diacid 17 gave optically active 17, the
subsequent decarboxylation resulted in complete race-
mization.13 Thus, it is obviously a problem to synthesize
ketone 14 and diol 12 or similar derivatives in optically
pure form in quantities necessary for multistep synthesis
or other applications. We here report a 1,2-carbonyl
transposition route of (-)-2 to give these and related
compounds in reasonable yields and high enantiomeric
purities.
Optically active (-)-2 of high enantiomeric purity can
be prepared by fermenting yeast reduction of 1,14 for
which we previously described an improved synthesis.15
Thus, compound (-)-2 may be reproducibly prepared in
multigram quantities and had generally an ee of >92%,
which could be improved to 98% by recrystallization from
ethyl acetate/heptane. The availability of (-)-2 made a
1,2-carbonyl transposition route16 to (+)-12 and (+)-14
feasible (Scheme 1). Protection of (-)-2 as its tert-
butyldimethylsilyl ether (+)-3 followed by TMS-enol
ether formation gave 4, which was thiophenylated using
phenylsulfenyl chloride17 to give 5 as a 73:27 mixture of
diastereomers. An inferior yield was obtained by using
the alternative thiophenylation route via reaction of the
lithium enolate of 3 with diphenyl disulfide. Subsequent
reduction of 5 with sodium borohydride gave 6, as a
mixture of all four diastereomers, which was mesylated
by treatment with mesyl anhydride and DMAP to give
7. Mesyl anhydride18 gave a much better yield here than
have interesting applications in organic synthesis, e.g.
for the construction of rigid template molecules suitable
as mimics for various bioactive compounds and as scaf-
folds for placing the dents of ligands in well-defined
relative positions in space. There are, however, surpris-
ingly few reports of such compounds based on the bicyclo-
[2.2.2]octane system in the literature. Recently the
bicyclo[2.2.2]octane system attracted interest as a struc-
tural unit suitable for application in combinatorial
synthesis via tandem Michael addition reactions1 of
polymer-bound acrylates and cyclohexenones.2
The racemic diol (()-12 is in principle available by
reduction of (()-14,3 but this reaction (LiAlH4) resulted
in a mixture of diastereomers, giving only a 7% yield of
the endo,endo diol (()-12.4,5 Despite the low yield, this
route was used for the preparation of (+)-12 (23% yield,
84% ee) via enzymatic hydrolysis of its racemic diacetate
followed by reductive deacetylation.6,7 Transesterfication
experiments with lipase YS on diol (()-12 did not improve
the situation with the low ee’s; the best result obtained
for (+)-12 was 21% ee in 31% chemical yield.8 Enzymatic
acetate hydrolysis has been used for the preparation also
of (-)-14 (25% yield, 21% ee).7 The enzymatic results
mentioned indicate that 14 would at best be synthesized
with 84% ee if diol (+)-12 were used as starting material.
Although (()-14 was reported already in 1939,3 it was
not until 1985 that optically pure (-)-14 was prepared
by Paquette et al.9 The procedure used, which is a
modification of that of Grob et al.,5 gave unfortunately a
low yield and involved several chromatographic separa-
tions, including separation of diastereomeric acetals.
More recent work has shown that (()-14 is easily avail-
able via a Diels-Alder reaction of the lithium enolate of
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993, 32,
1010-1022.
(10) Ahlbrecht, H.; Dietz, M.; Scho¨n, C.; Baumann, V. Synthesis
1991, 133-140.
(2) Ley, S. V.; Mynett, D. M.; Koot, W.-J . Synlett 1995, 1017-1020.
(3) Guha, P. C.; Krishnamurthy, C. Ber. Dtsch. Chem. Ges. B 1939,
72, 1374-1379.
(11) Werstiuk, N. H.; Yeroushalmi, S.; Guan-Lin, H. Can. J . Chem.
1992, 70, 974-980.
(4) Davalian, D.; Garratt, P. T.; Riguera, R. J . Org. Chem. 1977,
42, 368-369.
(12) Kinoshita, T.; Haga, K.; Ikai, K.; Takeuchi, K.; Okamoto, K.
Tetrahedron Lett. 1990, 31, 4057-4060.
(5) Grob, C. A.; Weiss, A. Helv. Chim. Acta 1960, 43, 1390-1393.
(6) Naemura, K.; Takahashi, N.; Ida, H.; Tanaka, S. Chem. Lett.
1991, 657-660.
(13) Buchanan, G. L.; Kean, N. B.; Taylor, R. Tetrahedron 1975,
31, 1583-1586.
(14) Mori, K.; Nagano, E. Biocatalysis 1990, 3, 25-36.
(15) Almqvist, F.; Eklund, L.; Frejd, T. Synth. Commun. 1993,
1499-1505.
(7) Naemura, K.; Takahashi, N.; Tanaka, S.; Ida, H. J . Chem. Soc.,
Perkin Trans. 1 1992, 2337-2343.
(8) Naemura, K.; Ida, H.; Fukuda, R. Bull. Chem. Soc. J pn. 1993,
66, 573-577.
(16) Trost, B. M.; Hiroi, K.; Kurozumi, S. J . Am. Chem. Soc. 1975,
97, 438-440.
(9) Hill, R. K.; Morton, G. H.; Peterson, J . R.; Walsh, J . A.; Paquette,
L. A. J . Org. Chem. 1985, 50, 5528-5533.
(17) Murai, S.; Kuroki, Y.; Hasegawa, K.; Tsutsumi, S. J . Chem. Soc.,
Chem. Commun. 1972, 946-947.
S0022-3263(96)00116-8 CCC: $12.00 © 1996 American Chemical Society

Bicyclo[2.2.2]octane-2,5-diol and -2,5-dione
J . Org. Chem., Vol. 61, No. 11, 1996 3795
Sch em e 1a
Sch em e 2. Red u ction Attem p ts via An ch or in g
Tech n iqu es (X ) H+ or Sn Cl4, Y ) CF 3COO- or
Cl-)
14 was then obtained after deprotection and Swern
oxidation.22 According to chiral phase GC analysis using
a â-cyclodextrin column the ee’s of (+)-12 and (+)-14 were
g98%.
In order to make an accurate analysis of the enantio-
meric purity of (+)-14, we prepared racemic 14 via a
Diels-Alder reaction of 2-((trimethylsilyl)oxy)-1,3-cyclo-
hexadiene and R-chloroacrylonitrile. We found that this
dienophile gave only the 2,5-dione 14, while R-acetoxy-
acrylonitrile was reported11 to give a 4:1 mixture of 14
and 1, respectively.
The stereoselctive reduction of (+)-9 to give (-)-11 was
more problematic than expected. We anticipated that the
large TBDMS group would prevent the reducing agents
from attacking from the endo face. This turned out to
be only partially true. Application of NaBH4, LiAlH-
(OtBu)3, LS-Selectride, LS-Selectride, together with 12-
crown-4, catecholborane, DIBALH (CH2Cl2) or DIBALH
(toluene) gave the endo,endo:endo,exo ratios 66:34, 54:
46, 60:40, 41:59, 58:42, 76:24, and 76:24, respectively. The
selectivity of the DIBALH reagent could be improved to
86:14 by using hexane as solvent. In this way (-)-11
could be obtained in 60% yield after chromatographic
separation of (-)-13. Reduction experiments in which
sterically more demanding protecting groups such as tert-
butyldiphenylsilyl and di-tert-butylsilyl (-SiHtBu2) were
used instead of the TBDMS group in (+)-9 did not
improve the stereoselectivity, nor did hydrosilylation
using Wilkinson’s catalyst together with triethylsilane.
The possibility of using the free 5-hydroxy group of (+)-
10 to direct the reduction from below via coordination or
reaction with the reagents and thus stereoselectively give
the (R,S)-endo,exo diol 22 was also investigated (Scheme
2). Unfortunately NaBH4, LiAlH4 or EtMe2N-AlH323 gave
58:42, 64:36 and 37:63 mixtures of the endo,endo (12) and
endo,exo (22) isomers, respectively. Triacetoxyborohy-
dride salts are known as hydroxyl-anchoring reagents,
providing intramolecular transfer of hydride.24,25 We
used the commercially available tetramethylammonium
triacetoxyborohydride,26 which gave exclusively the iso-
meric 2,6-endo,exo diol (+)-19 via 18. This result encour-
a
Legend: (a) TBDMSCl, imidazole, DMF, 97%; (b) LDA,
TMSCl, THF, -78 °C to room temperature; (c) PhSCl, CH2Cl2,
-78 °C to room temperature; (d) NaBH4, THF, MeOH, room
temperature, 24 h; (e) (MeSO2)2O, DMAP, CH2Cl2, room temper-
ature, 48 h; (f) KOtBu, DME, -30 °C to room temperature, 49%
from (+)-3; (g) Fe(NO3)3‚9H2O, Bentonite K-10, CH2Cl2, room
temperature, 3 h, 93%; (h) Bu4NF, 0 °C, room temperature, 3 h,
90%; (i) Swern oxidation, 98%; (j) DIBALH, 60% of (-)-11. The
acronyms recommended for this journal are followed.
did mesyl chloride. Thioenol ether (-)-8 was then
obtained by elimination using KOtBu. The elimination
was studied using GC analysis and showed that the
major isomer was consumed at a higher rate than the
other three isomers. Since a syn elimination should be
faster than an anti elimination in rigid compounds,19
this result indicates that the major isomer of 7 is
(1S,2S,3S,4R,5S)-3-(mesyloxy)-2-(phenylsulfenyl)-5-((tert-
butyldimethylsilyl)oxy)bicyclo[2.2.2]octane, i.e. the 2-exo,3-
endo,5-endo product. Thus, the attack of the borohydride
on 5 was only moderately exo-face selective. Attempts
to hydrolyze the thioenol ether functionality of (-)-8 to
give the corresponding ketone (+)-9 by the aid of HgCl2,
Hg(OAc)2, CuCl2, or NBS were sluggish and resulted in
several byproducts. However, ferric nitrate absorbed on
Bentonite K-10 clay20,21 was very efficient and gave a 90%
yield of (+)-9. Since this compound is a potentially very
useful intermediate but is not too stable against acidic
cleavage of the TBDMS group, it was important to keep
the reaction time as short as possible and to filter the
reaction mixture through neutral alumina immediately
after the starting material was consumed. Diketone (+)-
(22) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185.
(23) Marlett, E. M.; Park, W. S. J . Org. Chem. 1990, 55, 2968-2969.
(24) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24,
273-276.
(25) Nutaitis, C. F.; Gribble, G. W. Tetrahedron Lett. 1983, 24,
4287-4290.
(26) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560-3578.
(18) Owen, L. N.; Whitelaw, S. P. J . Chem. Soc. 1953, 3723-3723.
(19) Brown, H. C.; Liu, K.-T. J . Am. Chem. Soc. 1970, 92, 200-201.
(20) Corne´lis, A.; Laszlo, P. Synthesis 1980, 849-850.
(21) Balogh, M.; Corne´lis, A.; Laszlo, P. Tetrahedron Lett. 1984, 25,
3313-3316.

3796 J . Org. Chem., Vol. 61, No. 11, 1996
Almqvist et al.
8.3, 4.2, 1.7 Hz, 1H), 2.32 (m, 1H), 2.25 (m, 1H), 2.14-2.21
(m, 2H), 2.05 (m, 1H), 1.36-1.79 (m, 5H), 0.8 (s, 9H), -0.004
(s, 3H), -0.007 (s, 3H); 13C NMR (CDCl3) δ 214.45, 69.23,
50.51, 44.28, 37.38, 27.69, 25.63, 23.92, 20.01, 17.82, -4.87,
-4.94; MS m/ z 239 (M+ - CH3, 3), 197 (M+ - tBu, 100). Anal.
Calcd for C14H26O2Si: C, 66.09; H, 10.30. Found: C, 66.3; H,
10.0.
aged us to try the reagent on (+)-10, which then would
give 22 via 20, but unfortunately only starting material
was detected even after several days in contact with (+)-
10. Another possibility of delivering a hydride from the
endo face was to use the (di-tert-butylsilyl)oxy functional-
ity together with acids.27-29 Thus, (+)-21 was prepared,
but intramolecular hydride transfer induced by trifluo-
roacetic acid or SnCl4 did not succeed; only deprotection
occurred.
The unsuccessful hydride transfer reactions may be
explained by overly long distances between the carbonyl
carbon and the hydrogen to be transferred. This was
indeed indicated by AM1 calculations, which showed 3.3
and 3.5 Å for 20 and (+)-21, respectively, for their most
favorable conformations having the hydrogens pointing
directly toward the carbonyl carbons.
In conclusion, compounds (+)-12 and (+)-14 were
synthesized in 40% and 25% overall yields, respectively,
and high enantiomeric purities starting from (-)-2. The
corresponding enantiomers would be available by starting
the sequence from (+)-2, which can be prepared in six
steps from its enantiomer.30 We expect that a rather rich
chemistry can be developed from several of the interme-
diates shown in Scheme 1, which is now being explored
in our laboratory.
2-(P h en ylsu lfen yl)-4-((ter t-b u t yld im et h ylsilyl)oxy)-
bicyclo[2.2.2]octa n -3-on e (5). LDA, prepared by treatment
of diisopropylamine (3.33 g, 32.9 mmol) in THF (24 mL) at 0
°C with n-butyllithium (19.5 mL, 1.6 M in hexane), was added
dropwise to a solution of (+)-3 (5.34 g, 21.0 mmol) in THF (17
mL) at -78 °C, followed by TMSCl (5.6 mL, 44 mmol) after 30
min. The reaction mixture was warmed to room temperature
within 2 h and then kept at this temperature for 30 min.
During this time a precipitate was formed. The solvent was
then removed at reduced pressure and replaced with cold
pentane. The resulting mixture was filtered through Hyflo-
Supercel, and then the solvent was removed at reduced
pressure to give the TMS-enol ether 4 (6.36 g, 93%) as a pale
yellow oil, which was used directly in the next step. IR
(neat): 3060, 1640 cm-1
.
1H NMR (CDCl3): δ 5.08 (dd, J )
7.4, 2.1 Hz, 1H), 3.91 (m, 1H), 2.46 (m, 1H), 2.36 (m, 1H), 1.80
(m, 1H), 1.12-1.49 (m, 5H), 0.87 (s, 9H), 0.21 (s, 9H), 0.05 (s,
3H), 0.03 (s, 3H).
Phenylsulfenyl chloride32 (3.40 g, 23.5 mmol) diluted with
CH2Cl2 (25 mL) was slowly added to a solution of crude 4 in
CH2Cl2 (30 mL) at -78 °C. The reaction mixture was kept at
this temperature for 45 min and then at room temperature
for 30 min, whereafter it was poured into a separatory funnel
containing CH2Cl2, crushed ice, and saturated aqueous sodium
bicarbonate. The organic phase was dried, and the solvent
was removed at reduced pressure to give crude 5 (7.56 g,
quantitative) as an oil; TLC Rf 0.29, green spot. GC analysis
(column DBwax) showed a 73:27 ratio of the endo,exo and
endo,endo isomers, respectively. IR (neat): 3060, 1725, 1580
Exp er im en ta l Section
Gen er a l Con sid er a tion s. GC chromatographic analyses
were performed with a DBwax (J &W Scientific) capillary
column (30 m, 0.25 mm i.d., 0.25 µm stationary phase) and
with an â-DEX 120 (Supelco) permethylated â-cyclodextrin
fused silica capillary column for determination of enantiomeric
compositions. NMR spectra were recorded at 300 MHz using
CDCl3 (CHCl3 δ 7.26 (1H) and 77.0 (13C)) or CD3OD (CH3OH δ
3.35 (OH) (1H) and 49.0 (13C)) as solvents. Chromatographic
separations were performed on Matrex Amicon normal phase
silica gel 60 (0.035-0.070 mm), and for thin-layer chromatog-
raphy we used Merck precoated silica gel 60 F-254 (0.25 mm)
TLC plates. After elution the TLC plates were sprayed with
a solution of p-methoxybenzaldehyde (26 mL), glacial acetic
acid (11 mL), concentrated sulfuric acid (35 mL), and 95%
ethanol (960 mL) and the compounds were visualized upon
heating. All solvents were dried and distilled according to
standard procedures,31 and the reactions were performed in
septum-capped, oven-dried flasks under an atmospheric pres-
sure of argon. Organic extracts were dried using Na2SO4
throughout.
cm-1
. A small sample was purified using HPLC (Nucleosil
Silica, 500 × 10 mm, heptane-ethyl acetate 95:5) to give a
20
1
95:5 mixture of the isomers: [R]D -1.4 (c 1.76, CHCl3); H
NMR (CDCl3) δ 7.45 (m, 2H), 7.28 (m, 3H), 4.12 (m, 1H), 3.94
(m, 1H), 2.52 (m, 1H), 2.10-2.24 (m, 2H), 2.00 (m, 1H), 1.84
(m, 1H), 1.56-1.73 (m, 2H), 0.85 (s, 9H), 0.04 (s, 6H); 13C NMR
(CDCl3) δ 210.52, 136.72, 131.52, 128.96, 127.00, 68.75, 57.47,
50.91, 38.23, 33.44, 25.69, 20.56, 19.32, 17.88, -4.81, -4.90;
HRMS calcd for C20H30O2SSi 362.1736, obsd 362.1736.
2-(P h en ylsu lfen yl)-5-((ter t-b u t yld im et h ylsilyl)oxy)-
bicyclo[2.2.2]octa n -3-ol (6). Crude 5 (7.42 g, 20.5 mmol) was
diluted with THF (725 mL) and methanol (235 mL), whereafter
NaBH4 (2.58 g, 68.2 mmol) was added in portions. The
resulting mixture was kept at room temperature for 24 h,
whereafter most of the solvent was removed at reduced
pressure and replaced with ethyl acetate (400 mL). This
solution was washed with saturated aqueous ammonium
chloride (50 mL) and water (200 mL), and the combined
aqueous phase was extracted with ethyl acetate (2 × 200 mL).
The combined organic phase was dried, and the solvent was
removed at reduced pressure to give oily 6 (7.44 g, quantita-
tive) as a mixture of isomers; TLC Rf 0.29, blue spot. IR
(1R,4S,6S)-6-((ter t-Bu tyldim eth ylsilyl)oxy)bicyclo[2.2.2]-
octa n -2-on e ((+)-3). A solution of 2 (2.94 g, 21.0 mmol),
imidazole (3.58 g, 52.6 mmol), and tert-butyldimethylsilyl
chloride (TBDMSCl) (3.90 g, 25.9 mmol) in DMF (10 mL) was
kept at room temperature for 8 h. Diethyl ether (50 mL) was
then added, and the mixture was washed in sequence with
water (10 mL), cold 0.1 M HCl (2 × 10 mL), saturated aqueous
sodium bicarbonate (10 mL), and water (10 mL). The organic
phase was dried, the solvent was removed at reduced pressure,
and the residue was chromatographed (SiO2, heptane-ethyl
acetate 80:20) to give (+)-3 (5.2 g, 98%) as an oil that
crystallizes in the refrigerator but melts again on warming to
(neat): 3500 (broad, OH) 3060, 1585 cm-1
. A small sample
was purified using HPLC (Nucleosil Silica, 500 × 10, heptane-
ethyl acetate 95:5). The major and faster moving isomer had
20
[R]D +3.2 (c 1.64, CHCl3): 1H NMR (CDCl3) δ 7.45 (doublet
of multiplets, J ) 7.11 Hz, 2H), 7.29 (m, 2H), 7.19 (m, 1H),
4.42 (d, J ) 10.04 Hz, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.44
(m, 1H), 2.09 (m, 2H), 1.84 (m, 2H), 1.57 (m, 2H), 1.38 (m,
1H), 1.14 (m, 1H), 0.91 (s, 9H), 0.10 (s, broad, 6H); 13C NMR
(CDCl3) δ 135.86, 130.54, 128.78, 126.18, 76.36, 70.72, 56.78,
39.09, 37.80, 29.66, 25.73, 20.80, 17.96, 17.82, -4.80, -5.15;
HRMS calcd for C20H32O2SSi 364.1892, obsd 364.1891.
(1S ,4S ,5S )-2-(P h e n ylsu lfe n yl)-5-((t er t -b u t yld im e t h -
ylsilyl)oxy)b icyclo[2.2.2]oct -2-en e ((-)-8). 4-(Dimethyl-
amino)pyridine (DMAP) (11.22 g, 91.84 mmol) was added to a
solution of crude 6 (7.32 g, 20.1 mmol) in CH2Cl2 (350 mL)
20
room temperature: TLC Rf 0.37; [R]D +3.5 (c 4.95, CHCl3);
IR (neat) 1730 cm-1 (CdO); 1H NMR (CDCl3) δ 4.09 (ddd, J )
(27) McCombie, S. W.; Cox, B.; Ganguly, A. Tetrahedron Lett. 1991,
32, 2087-2090.
(28) McCombie, S. W.; Cox, B.; Lin, S.-I.; Ganguly, A. K. Tetrahedron
Lett. 1991, 32, 2083-2086.
(29) Ganguly, A. K.; McCombie, S. W.; Cox, B.; Lin, S. I.; McPhail,
A. T. Pure Appl. Chem. 1990, 62, 1289-1291.
(30) Almqvist, F.; Frejd, T. Tetrahedron: Asymmetry 1995, 6, 957-
960.
(31) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, U.K., 1989.
(32) Barrett, A. G. M.; Ghanak, D.; Graboski, G. G.; Taylor, S. J . In
Organic Syntheses; Wiley: New York, 1993; Vol. 8, pp 550-553.

Bicyclo[2.2.2]octane-2,5-diol and -2,5-dione
J . Org. Chem., Vol. 61, No. 11, 1996 3797
under a gentle stream of argon. After 5 min dry methane-
sulfonic anhydride18 (10.61 g, 60.91 mmol) was added, during
which time a precipitate was formed. The reaction mixture
was kept at 40 °C for 48 h. Water was then added, and the
layers were separated. The aqueous phase was extracted with
CH2Cl2, and the combined organic phase was dried. The
solvent was removed at reduced pressure to give 7 as a crude
oil (8.0 g, 90%) from which a small sample, filtered through
silica, showed a mixture of mesylated isomers according to
1H), 1.53-1.66 (m, 3H), 1.48 (s, broad, 1H), 1.23-1.37 (m, 2H),
1.18 (doublet of multiplets, J ) 11.5 Hz, 1H), 1.09 (doublet of
multiplets, J ) 14.1 Hz, 1H), 0.87 (s, 9H), 0.02 (s, 3H), 0.01
(s, 3H); 13C NMR (CDCl3) δ 68.71, 68.40, 36.87, 32.69, 32.52,
31.00, 25.83, 22.97, 18.01, 17.09, -4.75; CIMS (NH3) m/ z 274
(M+NH4+, 20), 257 (M+1, 100). Anal. Calcd for C14H28O2Si:
C, 65.57; H, 11.0. Found: C, 65.6; H, 11.0.
(1S,2S,4S,5S)-Bicyclo[2.2.2]octa n e-2,5-d iol ((+)-12). A
solution of tetrabutylammonium fluoride (TBAF) (0.5 mL, 0.5
mmol, 1 M in THF) was added dropwise to (-)-11 (80 mg, 0.31
mmol) dissolved in THF (6 mL) at 0 °C. The mixture was then
kept at room temperature for 5 h, whereafter it was concen-
trated under reduced pressure to a volume of approximately
1 mL. Ethyl acetate was added, and the resulting solution
was washed with aqueous saturated sodium hydrogen carbon-
ate. The aqueous phase was back-extracted three times with
ethyl acetate, the combined organic phase was dried and
concentrated at reduced pressure, and the residue was chro-
matographed (SiO2, heptane-ethyl acetate 15:85, Rf 0.20) to
give (+)-12 (41 mg, 93%); mp 279-281 °C (lit.8 280-283 °C);
NMR analysis. IR (neat): 3100, 3060, 1740, 1590 cm-1
.
1
Selected H NMR peaks (CDCl3): δ 4.58 (m, 1H, H3), 3.97 (m,
1H, H5), 3.67 (m, 1H, H2), 2.97 (s, 3H, SO2CH3). Potassium
tert-butoxide (6.07 g, 54 mmol) was added in small portions
to a solution of crude 7 (7.95 g, 18.0 mmol) in 1,2-dimethoxy-
ethane (750 mL) at -40 °C. After 2 h at -40 °C the reaction
was quenched by addition of cold aqueous saturated am-
monium chloride and the aqueous phase was extracted with
diethyl ether. The combined organic phase was dried, followed
by removal of the solvent at reduced pressure. The residue
was chromatographed (SiO2, heptane-ethyl acetate 95:5) to
give (-)-8 (3.57 g, 49% overall yield from 3) as an oil: TLC Rf
20
[R]D +52.6 (c 0.35, CH3OH); IR (KBr) 3260 cm-1 (broad); 1H
20
0.64; [R]D -394 (c 2.71, CHCl3); IR (neat) 3060, 1600, 1580
NMR (CD3OD) δ 3.84 (m, 2H), 1.74-1.89 (m, 4H), 1.65 (m,
2H), 1.48 (m, 4H); 13C NMR (CD3OD) δ 69.74, 33.72, 30.76,
23.59; HRMS calcd for C8H14O2 142.0994, obsd 142.0995.
(1S,4S,5S)-5-Hyd r oxybicyclo[2.2.2]octa n -2-on e ((+)-10).
(+)-9 was treated with TBAF as above to give, after chroma-
tography (SiO2, heptane-ethyl acetate 1:2, Rf 0.22), (+)-10 as
1
cm-1; H NMR (CDCl3) δ 7.5 (m, 2H), 7.25 (m, 3H), 6.27 (dd,
J ) 6.6, 1.2 Hz, 1H), 3.99 (dt, J ) 8.1, 2.4 Hz, 1H), 2.71 (m,
1H), 2.58 (m, 1H), 1.90 (ddd, J ) 13.2, 8.1, 2.5 Hz, 1H), 1.25-
1.50 (m, 5H), 0.90 (s, 9H), 0.072 (s, 3H), 0.078 (s, 3H); 13C NMR
(CDCl3) δ 136.80, 135.09, 133.13, 130.86, 128.75, 126.50, 71.62,
40.15, 40.07, 37.33, 25.82, 24.92, 22.54, 18.00, -4.60, -4.63;
MS m/ z 346 (M+, 2), 289 (M+ - tBu, 8), 188 (100). Anal. Calcd
for C20H30OSSi: C, 69.31; H, 8.72. Found: C, 69.0; H, 8.7.
(1S,4S,5S)-5-((ter t-Bu tyldim eth ylsilyl)oxy)bicyclo[2.2.2]-
octa n -2-on e ((+)-9). Freshly prepared clayfen20 (1.08 g) was
added in portions (nitrous gases were evolved) to a solution of
(-)-8 (269 mg, 0.776 mmol) in CH2Cl2 (27 mL). The mixture
was kept at room temperature for 30 min and then filtered
through a pad of neutral alumina. The alumina was washed
with diethyl ether, the solvent was removed at reduced
pressure, and the residue was chromatographed (SiO2, hep-
tane-ethyl acetate 90:10) to give (+)-9 (178 mg, 90%) as an
oil which crystallized in the refrigerator (mp 33.5-34.5 °C):
20
a white solid (105 mg, 92%): mp 151-153 °C; [R]D +18.2 (c
1
5.33, CHCl3); IR (KBr) 3390, 1700 cm-1; H NMR (CDCl3) δ
4.11 (m, 1H), 2.71 (doublet of multiplets, J ) 18.9 Hz, 1H),
2.16-2.33 (m, 3H), 2.09 (ddd, J ) 18.9, 2.8, 1.1 Hz, 1H), 1.88-
2.01 (s, broad, 1H), 1.59-1.78 (m, 5H); 13C NMR (CDCl3) δ
216.45, 67.31, 42.89, 37.99, 35.40, 35.32, 22.08, 22.06; MS m/ z
140 (M+, 17), 122 (17), 80 (100). Anal. Calcd for C8H12O2: C,
68.55; H, 8.63. Found: C, 68.5; H, 8.6.
(2S,6S)-Bicyclo[2.2.2]octa n e-2,6-d iol ((+)-19). A solution
of the hydroxy ketone (-)-2 (20 mg, 0.14 mmol) in acetone (0.2
mL) was added to a solution of tetramethylammonium triac-
etoxyborohydride (92 mg, 0.35 mmol) and acetic acid (40 µL,
0.70 mmol) in acetone (1.6 mL). The reaction mixture was
stirred for 6 h at room temperature before it was quenched
with saturated aqueous ammonium chloride solution (0.5 mL).
The mixture was concentrated to approximately 0.5 mL
followed by neutralization with solid sodium carbonate and
then extracted with ethyl acetate. Concentration of the
organic extract at reduced pressure gave a crude product which
was dissolved in ethyl acetate. The resulting solution was
filtered through a pad of silica gel to give (+)-19 (19 mg, 95%)
20
TLC Rf 0.28; [R]D +14.5 (c 5.07, CHCl3); IR (neat) 1725 cm-1
(CdO); 1H NMR (CDCl3) δ 3.95 (m, 1H), 2.68 (doublet of
multiplets, J ) 18.7 Hz, 1H), 2.23 (m, 1H), 2.14 (ddd, J ) 14.2,
8.9, 2.9 Hz, 1H), 2.05 (m, 1H), 2.00 (doublet of multiplets, J )
18.6 Hz, 1H), 1.50-1.73 (m, 5H), 0.83 (s, 9H), 0.00 (s, 6H); 13
C
NMR (CDCl3) δ 216.70, 67.67, 42.95, 38.06, 36.63, 35.70, 25.68,
22.22, 21.83, 17.89, -4.78, -4.85; MS m/ z 254 (M+, 0.8), 239
(M+ - CH3, 6), 197 (M+ - tBu, 100). Anal. Calcd for C14H26O2-
Si: C, 66.09; H, 10.3. Found: C, 66.1; H, 10.2.
20
after removal of the solvent as a white solid: mp 358 °C; [R]D
+23 (c 0.96, MeOH); IR (KBr) 3100-3500 cm-1 1H NMR
;
(1S,2S,4S,5S)-2-((ter t-Bu tyld im eth ylsilyl)oxy)bicyclo-
[2.2.2]oct a n -5-ol ((-)-11) a n d (1S,2S,4S,5R)-2-((ter t-
Bu tyld im eth ylsilyl)oxy)bicyclo[2.2.2]octa n -5-ol ((-)-13).
Diisobutylaluminum hydride (1.5 mL, 20% in hexane) was
added dropwise to (+)-9 (139 mg, 0.546 mmol) diluted with
hexane (20 mL) at -78 °C. The cooling bath was removed,
and after 2 h cold aqueous saturated ammonium chloride was
added to the reaction mixture. The aqueous phase was
extracted with ethyl acetate, the combined organic phase was
dried, and the solvent was removed at reduced pressure to give
an oil containing a 84:16 mixture of (-)-11 and (-)-13
according to GC and NMR analysis. The two isomers were
separated (SiO2, heptane-ethyl acetate 85:15), which gave (-)-
11 (84 mg, 60%) as an oil that crystallized in the refrigerator
(mp 32.5-33 °C (TLC Rf 0.34)) and (-)-13 (21 mg, 15%; mp
70-71 °C (TLC Rf 0.22)).
(CDCl3) δ 4.28 (m, 1H), 4.01 (ddd, J ) 9.5, 4.4, 3.4 Hz, 1H),
2.10 (m, 1H), 1.98 (m, 2H), 1.77 (quintet, J ) 3.0 Hz, 1H), 1.71
(m, 1H), 1.54 (m, 1H), 1.23-1.42 (m, 4H); 13C NMR (CDCl3) δ
69.75, 64.62, 40.49, 37.89, 36.92, 27.31, 25.39, 17.82; MS m/ z
124 (28), 95 (100), 80 (71); HRMS (-H2O) calcd for C8H12
O
124.0888, obsd 124.0885; HRCIMS (CH4) (-1H) calcd for
C8H13O2 141.0916, obsd 141.0908.
(1S,4S,5S)-5-((Di-ter t-bu tylsilyl)oxy)bicyclo[2.2.2]octan -
2-on e ((+)-21). Using the same procedure as for the synthesis
of (+)-3, (+)-21 was prepared from (+)-10 (33 mg, 0.24 mmol),
di-tert-butylchlorosilane (90 mg, 0.50 mmol), and imidazole (80
mg, 1.2 mmol) in DMF (1.5 mL). Chromatography (neutral
alumina, heptane-ethyl acetate 95:5, Rf 0.39) gave (+)-21 as
an oil (61 mg, 90%): [R]D20 +16 (c 0.61, CHCl3); IR (KBr) 2080
1
(SisH), 1725 cm-1 (CdO); H NMR (CDCl3) δ 4.07 (m, 1H),
For (-)-11: [R]D20 -46.9 (c 3.87, CHCl3); IR (neat) 3420 cm-1
4.00 (s, 1H, SisH), 2.72 (doublet of multiplets, J ) 18.8 Hz,
1H), 2.27 (m, 1H), 2.18-2.25 (m, 2H), 2.05 (ddd, J ) 18.9, 2.9,
1.1 Hz, 1H), 1.55-1.81 (m, 5H), 0.96 (s, broad, 18H); 13C NMR
(CDCl3) δ 216.72, 71.16, 43.03, 38.13, 36.06, 35.22, 27.28, 27.21,
22.27, 21.96, 19.94, 19.77; HRMS (-tBu) calcd for C12H21O2Si
225.1311, obsd 225.1312.
1
(OH, broad); H NMR (CDCl3) δ 3.88 (m, 1H), 3.76 (m, 1H),
3.02 (d, J ) 10.3 Hz, 1H), 1.63-1.88 (m, 6H), 1.20-1.52 (m,
4H), 0.90 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3)
δ 69.23, 68.35, 31.57, 31.27, 31.24, 31.20, 25.84, 21.91, 21.67,
18.05, -4.86, -4.99; CIMS (NH3) m/ z 274 (M+NH4+, 7), 257
(M+1, 100). Anal. Calcd for C14H28O2Si: C, 65.57; H, 11.0.
Found: C, 65.3; H, 10.8.
(1S,4S)-Bicyclo[2.2.2]oct a n e-2,5-d ion e ((+)-14). Dry
DMSO (0.56 g, 7.2 mmol) diluted with CH2Cl2 (0.9 mL) was
added dropwise to a solution of freshly distilled oxalyl chloride
(0.18 mL, 2.1 mmol) in CH2Cl2 (1.8 mL) at -60 °C. The
temperature was raised to -15 °C, and then (+)-10 (100 mg,
For (-)-13: [R]D20 -13.6 (c 0.97, CHCl3); IR (KBr) 3320 cm-1
1
(OH, broad); H NMR (CDCl3) δ 4.00 (m, 1H), 3.78 (m, 1H),
2.35 (m, 1H), 1.93 (ddd, J ) 14.0, 8.8, 3.4 Hz, 1H), 1.80 (m,

3798 J . Org. Chem., Vol. 61, No. 11, 1996
Almqvist et al.
0.71 mmol) in CH2Cl2 (0.8 mL) was added. The mixture was
kept for 10 min at -15 °C and then cooled to -20 °C followed
by addition of freshly distilled triethylamine (1.2 mL, 8.6
mmol). The mixture was kept for 10 min at -20 °C and then
30 min at room temperature followed by addition of water and
separation of the phases. The aqueous phase was extracted
with CH2Cl2, and the combined organic phase was washed
sequentially with brine, 0.1 M HCl, aqueous saturated sodium
hydrogen carbonate, and brine and dried. Concentration of
the organic extract at reduced pressure gave a crude product
which was dissolved in ethyl acetate. The resulting solution
was filtered through a pad of silica gel to give (+)-14 (96 mg,
98%) after removal of the solvent; mp 202-204 °C (lit.9 mp
to a solution of (()-14 (50 mg, 0.36 mmol) in methanol-water
(80:20, 5 mL) at 0 °C. The solution was kept at this temper-
ature for 30 min and then concentrated at reduced pressure
to approximately 1 mL. Saturated sodium chloride was added,
and the mixture was extracted several times with CH2Cl2. The
combined organic phase was dried and then concentrated at
reduced pressure to give a mixture of (()-12, (()-15, and (()-
22 (41 mg, 80%).
Det er m in a t ion of t h e E n a n t iom er ic P u r it ies. GC
An a lyses. The samples were analyzed by GC using a â-DEX
120 column (Supelco) at 120 °C isothermic and were found to
be 98% ee for (+)-12 and (+)-14. A mixture of (()-14 and the
optically active sample gave only two peaks. The retention
times were 45.57 and 46.07 min for (-)- and (+)-14, respec-
tively. Retention times for the trifluoroacetate derivatives of
the optically active sample (+)-12 and the racemic mixture of
endo,exo, exo,exo, and endo,endo ((()-12) diols were 14.08 min
((()-endo,exo, double intensity), 17.54 and 17.80 min ((()-
exo,exo), 24.16 min ((+)-12), and 26.34 min ((-)-12), respec-
tively. It is worth noting the extraordinary separation of
the diastereomers (e.g. 10.08 min between (()-endo,exo and
(+)-12).
HP LC An a lyses. The enantiomeric purity of 14 could also
be determined using HPLC with a Chiralcel OJ (J . T. Baker)
column (hexane-2-propanol 1:1, flow rate 1 mL/min). Under
these conditions (-)-14 eluted at 8.60 min and (+)-14 at 11.33
min. Columns such as R-DEX 120 (Supelco) for GC or DNBPG
(covalent) (J . T. Baker) for HPLC gave no separation of the
enantiomers.
Diastereomeric separations efficient enough to increase or
decrease the enantiomeric purities were not involved in the
synthetic operations presented. All optically active compounds
in this article should therefore have enantiomeric purities as
determined for (+)-12 and (+)-14.
20
205 °C); [R]D +50 (c 0.55, CHCl3); IR and NMR data were
consistent with those reported;9 HRMS calcd for C8H10O2
138.0681, obsd 138.0682.
Racem ic Bicyclo[2.2.2]octan e-2,5-dion e ((()-14). A mix-
ture of 1-((trimethylsilyl)oxy-1,3-cyclohexadiene (0.90 g, 5.4
mmol), 2-chloroacrylonitrile (0.60 g, 6.9 mmol), 2,6-di-tert-
butyl-4-methylphenol (approximately 20 mg) as a radical
scavenger, and sodium carbonate (approximately 20 mg) in
benzene (3 mL) was degassed with argon and kept at 70 °C
for 36 h in a thick-walled screw-capped test tube. The mixture
was cooled to room temperature, water and ethyl acetate were
added, and the organic phase was separated. The aqueous
phase was extracted twice with ethyl acetate, and the com-
bined organic phase was washed twice with 0.2 M HCl and
dried. Concentration at reduced pressure gave a 1:1 mixture
of the 2-cyano-2-chloro diastereomers (0.73 g, 74%) as an oil.
Hydrolysis to give racemic bicyclo[2.2.2]octane-2,5-dione was
perfomed as follows (KOH/DMSO33 resulted in a very low
yield): a solution of the crude diastereomeric mixture (0.10 g,
0.54 mmol), CH2Cl2 (10 mL), 2 M NaOH (10 mL), and
tetrabutylammonium hydrogen sulfate (0.20 g, 0.59 mmol) was
kept at room temperature with vigorous stirring for 3 days.
The phases were separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic phase was
washed in sequence with 0.1 M HCl, saturated aqueous sodium
bicarbonate, and brine and dried. Concentration at reduced
pressure followed by chromatography (SiO2, heptane-ethyl
acetate 1:1, Rf 0.28) gave (()-14 (43 mg, 58%), mp 202-204
°C (benzene), (lit.3 mp 205-206 °C). IR and NMR data were
consistent with those reported.9
Ack n ow led gm en t. We thank the Swedish Natural
Science Research Council for generous economic sup-
port.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
those compounds whose elemental analysis data are given as
HRMS data (6 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ra cem ic Bicyclo[2.2.2]octa n e-2,5-d iols (()-12, (()-15,
a n d (()-22. Sodium borohydride (20 mg, 53 mmol) was added
(33) Ranganathan, S.; Ranganathan, D.; Mehrota, A. K. Synthesis
1977, 289-296.
J O9601167