Enantiospecific syntheses of (+)-crotepoxide, (+)-boesenoxide, (+)-β- senepoxide, (+)-pipoxide acetate, (-)-iso-crotepoxide, (-)-senepoxide, and (- )-tingtanoxide from (-)-quinic acid

Article abstract of DOI:10.1021/jo970907o

A convenient strategy that is ideally suited for the Construction of all the naturally occurring cyclohexane diepoxides and cyclohexene epoxides is described. The key intermediate 12, a 1,3-cyclohexadiene, has been prepared from (-)-quinic acid in 11 steps with 18% overall yield: Singlet oxygen photooxygenation of the 1,3-cyclohexadiene followed by rearrangement of the resultant endoperoxides with either cobalt-meso-tetraphenylporphyrin or trimethyl phosphite afforded enantiopure (+)-crotepoxide, (+)-boesenoxide, and (-)-iso-crotepoxide or (-)-senepoxide, (+)-β-senepoxide, (+)-pipoxide acetate, and (-)-tingtanoxide, respectively.

Full text of DOI:10.1021/jo970907o

J . Org. Chem. 1998, 63, 1547-1554
1547
En a n tiosp ecific Syn th eses of (+)-Cr otep oxid e, (+)-Boesen oxid e,
(+)-â-Sen ep oxid e, (+)-P ip oxid e Aceta te, (-)-iso-Cr otep oxid e,
(-)-Sen ep oxid e, a n d (-)-Tin gta n oxid e fr om (-)-Qu in ic Acid 1
Tony K. M. Shing* and Eric K. W. Tam
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong
Received October 2, 1997
A convenient strategy that is ideally suited for the construction of all the naturally occurring
cyclohexane diepoxides and cyclohexene epoxides is described. The key intermediate 12, a 1,3-
cyclohexadiene, has been prepared from (-)-quinic acid in 11 steps with 18% overall yield. Singlet
oxygen photooxygenation of the 1,3-cyclohexadiene followed by rearrangement of the resultant
endoperoxides with either cobalt-meso-tetraphenylporphyrin or trimethyl phosphite afforded
enantiopure (+)-crotepoxide, (+)-boesenoxide, and (-)-iso-crotepoxide or (-)-senepoxide, (+)-â-
senepoxide, (+)-pipoxide acetate, and (-)-tingtanoxide, respectively.
1. In tr od u ction
Naturally occurring cyclohexane epoxides,2,3 which
belong to a small family of heavily oxygenated cyclohex-
ane derivatives, have attracted considerable attention
from the natural product and synthetic chemists due to
their unusual structures, biogenesis, and biological activ-
ity. (+)-Crotepoxide (1)4 and the recently discovered (+)-
boesenoxide (2)5 are members which possess a bisepoxide
functionality. (+)-Crotepoxide (1) was first discovered by
Kupchan et al. from the fruits of Croton macrostachys4
and then by Takahashi from Piper futokadzura6 and has
been shown to display significant tumor-inhibitory activ-
ity against Lewis lung carcinoma in mice (LL) and
Walker intramuscular carcinosarcoma in rats (WM).7
At roughly the same time, cyclohexene epoxides (+)-
pipoxide (4) and (-)-senepoxide (7) were isolated from
Piper hookeri8 and Uvaria catocarpa,9 respectively, and
also exhibited interesting biological properties including
tumor-inhibitory, antileukemic, and antibiotic activity.
The constitution and the absolute configurations of 1,10
4,11 and 712 were conclusively established by X-ray
crystallography. Recently, two additional oxiranes, (+)-
â-senepoxide (3) and (-)-tingtanoxide (8), were discov-
F igu r e 1. Configurational relationship between cyclohexane/
cyclohexene epoxides and monosaccharides.
ered.13 The absolute configurations of crotepoxide (1),
(+)-boesenoxide (2), (+)-â-senepoxide (3), (+)-pipoxide (4),
and (+)-pipoxide acetate (5) are similar to that of (1R,6S)-
cyclophellitol whereas the absolute configurations of (-)-
senepoxide (7), (-)-tingtanoxide (8), and nonnatural iso-
crotepoxide (6) are related to that of cyclophellitol.
(1R,6S)-Cyclophellitol14 and cyclophellitol15 have been
demonstrated to be potent â-D- and R-D-glucosidase
inhibitors, respectively, presumably attributable to the
structural resemblance to â-D- and R-D-glucose (Figure
1).
Most of the earlier syntheses of cyclohexane diepoxides
afforded racemic material. Approaches toward (()-
crotepoxide (1) were based on transformations from a
quinone,16 a 1,4-cyclohexadiene17 or a styrene deriva-
tive.18 The first approach was also used to obtain (()-
senepoxide (7),19 and the second approach afforded iso-
* To whom correspondence should be addressed. Fax: (852)-2603
5057. E-mail: tonyshing@cuhk.edu.hk.
(1) (-)-Quinic Acid in Organic Synthesis. 8. Part 7: (a) Shing, T.
K. M.; Wan, L. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 1643. (b) J .
Org. Chem. 1996, 61, 8468. Part 6: (c) Shing, T. K. M.; Tai, V. W.-F.
J . Org. Chem. 1995, 60, 5332.
(2) Thebtaranonth, C.; Thebtaranonth, Y. Acc. Chem. Res. 1986, 19,
84.
(3) Balci, M.; Su¨tbeyaz, Y.; Secen, H. Tetrahedron 1990, 46, 3715.
(4) Kupchan, S. M.; Hemingway, R. J .; Coggon, P.; McPhail, A. T.;
Sim, G. A. J . Am. Chem. Soc. 1968, 90, 2982.
(5) Tuntiwachwuttikul, P.; Pancharoen, O.; Bubb, W. A.; Hambley,
T. W.; Taylor, W. C.; Reutrakul, V. Aust. J . Chem. 1987, 40, 2049.
(6) Takahashi, S. Phytochemistry 1969, 8, 321.
(7) Kupchan, S. M.; Hemingway, R. J .; Smith, R. M. J . Org. Chem.
1969, 34, 3898.
(8) Singh, J .; Dhar, K. L.; Atal, C. K. Tetrahedron 1970, 26, 4403.
(9) Hollands, R.; Becher, D.; Gaudemer, A.; Polonsky, J . Tetrahedron
1968, 24, 1633.
(10) Coggon, P.; McPhail, A. T.; Sim, G. A. J . Chem. Soc. B 1969,
534.
(11) Holbert, G. W.; Ganem, B.; Van Engen, D.; Clardy, J .; Borsub,
L.; Chantrapromma, K.; Sadavongvivad, C.; Thebtaranonth, Y. Tet-
rahedron Lett. 1979, 20, 715.
(13) Kodpinid, M.; Sadavongvivad, C.; Thebtaranonth, C.; Theb-
taranonth, Y. Tetrahedron Lett. 1983, 24, 2019.
(14) (a) Tatsuta, K.; Niwata, K.; Umezawa, K.; Toshima, K.; Nakata,
M. J . Antibiot. 1991, 44, 912. (b) Atsumi, S.; Nosaka, C.; Ochi, Y.;
Iinuma, H.; Umezawa, K. Cancer Res. 1993, 53, 4896.
(15) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.; Naka-
mura, H.; Iitaka, Y.; Takeucki, T. J . Antibiot. 1990, 43, 49.
(16) Oda, K.; Ichihara, A.; Sakamura, S. Tetrahedron Lett. 1975,
16, 3187.
(17) Demuth, M. R.; Garrett, P. E.; White, J . D. J . Am. Chem. Soc.
1976, 98, 634.
(12) Ducruix, A.; Pascard, C.; Polonsky, J . Acta Crystallogr. Sect. B
1976, 32, 1589.
(18) Matsumoto, M.; Dobashi, S.; Kuroda, K. Tetrahedron Lett. 1977,
18, 3361.
S0022-3263(97)00907-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/18/1998

1548 J . Org. Chem., Vol. 63, No. 5, 1998
Shing and Tam
crotepoxide (6),17 (()-senepoxide (7),20 (()-â-senepoxide
(3),20 and (()-pipoxide (4).11 A Diels-Alder route was
employed by Schlessinger to synthesize (()-senepoxide
(7) and to provide formal syntheses of (()-crotepoxide (1)
and (()-pipoxide (4).21 Recently, Ogawa et al. published
the syntheses of enantiopure crotepoxide (1),22 (+)-â-
senepoxide (3),23 and (+)-pipoxide (4)23 from (1S)-endo-
7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid,24 a chemi-
cally resolved Diels-Alder adduct of furan and acrylic
acid.
Our own quest for a general, flexible, and efficient
entry to cyclohexane epoxides from (-)-quinic acid (24)
has already produced cyclophellitol and its diastereo-
mers.25 In continuation with our investigation into the
preparation of potential glycosidase inhibitors,1,25 we now
report facile syntheses of (+)-crotepoxide (1), (+)-boese-
noxide (2), (+)-â-senepoxide (3), (+)-pipoxide acetate (5),
(-)-iso-crotepoxide (6), (-)-senepoxide (7), and (-)-ting-
tanoxide (8) and hence further demonstrate the versatil-
ity of quinic acid in the fabrication of heavily oxygenated
cyclohexanoid natural products. A preliminary account
on the construction of 1 and 6 has appeared.26
However, the oxirane moiety in senepoxide (7) could not
be constructed directly via this method. Attempts to
prepare crotepoxide (1) by direct introduction of the cis-
1,2:3,4-bisepoxy function to the diene using peracid were
also unsuccessful. White17 found that benzyl diene 15
reacted with tert-butyl hydroperoxide in the presence of
VO(acac)2 as catalyst to give R-bisepoxide 17 stereospe-
cifically, albeit in 15% yield. Using m-CPBA even under
the forcing conditions devised by Kishi, a mixture of
trans-bisepoxide 18 and â-cis-bisepoxide 19 was obtained
from diacetyl diene 16 in a total yield of 55% and in a
ratio of 8:1, respectively.27 Hence, the fabrication of the
bisepoxide functionality from 9 using the classical ap-
proach does not appear to be efficient and convenient.
Singlet oxygen photooxygenation28 seems to be the
solution to construct the target molecules (Figure 2).
Fundamentally, 1,4-cycloaddition of singlet oxygen to a
cyclic diene results in the formation of a bicyclic endop-
eroxide (20 f 21).29 This cycloadduct provides an excel-
lent opportunity to form the cis-bisepoxide functionality
by metal complex catalyzed rearrangement (21 f 22).30
2. Resu lts a n d Discu ssion
2.1. An tith etic An a lysis a n d Str a tegy. All the
target molecules share two common stereogenic centers
at C-3,4. Compounds 1, 2, and 6 are bisepoxides whereas
the others are monoepoxides. Crotepoxide (1), boesenox-
ide (2), â-senepoxide (3), and pipoxide acetate (5) as a
group are distinct from the group comprising iso-crote-
poxide (6), senepoxide (7), and tingtanoxide (8) by the
epoxide stereochemistry, i.e., the former group has â-ep-
oxide(s) while the latter has R-epoxide(s). Retrosyntheti-
cally, diene 9 with suitable protecting groups was be-
lieved to be the key intermediate for the construction of
cyclohexane epoxides if we can epoxidize the alkene
moiety regio- and stereoselectively.
ref. 30
ref. 31
According to literature reports, direct transformation
of diene 9 into the target molecules by peracid oxidation
posed numerous problems. Ogawa23 subjected diene 10
to m-CPBA and obtained â-senepoxide (3) together with
monoepoxide isomers 13 and 14 in poor yields (eq 1).
F igu r e 2. Synthetic strategy.
On the other hand, the reduction of endoperoxide by
phosphite provides a facile entry to unsaturated monoe-
poxides (21 f 23).31 The earlier work by White17 and by
Ganem20 further convinced us that photooxygenation of
diene 9 should be an attractive route to cyclohexane
diepoxides. The synthetic problem is now reduced to the
choice of suitable hydroxy blocking groups (R1 and R2)
for diene 9. Analysis of the structure of all the target
molecules reveals that R1 should be an acetyl group in
order to shorten the synthetic route. Since diacetate 10
could not be oxidized under the singlet oxygen photooxy-
genation conditions,17 R2 was not recommended to be an
acyl group. Finally, we decided to employ diene 12 with
R2 being a silyl group as our key intermediate.
(19) (a) Ichihara, A.; Oda, K.; Kobayashi, M.; Sakamura, S. Tetra-
hedron Lett. 1974, 15, 4235. (b) Ichihara, A.; Oda, K.; Kobayashi, M.;
Sakamura, S. Tetrahedron 1980, 36, 183.
(20) (a) Holbert, G. W.; Ganem, B. J . Am. Chem. Soc. 1978, 100,
352. (b) Ganem, B.; Holbert, G. W.; Weiss, L. B.; Ishizumi, K. J . Am.
Chem. Soc. 1978, 100, 6483.
(21) Schlessinger, R. H.; Lopes, A. J . Org. Chem. 1981, 46, 5252.
(22) Ogawa, S.; Takagaki, T. Bull. Chem. Soc. J pn. 1987, 60, 800.
(23) Ogawa, S.; Takagaki, T. J . Org. Chem. 1985, 50, 2356.
(24) (a) Suami, T.; Ogawa, S.; Nakamoto, K.; Kasahara, I. Carbo-
hydr. Res. 1977, 58, 240. (b) Ogawa, S.; Iwasawa, Y.; Suami, T. Chem.
Lett. 1984, 355. (c) Ogawa, S.; Iwasawa, Y.; Noso, T.; Suami, T.; Ohbo,
S.; Ito, M.; Saito, Y. J . Chem Soc., Perkin Trans. 1 1985, 903.
(25) Shing, T. K. M.; Tai, V. W.-F. J . Chem. Soc., Chem. Commun.
1993, 995. (b) J . Chem. Soc., Perkin Trans. 1 1994, 2017.
(26) Shing, T. K. M.; Tam, E. K. W. Tetrahedron: Asymmetry 1996,
7, 353.
(27) Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T. J .
Chem. Soc., Chem. Commun. 1972, 64.
(28) For an excellent review on the use of singlet oxygen in organic
synthesis, see: Wasserman, H. H.; Ives, J . L. Tetrahedron 1981, 37,
1825.
(29) For an excellent review on this subject, see: (a) Adam, W.; Balc`ı,
M. Tetrahedron 1980, 36, 833. (b) Balc`ı, M. Chem. Rev. 1981, 81, 91.
(30) Boyd, J . D.; Foote, C. S.; Imagawa, D. K. J . Am. Chem. Soc.
1980, 102, 3641.
(31) (a) Bartlett, P. D.; Baumstark, A. L.; Landis, M. E. J . Am. Chem.
Soc. 1973, 95, 6486. (b) Bartlett, P. D.; Landis, M. E.; Baumstark, A.
L.; Lerman, C. L. J . Am. Chem. Soc. 1974, 96, 5267. (c) Bartlett, P.
D.; Landis, M. E.; Shapiro, M. J . J . Org Chem. 1977, 42, 1661. (d)
Baumstark, A. L.; Wilson, T.; Landis, M. E.; Bartlett, P. D. Tetrahedron
Lett. 1976, 17, 2397.

Syntheses of Cyclohexene Epoxides and Diepoxides
J . Org. Chem., Vol. 63, No. 5, 1998 1549
Sch em e 1
2.2. Syn th esis of Key In ter m ed ia te 12. Our previ-
ous work has shown that (-)-quinic acid (24) could be
transformed into the alcohol 25 in seven steps with an
overall yield of 47%.32 Standard benzoylation of 25 in
pyridine (pyr) furnished silyl benzoate 26 smoothly in
quantitative yield (eq 2). In another approach, through
a shorter sequence of functional group manipulation, silyl
benzoate 26 could be elaborated from diol 27 which in
turn could be derived, in four steps, also from (-)-quinic
acid (24) according to our previous endeavor.33
amount of osmium tetraoxide,37 leading to 30 as the sole
product in the same yield. Selective acetylation of the
secondary hydroxy group in 30 gave monoacetate 31.
Through this two-step conversion (26 f 30 f 31), the
OAc group at C-2 with the correct stereochemistry was
established.
Table 1 summarizes the results of the regioselective
benzoylation of the primary hydroxy group in diol 27.
Dibenzoate 29 was identified and isolated as the sole side
product. The best result (Table 1, entry 4) of obtaining
monobenzoate 28 was by treating diol 27 with 1 equiv of
benzoyl chloride and 3 equiv of collidine in dry dichlo-
romethane at -78 °C for 3 h and then at room temper-
ature for another 1 h.
With tertiary alcohol 31 at hand, we set out to prepare
alkene 32 via a suitable dehydration protocol. Several
literature methods were studied such as phosphorus
oxychloride (POCl3)38 and Martin sulfurane dehydrating
agent {[PhC(CF3)2O]2S(Ph)2}.39 However, these one-pot
reactions were found ineffective. The former gave de-
composition products while the latter yielded only a trace
amount of alkene 32. Gratifyingly, we discovered that
the traditional method of reacting alcohol 31 with thionyl
chloride in pyridine40 at room temperature furnished
alkene 32 in good yields. This procedure initially proved
inefficient on a large scale (>1 g) (usually the yield
decreased from 81% to 50%). We had overcome this
problem by slow addition of a solution of alcohol 31 to a
mixture of 1.5 equiv of thionyl chloride and 10 equiv of
pyridine in dry dichloromethane at 0 °C, followed by
stirring the reaction mixture for 12 h at room tempera-
ture. The best result obtained by this protocol on a 10 g
scale was 86% yield.
Selective hydrolysis of the cyclohexylidene ketal in 32
with 50% aqueous trifluoroacetic acid in dichloromethane
afforded vicinal diol 33. The workup was best conducted
after 6 h, and the reaction showed only 95% conversion.
Prolonging the reaction time resulted in the isolation of
triol 34 as the side product which became the sole product
after hydrolysis for 12 h at room temperature. Corey-
Winter41 deoxygenation of the vicinal diol moiety in 33
provided the key intermediate diene 12 that now pos-
sessed the functionality required for the bisoxirane
formation via a singlet oxygen photooxidation reac-
tion.29,42
Ta ble 1. Regioselective Ben zoyla tion of 27
isolated
entry
1
reagents
conditions
0 °C
yield, %
1 equiv of BzCl +
2 equiv of pyr
trace 28
44% 29
55% 28
20% 29
20% 28
34% 29
82% 28
5% 29
2
3
4
1 equiv of BzCl +
10 °C
2 equiv of Im34
1 equiv of BzCl +
2 equiv of Im
-78 °C f 25 °C
-78 °C f 25 °C
1 equiv of BzCl +
3 equiv of collidine35
Silylation of the remaining alcohol afforded the desired
silyl benzoate 26 in 97% yield. According to this im-
proved procedure, we could shorten the synthetic route
by two steps together with an increase of 4% overall yield
from quinic acid.
At this stage, we had to transform the silyl benzoate
26 into alkene 12. The double bond in 26 was subjected
to our recently developed ruthenium-catalyzed flash
dihydroxylation protocol at the less hindered convex face
(â-face) of the bicyclic skeleton to give, exclusively, the
desired â-diol 30 in 75% yield (Scheme 1).36 Alterna-
tively, alkene 26 could be dihydroxylated with a catalytic
2.3. Syn th eses of (+)-Cr otep oxid e (1), (+)-Boesen -
oxid e (2), a n d (-)-iso-Cr otep oxid e (6). The photoen-
(35) Ishihara, K.; Kurihara, H., Yamamoto, H. J . Org. Chem. 1993,
58, 3791.
(36) (a) Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2312. (b) Shing, T. K. M.; Tam, E. K. W.; Tai,
V. W.-F.; Chung, I. H. F.; J iang, Q. Chem. Eur. J . 1996, 2, 142.
(37) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655.
(38) Engel, P. S.; Keys, D. E.; Kitamura, A. J . Am. Chem. Soc. 1985,
107, 4964.
(39) Martin, J . C.; Arhart, R. J . J . Am. Chem. Soc. 1971, 93, 4327.
(40) Schwartz, A.; Madan, P. J . Org. Chem. 1986, 51, 5463.
(41) Corey, E. J .; Winter, R. A. E. J . Am. Chem. Soc. 1963, 85, 2677.
(42) Su¨tbeyaz, Y.; Secen, H.; Balc`ı, M. J . Chem. Soc., Chem.
Commun. 1988, 1330.
(32) (a) Shing, T. K. M.; Tang, Y. J . Chem. Soc., Chem. Commun.
1990, 312. (b) Tetrahedron 1990, 46, 6575.
(33) (a) Shing, T. K. M.; Tang, Y. J . Chem. Soc., Chem. Commun.
1990, 748. (b) Tetrahedron 1991, 47, 4571. (c) Shing, T. K. M.; Cui,
Y.-X.; Tang, Y. J . Chem. Soc., Chem. Commun. 1991, 756; (d)
Tetrahedron 1992, 48, 2349.
(34) (a) Holder, N. L.; Fraser-Reid, B. Synthesis 1972, 83. (b) Staab,
H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351.

1550 J . Org. Chem., Vol. 63, No. 5, 1998
Shing and Tam
Sch em e 2
Sch em e 3
a similar line as shown in Scheme 3. The R-endoperoxide
36 underwent CoTPP catalyzed rearrangement without
incidence to the R-bisepoxide 39 in quantitative yield.
Desilylation of 39 gave alcohol 40 that was acetylated to
doperoxidation reaction42 was set up as follows: diene
12 was mixed with a catalytic amount (substrate:catalyst,
ca. 1000:1) of the sensitizer tetraphenylporphyrin (TPP)
in carbon tetrachloride (singlet oxygen has a long lifetime
in CCl4)43 at 0 °C. Oxygen gas was bubbled into the
solution. After 3 min, the reaction mixture was il-
luminated with a projection lamp (450 W) for 5 h. A
mixture of endoperoxides 35 and 36 in a respective ratio
of 54:1 was obtained, readily separable by flash chroma-
tography (eq 3). On the basis of the spectral data, we
yield iso-crotepoxide (6) as an oil: [R]27 ) -35.8 (c )
D
0.7, CHCl3). The 1H NMR spectral data were in close
agreement with the reported values17 of racemic 6.
As expected, the high stereoselectivity of photooxygen-
ation of diene 12 does not provide an efficient route to
cyclohexane epoxides having an R-epoxide moiety. To
remedy this situation, we needed to find an alternative
avenue, and diene 41 should be a suitable intermediate
for the photooxidation. Initial attempts to desilylate the
diene 12 with TBAF in THF or HF-pyridine in aceto-
nitrile resulted in 4% of monoalcohol 41 and 60% of the
undesired triol 42 with the former protocol (eq 4). The
were unable to assign the stereochemistry of the com-
pounds at this stage. The exact stereochemistry was
determined by converting the endoperoxides into the
target molecules. As expected, the photooxidation of 12
proceeded selectively at the less hindered â-face, giving
the â-endoperoxide 35 as the preponderant product. The
high diastereoselectivity (35:36 ) 54:1) indicated that it
was highly efficient to use the tert-butyldimethyl silyl
ether as the stereodirecting group in the endoperoxida-
tion. Subjection of the endoperoxide 35 to the cobalt-
meso-tetraphenylporphyrin (CoTPP) catalyzed rearrange-
ment reaction44 at 0 °C gave smoothly the bisepoxide 37
in essentially quantitative yield.
latter procedure led to the recovery of most of the starting
material together with only a trace amount of the desired
alcohol 41. The best result of desilylation of 12 was
achieved with 48% aqueous HF in acetonitrile, providing
the alcohol 41 exclusively in 80% yield. Acetylation of
alcohol 41 led to the benzoyl diacetate diene 10. Surpris-
ingly, photooxygenation of 10 could not be effected. In
another report,17 it was found that benzyl ether diacetate
16 was also unreactive toward singlet oxygen. Presum-
ably, the presence of two electron-withdrawing groups
(acetate) diminished the nucleophilicity of the diene
toward photoendoperoxidation. Photooxygenation of di-
ene-alcohol 41 was successful and gave a mixture of
â-endoperoxide 43 and R-endoperoxide 44 in a ratio of
3:2 (eq 5). It is noteworthy that in the absence of the
With the bisepoxide in hand, we should obtain the
target molecules simply by desilylation and esterification
(Scheme 2). Exposure of bisepoxide 37 to pyridinium
hydrogen fluoride45 resulted in the cleavage of the silyl
ether, providing alcohol 38 in 85% yield. Finally, acetyl-
ation of the free alcohol in 38 yielded crotepoxide (1), mp
146-148 °C (Et2O-hexane) (lit.4 mp 150-151 °C); [R]26
D
) +71.9 (c ) 0.6, CHCl3) {lit.4 [R]25 ) +74 (c ) 1.7,
D
CHCl3)}. On the other hand, benzoylation of 38 fur-
nished, for the first time, optically active boesenoxide (2),
mp 169-170 °C (Et2O-hexane) (lit.5 mp 171-172 °C);
[R]20 ) +34.9 (c ) 0.1, CHCl3) {lit.5 [R]20 ) +35.0 (c )
D
D
0.1, CHCl3)}. The first enantiospecific synthesis of
optically active iso-crotepoxide (6) could be realized along
bulky silyl group at C-2 production of the R-endoperoxide
becomes significant. The mixture of endoperoxides could
be separated by flash chromatography. On treatment
with a catalytic amount of CoTPP, â-endoperoxide 43
rearranged smoothly to the corresponding bisepoxide 38,
which was identical to the product of desilylation of
bisepoxide 37. This bisepoxide 38 was also converted into
(43) (a) Merkel, P. B.; Kearns, D. R. J . Am. Chem. Soc. 1972, 94,
1029. (b) Merkel, P. B.; Kearns, D. R. J . Am. Chem. Soc. 1972, 94,
7244.
(44) Boyd, J . D.; Foote, C. S.; Imagawa, D. K. J . Am. Chem. Soc.
1980, 102, 3641.
(45) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J . Org.
Chem. 1979, 44, 4011.

Syntheses of Cyclohexene Epoxides and Diepoxides
J . Org. Chem., Vol. 63, No. 5, 1998 1551
Sch em e 4
toendoperoxidation of diene 12 in 15 steps with 9%
overall yields. On the other hand, (-)-iso-crotepoxide (6)
was prepared from (-)-quinic acid (24) via photooxygen-
ation of diene 41 in 15 steps with 3% overall yield. (+)-
Pipoxide acetate (5) and (+)-â-senepoxide (3) were con-
structed from (-)-quinic acid (24) via rearrangement of
â-endoperoxide 43 in 15 steps with 6% overall yield in
each case. On the other hand, (-)-senepoxide (7) and
(-)-tingtanoxide (8) were fabricated from (-)-quinic acid
(24) via rearrangement of R-endoperoxide 44 in 15 steps
with 3% overall yield. Enantiospecific syntheses of (+)-
boesenoxide (2), (-)-iso-crotepoxide (6), (-)-senepoxide
(7), and (-)-tingtanoxide (8) are reported for the first
time.
4. Exp er im en ta l Section
Sch em e 5
Melting points are reported in degrees Celsius and are
uncorrected. Optical rotations were measured at 589 nm. IR
spectra were recorded on a FT-IR spectrometer as thin films
on NaCl disks. Unless stated to the contrary, NMR spectra
were measured in solutions of CDCl3 at 250 MHz (1H) or at
62.9 MHz (13C). Spin-spin coupling constants (J ) were
measured directly from the spectra. Carbon and hydrogen
elemental analyses were carried out at either the Shanghai
Institute of Organic Chemistry, The Chinese Academy of
Sciences, China, or the MEDAC Ltd., Department of Chem-
istry, Brunel University, Uxbridge, U.K. All reactions were
monitored by analytical TLC on aluminum precoated with
silica gel 60F254 (E. Merck), and compounds were visualized
with a spray of either 5% w/v dodecamolybdophosphoric acid
in ethanol or 5% v/v concentrated sulfuric acid in ethanol and
subsequent heating. All columns were packed wet using E.
Merck silica gel 60 (230-400 mesh) as the stationary phase
and eluted using flash39 chromatographic technique. Pyridine
was distilled over barium oxide and stored in the presence of
potassium hydroxide pellets. THF was distilled from sodium
benzophenone ketyl under a nitrogen atmosphere. CH2Cl2 was
distilled over phosphorus pentoxide and stored in the presence
of 4 Å molecular sieves. Other reagents were purchased from
commercial suppliers and were used without purification.
(+)-Cr otep oxid e (1). To a solution of the alcohol 38 (320
mg, 1.0 mmol), TEA (312 µL, 2.0 mmol), and a catalytic amount
of DMAP in dry CH2Cl2 (50 mL) was added acetic anhydride
(104 µL, 1.1 mmol) at room temperature. The solution was
stirred at room temperature for 12 h and poured into saturated
aqueous NH4Cl (10 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 10 mL), and the combined organic extracts
were washed with brine (10 mL), dried (MgSO4), and filtered.
Concentration of the filtrate followed by flash chromatography
(Et2O-hexane, 2:1) provided (+)-crotepoxide (1) (362 mg,
100%) as a white solid: mp 146-148 °C (lit.4 mp 150-151 °C);
crotepoxide (1) and bosenoxide (2). In a similar manner,
treatment of R-endoperoxide 44 with CoTPP followed by
acetylation of the resulting R-bisoxirane furnished iso-
crotepoxide (6) (Scheme 3).
2.4. Syn th eses of th e (+)-â-Sen ep oxid e (3), (+)-
P ip oxid e Aceta te (5), (-)-Tin gta n oxid e (8), a n d (-)-
Sen ep oxid e (7). With the â-endoperoxide 43 in hand,
we conducted reductive rearrangement29b using trimethyl
phosphite in benzene to give cyclohexene epoxide 45
exclusively in 85% yield (Scheme 4). It is noteworthy
that this reaction is highly regio- and stereoselective, and
none of the regio- or stereoisomer was isolated.
Having established all the requisite stereocenters, we
then acetylated the alcohol in cyclohexene epoxide 45 to
give (+)-â-senepoxide (3); mp 69-71 °C (Et2O-hexane)
(lit.13 mp 72-73 °C); [R]20D ) +62.9 (c ) 0.1, CHCl3) {lit.13
[R]25 ) +62.0 (c ) 0.6, CHCl3)}. On the other hand,
D
Rf ) 0.50 (Et2O-hexane, 4:1); [R]26 +71.9 (c ) 0.6, CHCl3)
benzoylation of the alcohol in 45 gave (+)-pipoxide acetate
(5): mp 172-173 °C (Et2O-hexane) (lit.13 mp 171-172
°C); [R]20 ) + 8.9 (c ) 1.0, CHCl3) {lit.13 [R]28 ) + 9.0
D
(lit.4 [R]25D +74 (c ) 1.7, CHCl3); IR (thin film) 1725, 1750 cm-1
;
1H NMR δ 2.03 (3H, s), 2.13 (3H, s), 3.11 (1H, dd, J ) 1.6, 3.9
Hz), 3.46 (1H, dd, J ) 2.7, 3.9 Hz), 3.67 (1H, d, J ) 2.7 Hz),
4.24 (1H, d, J ) 12.1 Hz), 4.58 (1H, d, J ) 12.1 Hz), 4.99 (1H,
dd, J ) 1.6, 9.0 Hz), 5.71 (1H, d, J ) 9.0 Hz), 7.47 (2H, t, J )
D
D
(c ) 4.4, CHCl3)}.
The R-endoperoxide 44 was treated with trimethyl
phosphite in a similar manner, furnishing cyclohexene
epoxide 46 in 85% yield. Standard acetylation of 46
afforded target molecule (-)-senepoxide (7): mp 85-86
7.1 Hz), 7.57 (1H, t, J ) 7.6 Hz), 8.02 (2H, d, J ) 7.0 Hz); 13
C
NMR δ 20.6, 48.0, 52.6, 53.8, 59.4, 62.5, 69.5, 70.4, 128.6, 129.2,
129.8, 133.5, 165.8, 169.7, 170.0.
°C (Et2O-hexane) (lit.9 mp 85 °C); [R]20 ) -194.6 (c )
(+)-Boesen oxid e (2). To a solution of the alcohol 38 (160
mg, 0.5 mmol), TEA (156 µL, 1.0 mmol), and a catalytic amount
of DMAP in dry CH2Cl2 (20 mL) was added benzoyl chloride
(70 µL, 0.6 mmol) at room temperature. The solution was
stirred at room temperature for 12 h and poured into saturated
aqueous NH4Cl (10 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 10 mL), and the combined organic extracts
were washed with brine (10 mL), dried (MgSO4), and filtered.
Concentration of the filtrate followed by flash chromatography
(EtOAc-hexane, 1:2) provided (+)-boseneoxide (2) (362 mg,
100%) as a white solid: mp 169-170 °C (lit.5 mp 171-172 °C);
D
0.2, CHCl3) {lit.9 [R]25 ) -197.0 (c ) 1.2, CHCl3)}.
D
Benzoylation of 46 provided (-)-tingtanoxide (8): mp 69-
71 °C (Et2O-hexane) (lit.13 mp 72-73 °C); [R]20D ) -303
(c ) 0.1, CHCl3) {lit.13 [R]28 ) -306 (c ) 6.3, CHCl3)}
D
respectively (Scheme 5).
3. Con clu sion s
In conclusion, (+)-crotepoxide (1) and (+)-boesenoxide
(2) were synthesized from (-)-quinic acid (24) via pho-
Rf ) 0.62 (EtOAc-hexane, 1:1); [R]20 +34.9 (c ) 0.1, CHCl3)
D

1552 J . Org. Chem., Vol. 63, No. 5, 1998
Shing and Tam
(lit.5 [R]20 +35.0 (c ) 0.1, CHCl3); IR (thin film) 1725, 1745
solution of the diol 33 (109 mg, 0.25 mmol) in toluene (25 mL)
was added 1,1′-thiocarbonyldiimidazole (66.7 mg, 0.37 mmol)
in three equal portions within 3 h. The mixture was heated
under reflux for 24 h and filtered through a thin layer pad of
silica gel. Removal of the solvent from the filtrate under
reduced pressure gave a yellow oil. Without further purifica-
tion, the oil was dissolved in trimethyl phosphite (25 mL) and
the solution was heated under reflux for 24 h. Solvent removal
under reduced pressure followed by flash chromatography
(Et2O-hexane, 1:10) provided the diene 12 (68.5 mg, 68%) as
D
cm-1; H NMR δ 2.07 (3H, s), 3.20 (1H, dd, J ) 1.6, 3.9 Hz),
1
3.48 (1H, dd, J ) 2.7, 3.9 Hz), 3.72 (1H, d, J ) 2.7 Hz), 4.28
(1H, d, J ) 12.0 Hz), 4.62 (1H, d, J ) 12.0 Hz), 5.17 (1H, dd,
J ) 1.6, 9.5 Hz), 5.95 (1H, d, J ) 9.5 Hz), 7.43 (4H, m), 7.59
(2H, m), 8.04 (4H, m); 13C NMR δ 21.3, 48.9, 53.7, 54.6, 60.5,
63.1, 70.1, 71.9, 129.3, 129.8, 130.5, 134.2, 166.2, 166.5, 170.7.
(+)-â-Sen ep oxid e (3). Following the same procedure as
for acetylation of 38, cyclohexene oxide 45 (30 mg, 0.1 mmol)
gave a quantitative yield of (+)-â-senepoxide (3) as a white
solid, after fractionation by flash chromatography (Et2O-
hexane, 2:1): mp 69-71 °C (lit.13 mp 72-73 °C); Rf ) 0.54
a colorless oil: Rf ) 0.43 (Et2O-hexane, 1:6); [R]22 -2.5 (c )
D
28.9, CHCl3); IR (thin film) 1724 cm-1; 1H NMR δ 0.07 (6H, s)
0.87 (9H, s), 2.02 (3H, s), 4.48 (1H, ddd, J ) 1.3, 3.5, 8.0 Hz),
4.85 (2H, s), 5.80 (1H, dd, J ) 1.0, 8.0 Hz), 5.86 (1H, m), 5.98
(1H, ddd, J ) 1.4, 5.3, 9.7 Hz), 6.17 (1H, dt, J ) 1.1, 5.3 Hz),
7.44 (2H, t, J ) 6.4 Hz), 7.54 (1H, t, J ) 7.5 Hz), 8.04 (2H, d,
J ) 8.3 Hz); MS m/z (relative intensity) 402 (M+, 1). Anal.
Calcd for C22H30O5Si: C, 65.64; H, 7.51. Found: C, 66.04; H,
7.68.
(EtOAc-hexane, 1:1); [R]20D +62.9 (c ) 0.1, CHCl3) (lit.13 [R]25
D
+62 (c ) 0.55, CHCl3); IR (thin film), 1747 cm-1; H NMR δ
1
2.05 (3H, s), 2.14 (3H, s), 3.58 (1H, dd, J ) 1.9, 4.1 Hz), 4.37
(1H, d, J ) 12.1 Hz), 4.63 (1H, d, J ) 12.0 Hz), 5.56 (1H, dt,
J ) 2.0, 8.3 Hz), 5.68 (1H, d, J ) 8.4 Hz), 5.77 (1H, dt, J ) 2.0,
9.9 Hz), 6.07 (1H, dt, J ) 2.0, 10.1 Hz),7.46 (2H, t, J ) 6.4
Hz), 7.57 (1H, t, J ) 7.1 Hz), 8.03 (2H, d, J ) 7.1 Hz); 13C
NMR δ 20.7, 20.9, 54.5, 58.3, 62.2, 71.3, 124.1, 128.5, 129.3,
129.8, 133.4, 165.8, 170.2.
(1R ,2R ,3S )-5-(Be n zoyloxym e t h yl)-3-O-(t er t -b u t yld i-
m eth ylsilyl)-1,2-O-cycloh exylid en ee-4-cycloh exen -1,2,3-
tr iol (26). A solution of allylic alcohol 28 (344 mg, 1.0 mmol),
imidazole (136 mg, 2.0 mmol), tert-butyldimethylsilyl chloride
(181 mg, 1.2 mmol), and a catalytic amount of DMAP in dry
CH2Cl2 (50 mL) was stirred at room temperature for 12 h. The
mixture was poured into saturated aqueous NH4Cl (10 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 10 mL),
and the combined organic extracts were washed with brine
(10 mL), dried (MgSO4), and filtered. Concentration of the
filtrate followed by flash chromatography (Et2O-hexane, 1:10)
provided the title compound 26 (445 mg, 97%) as a colorless
oil: Rf ) 0.57 (Et2O-hexane, 1:4); [R]26D +13.7 (c ) 1.7, CHCl3);
IR (thin film) 1722 cm-1; 1H NMR δ 0.13 (6H, s), 0.93 (9H, s),
1.36-1.60 (10H, m), 2.02 (1H, d, J ) 16.0 Hz), 2.44 (1H, d, J
) 16.0 Hz), 4.20 (1H, s), 4.41 (1H, m), 4.51 (1H, m), 4.76 (2H,
s), 5.89 (1H, br s), 7.42 (2H, t, J ) 7.6 Hz), 7.54 (1H, t, J ) 6.9
Hz), 8.06 (2H, d, J ) 7.4 Hz); 13C NMR δ 4.5 (×2), 18.3, 23.6,
23.9, 25.3, 25.8, 25.9, 29.9, 33.9, 35.7, 67.1, 69.3, 72.5, 77.2,
109.1, 128.2, 129.5, 129.6, 129.9, 130.2, 131.7, 132.7, 166.1;
MS m/z (relative intensity) 458 (M+, 4.3). Anal. Calcd for
P ip oxid e Aceta te (5). Following the same procedure as
for benzoylation of 38, cyclohexene oxide 45 (30 mg, 0.1 mmol)
gave a quantitative yield of pipoxide acetate (5) as a colorless
oil, after fractionation by flash chromatography (Et2O-hexane,
1:1): Rf ) 0.58 (Et2O-hexane, 1:1); [R]20D +8.9 (c ) 1.3, CHCl3)
(lit.13 [R]28 +9.0 (c ) 4.4, CHCl3); IR (thin film), 1732 cm-1
;
D
1H NMR δ 2.11 (3H, s), 3.63 (1H, dd, J ) 1.9, 3.8 Hz), 4.42
(1H, d, J ) 12.1 Hz), 4.68 (1H, d, J ) 12.0 Hz), 5.89 (1H, ddd,
J ) 1.7, 4.2, 6.9 Hz), 5.92 (1H, m), 6.09 (1H, ddd, J ) 2.6, 3.8,
9.9 Hz), 7.46 (4H, m), 7.57 (2H, m), 8.04 (4H, m); 13C NMR δ
20.6, 54.5, 58.4, 62.3, 71.2, 72.2, 124.3, 128.5, 129.5, 129.6,
129.8, 133.3, 133.6, 165.8, 170.1.
(-)-iso-Cr otep oxid e (6). Following the same procedure
as for the acetylation of 38, the alcohol 40 (21 mg, 0.07 mmol)
gave a quantitative yield of (-)-iso-crotepoxide (6) as a colorless
oil, after fractionation by flash chromatography (Et2O-hexane,
4:1): Rf ) 0.45 (EtOAc-hexane, 1:1); [R]27 -35.8 (c ) 0.7,
D
CHCl3); IR (thin film), 1720 cm-1; 1H NMR δ 2.00 (3H, s), 2.11
(3H, s), 3.42 (1H, d, J ) 4.0 Hz), 3.50 (1H, d, J ) 2.7 Hz), 3.57
(1H, dd, J ) 2.7, 4.0 Hz), 4.39 (2H, ABq, J ) 12.3 Hz), 5.36
(2H, s), 7.47 (2H, t, J ) 6.4 Hz), 7.60 (1H, t, J ) 7.1 Hz), 8.02
(2H, d, J ) 7.1 Hz); 13C NMR δ 20.4, 20.7, 47.9, 53.1, 53.2,
56.9, 63.1, 68.7, 70.9, 76.0, 128.6, 129.3, 129.7, 133.5, 165.8,
169.4, 170.4; HRMS calcd for C18H19O8 363.1080 (HM+), found
363.1072 (HM+).
C
26H38O5Si: C, 68.09; H, 8.35. Found: C, 67.85; H, 8.27.
(1R ,2R ,3S )-5-(B e n zo y lo x y m e t h y l)-1,2-O -c y c lo h e x -
ylid en e-4-cycloh exen e-1,2,3-tr iol (28). To a solution of the
diol 27 (240 mg, 1.0 mmol) and collidine (263 µL, 2.0 mmol)
in dry CH2Cl2 (50 mL) at -78 °C was added a solution of
benzoyl chloride (115 µL, 1.0 mmol) in 10 mL of CH2Cl2
dropwise over 5 min. The reaction mixture was allowed to
warm to room temperature and stirred for 2 h. The resulting
mixture was then poured into saturated aqueous NH4Cl (10
mL). The aqueous phase was extracted with CH2Cl2 (3 × 10
mL), and the combined organic extracts were washed with
brine (10 mL), dried (MgSO4), and filtered. Concentration of
the filtrate followed by flash chromatography (Et2O-hexane,
2:1) provided the benzoate 28 (282 mg, 82%) as a white solid:
(-)-Sen ep oxid e (7). Following the same procedure as for
the preparation of 1, cyclohexene oxide 46 (30 mg, 0.1 mmol)
gave a quantitative yield of (-)-senepoxide (7) as a white solid,
after fractionation by flash chromatography (Et2O-hexane,
2:1): mp 85-86 °C (lit.9 mp, 85 °C); Rf ) 0.55 (EtOAc-hexane,
1:1); [R]20 -194.6 (c ) 0.2, CHCl3) (lit.9 [R]25 -197 (c ) 1.2,
D
D
CHCl3); IR (thin film), 1732 cm-1; 1H NMR δ 2.07 (3H, s), 2.10
(3H, s), 3.47 (1H, d, J ) 3.3 Hz), 4.25 (1H, d, J ) 12.5 Hz),
4.85 (1H, d, J ) 12.5 Hz), 5.19 (1H, dd, J ) 2.0, 5.6 Hz), 5.59
(1H, d, J ) 1.3 Hz),6.09 (1H, dd, J ) 4.9, 9.3 Hz), 6.39 (1H,
dd, J ) 3.9, 10.0 Hz), 7.47 (2H, t, J ) 6.4 Hz), 7.58 (1H, t, J )
7.1 Hz), 8.06 (2H, d, J ) 7.1 Hz); 13C NMR δ 20.6, 20.9, 49.7,
61.6, 64.0, 67.3, 67.6, 128.5, 128.9, 129.0, 129.6, 129.8, 133.3,
166.0, 170.0.
Rf ) 0.62 (Et2O-hexane, 4:1); [R]26 +13.7 (c ) 1.7, CHCl3);
D
IR (thin film) 1721, 3489 cm-1
;
1H NMR δ 1.36-1.60 (10H,
m), 2.04 (1H, d, J ) 15.8 Hz), 2.24 (1H, d, J ) 14.9 Hz), 2.47
(1H, d, J ) 16.0 Hz), 3.88 (1H, s), 4.49 (2H, br s), 4.76 (2H, t,
J ) 13.7 Hz), 5.91 (br s, 1H), 7.42 (2H, t, J ) 7.6 Hz), 7.54
(1H, t, J ) 6.9 Hz), 8.06 (2H, d, J ) 7.4 Hz); MS (FAB) m/z
(relative intensity) 344 (M+, 3). Anal. Calcd for C20H24O5: C,
69.75; H, 7.02. Found: C, 69.76, H, 6.87.
(-)-Tin gta n oxid e (8). Following the same procedure as
for benzoylation of 38, cyclohexene oxide 46 (30 mg, 0.1 mmol)
gave a quantitative yield of (-)-tingtanoxide (8) as a colorless
oil, after fractionation by flash chromatography (Et2O-hexane,
1:1): mp 69-71 °C (Et2O-hexane) (lit.13 mp 72-73 °C); Rf )
(1R,2R,3S,4S,5S)-5-(Ben zoyloxym et h yl)-3-O-(ter t-b u -
t yld im e t h ylsilyl)-1,2-O-cycloh e xylid e n e cycloh e xa n e -
1,2,3,4,5-p en tol (30). To a vigorously stirred solution of the
alkene 26 (459 mg, 1.0 mmol) in EtOAc-CH3CN (6 mL-6 mL)
at 0 °C (ice-water bath) was added a solution of RuCl3‚3H2O
(19 mg, 0.07 mmol) and NaIO4 (320 mg, 1.5 mmol) in distilled
water (2 mL). The biphasic mixture was stirred vigorously
for 3 min and quenched with saturated aqueous Na2S2O3 (10
mL). The aqueous phase was separated and extracted with
EtOAc (3 × 15 mL). The combined organic extracts were dried
(MgSO4) and filtered. Concentration of the filtrate followed
by flash chromatography (Et2O-hexane, 1:2) afforded the diol
30 (370 mg, 75%) as a white solid: mp 116-117 °C; Rf ) 0.31
0.69 (EtOAc-hexane, 1:1); [R]20 -303 (c ) 1.0, CHCl3) (lit.13
D
[R]28D -306 (c ) 6.3, CHCl3); IR (thin film), 1732 cm-1; 1H NMR
δ 2.09 (3H, s), 3.53 (1H, d, J ) 3.7 Hz), 4.33 (1H, d, J ) 12.5
Hz), 4.86 (1H, d, J ) 12.5 Hz), 5.46 (1H, dd, J ) 2.5, 5.5 Hz),
5.74 (1H, d, J ) 0.8 Hz), 6.19 (1H, dd, J ) 4.8, 9.2 Hz), 6.43
(1H, dd, J ) 4.0, 9.9 Hz), 7.46 (4H, m), 7.57 (2H, m), 8.04 (4H,
m); 13C NMR δ 20.7, 50.1, 61.6, 64.5, 67.2, 67.6, 124.6, 128.5,
129.1, 129.2, 129.8, 133.3, 133.5, 165.9, 170.0.
(3R,4R)-4-O-Acetyl-5-(ben zoyloxym eth yl)-3-O-(ter t-bu -
tyld im eth ylsilyl)cycloh exa -1,5-d ien e-3,4-d iol (12). To a

Syntheses of Cyclohexene Epoxides and Diepoxides
J . Org. Chem., Vol. 63, No. 5, 1998 1553
(Et2O-hexane, 1:2); [R]26D -22.2 (c ) 1.6, CHCl3); IR (thin film)
(M+, 1). Anal. Calcd for C22H32O7Si: C, 60.53; H, 7.39.
Found: C, 60.32; H, 7.30.
1724, 3473 cm-1 1H NMR δ 0.15 (3H, s), 0.16 (3H, s), 0.94
;
(9H, s), 1.38-1.75 (10H, m), 1.83 (1H, ddd, J ) 1.85, 8.45, 14.2
Hz), 2.13 (1H, dd, J ) 6.2, 14.2 Hz), 2.60 (1H, d, J ) 1.8), 2.62
(1H, d, J ) 2.25 Hz), 3.91 (1H, dd, J ) 2.25, 9.45 Hz), 4.07
(1H, dd, J ) 3.75, 9.45 Hz), 4.25 (1H, d, J ) 11.2 Hz), 4.27-
4.40 (m, 3H, m), 7.44 (2H, t, J ) 7.75 Hz), 7.57 (1H, t, J ) 6.0
Hz), 8.05 (2H, d, J ) 5.1 Hz); 13C NMR δ -4.3, -4.4, 18.2,
23.7, 24.1, 25.1, 25.9, 35.0, 35.5, 38.2, 68.8, 70.5, 71.2, 72.0,
73.3, 76.3, 109.9, 128.4, 129.7, 130.0, 133.1, 166.5; MS m/z
(relative intensity) 493 (M+, 2). Anal. Calcd for C26H40O7Si:
C, 63.38; H, 8.18. Found: C, 63.38; H, 8.21.
Silyla t ed â-E n d op er oxid e 35 a n d Silyla t ed r-E n d o-
p er oxid e 36. Oxygen was bubbled through a solution of the
diene 12 (402 mg, 1.0 mmol) in CCl4 (70 mL) at 0 °C containing
a catalytic amount (0.1 mol %) of 5,10,15,20-tetraphenyl-
21H,23H-porphine (0.6 mg, 1 × 10-3 mmol). After 5 min, the
reaction mixture was irradiated with 450 W projection lamp
for 7 h and poured into a thin layer pad of silica gel. Removal
of the solvents under reduced pressure followed by flash
chromatography (Et2O-hexane, 1:5) gave 339.8 mg of â-en-
doperoxide 35 and 6.3 mg of R-endoperoxide 36 as colorless
oils (80%). The ratio of 35 to 36 (ca. 54:1) was determined by
the isolated yields. Pure compounds were obtained by flash
chromatography. The less polar 35 was obtained as a colorless
oil: Rf ) 0.45 (Et2O-hexane, 1:3); 1H NMR δ 0.07 (6H, s), 0.86
(9H, s), 2.17 (3H, s), 4.14 (1H, dd, J ) 1.4, 2.0 Hz), 4.41 (1H,
d, J ) 12.0 Hz), 4.52 (1H, d, J ) 12.0 Hz), 4.56 (1H, m), 4.84
(1H, d, J ) 1.5 Hz), 6.71 (2H, m), 7.45 (2H, m), 7.55 (1H, t, J
) 7.3 Hz), 8.04 (2H, d, J ) 7.3 Hz). The more polar 36 was
(1R,2R,3R,4S,5S)-4-O-Acet yl-5-(b en zoyloxym et h yl)-3-
O-(ter t-bu tyl-d im eth ylsilyl)-1,2-O-cycloh exylid en ecyclo-
h exa n e-1,2,3,4,5-p en tol (31). To a solution of the diol 30 (493
mg, 1.0 mmol), pyridine (172 µL, 2.0 mmol), and a catalytic
amount of DMAP in dry CH2Cl2 (50 mL) was added acetic
anhydride (104 µL, 1.1 mmol) at room temperature. The
solution was stirred at room temperature for 12 h and poured
into saturated aqueous NH4Cl (10 mL). The aqueous phase
was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic extracts were washed with brine (10 mL), dried
(MgSO4), and filtered. Concentration of the filtrate followed
by flash chromatography (Et2O-hexane, 1:2) provided monoac-
etate 31 (519 mg, 97%) as a colorless oil: Rf ) 0.31 (Et2O-
hexane, 1:1); [R]26D -19.1 (c ) 1.0, CHCl3); IR (thin film) 1725,
1
obtained as a colorless oil: Rf ) 0.27 (Et2O-hexane, 1:3); H
NMR δ 0.07 (6H, s), 0.86 (9H, s), 2.17 (3H, s), 3.69 (1H, s),
4.47 (1H, d, J ) 12.9 Hz), 4.59 (2H, m), 5.20 (1H, s), 6.46 (1H,
d, J ) 8.3 Hz), 6.79 (1H, dd, J ) 6.3, 8.2 Hz), 7.45 (2H, t, J )
7.4 Hz), 7.56 (1H, t, J ) 7.2 Hz), 8.04 (2H, d, J ) 7.1 Hz).
Silyla ted â-Bisep oxid e 37. A solution of the â-endoper-
oxide 35 (109 mg, 0.25 mmol) in CHCl3 (10 mL) was added
5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II) (0.7 mg,
1 × 10-3 mmol) at 0 °C. The reaction was stirred for 3 h and
poured into saturated aqueous NH4Cl (10 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL), and the
combined organic extracts were washed with brine (10 mL),
dried (MgSO4), and filtered. Concentration of the filtrate
followed by flash chromatography (Et2O-hexane, 1:3) provided
the bisepoxide 37 (109 mg, 100%) as a white solid: mp 68-71
°C; Rf ) 0.50 (Et2O-hexane, 1:1); [R]22D +38.7 (c ) 3.4, CHCl3);
IR (thin film) 1725 cm-1; 1H NMR δ 0.07 (3H, s), 0.08 (3H, s),
0.85 (9H, s), 2.17 (3H, s), 3.07 (1H, dd, J ) 0.9, 4.0 Hz), 3.40
(1H, dd, J ) 2.7, 4.0 Hz), 3.61 (1H, d, J ) 2.5 Hz), 3.90 (1H,
dd, J ) 1.4, 9.1 Hz), 4.23 (1H, d, J ) 12.1 Hz), 4.51 (1H, d, J
) 12.1 Hz), 5.58 (1H, d, J ) 9.2 Hz), 7.46 (2H, t, J ) 7.3 Hz),
7.58 (1H, t, J ) 7.2 Hz), 8.02 (2H, d, J ) 7.1 Hz); HRMS calcd
for C22H30O7SiNa 457.1653 (NaM+), found 457.1692 (NaM+).
â-Bisep oxid e 38. (a ) F r om 37. To a solution of the
silylated bisepoxide 37 (44 mg, 0.1 mmol) in THF (10 mL) was
added 3 drops of pyridinium fluoride (pH ) 5). The reaction
was stirred vigorously for 12 h and quenched with saturated
NH4Cl (5 mL). The aqueous phase was extracted with CH2-
Cl2 (3 × 5 mL), and the combined organic extracts were washed
with brine (5 mL), dried (MgSO4), and filtered. Concentration
of the filtrate followed by flash chromatography (Et2O-hexane,
1:1) provided the title compound 38 (27 mg, 84%) as a white
1750, 3448 cm-1 1H NMR δ 0.13 (3H, s), 0.17 (3H, s), 0.86
;
(9H, s), 1.38-1.75 (10H, m), 2.05 (3H, s), 2.21-2.32 (2H, m),
2.62 (1H, br s), 4.05 (1H, d, J ) 11.5 Hz), 4.26-4.42 (4H, m),
5.39 (1H, d, J ) 9.13 Hz), 7.44 (2H, t, J ) 7.75 Hz), 7.57 (1H,
t, J ) 6.0 Hz), 8.05 (2H, d, J ) 5.1 Hz); MS m/z (relative
intensity) 535 (M+, 3). Anal. Calcd for C28H42O8Si: C, 62.89;
H, 7.92. Found: C, 63.13; H, 8.23.
(1R,2R,3S,4R)-4-O-Acet yl-5-(b en zoyloxym et h yl)-3-O-
(ter t-bu tyld im eth ylsilyl)-1,2-O-cycloh exylid en e-5-cyclo-
h exen e-1,2,3,4-tetr a ol (32). To a solution of thionyl chloride
(0.89 mL, 12.0 mmol) in dry CH2Cl2 (600 mL) at 0 °C was
added dropwise a solution of tertiary alcohol 31 (5.35 g, 10.0
mmol) in dry CH2Cl2 (200 mL) and pyridine (2.58 mL, 30.0
mmol) for 2.5 h at 0 °C. The resultant mixture was stirred
for 12 h at room temperature and poured into a solution of
saturated aqueous NH4Cl (100 mL). The aqueous phase was
extracted with CH2Cl2 (3 × 100 mL), and the combined organic
extracts were washed with brine (100 mL), dried (MgSO4), and
filtered. Concentration of the filtrate followed by flash chro-
matography (Et2O-hexane, 1:4) provided the alkene 32 (4.60
g, 89%) as a colorless oil: Rf ) 0.66 (Et2O-hexane, 1:2); [R]26
D
+45.5 (c ) 1.0, CHCl3); IR (thin film) 1721 cm-1; H NMR δ
1
0.13 (3H, s), 0.17 (3H, s), 0.89 (9H, s), 1.38-1.75 (10H, m),
2.07 (3H, s), 3.97 (1H, dd, J ) 2.3, 8.3 Hz), 4.39 (1H, m), 4.62
(1H, m), 4.76 (2H, br s), 5.81 (1H, m), 5.92 (1H, d, J ) 8.3 Hz),
7.44 (2H, t, J ) 7.75 Hz), 7.53 (1H, t, J ) 6.0 Hz), 8.04 (2H, d,
J ) 5.1 Hz); MS m/z (relative intensity) 517 (M+, 2). Anal.
Calcd for C28H40O7Si: C, 65.09; H, 7.80. Found: C, 64.70; H,
8.04.
solid: mp 134-136 °C; Rf ) 0.27 (EtOAc-hexane, 1:1); [R]25
D
+75.8 (c ) 0.3, CHCl3); IR (thin film) 3300, 1722 cm-1; 1H NMR
δ 2.17 (3H, s), 2.63 (1H, d, J ) 5.5 Hz), 3.03 (1H, m), 3.18 (1H,
dd, J ) 1.3, 2.7 Hz), 3.43 (1H, dd, J ) 2.7, 3.8 Hz), 3.63 (1H,
dd, J ) 2.7 Hz), 3.97 (1H, ddd, J ) 1.3, 5.5, 6.8 Hz), 4.23 (1H,
d, J ) 12.1 Hz), 4.60 (1H, d, J ) 12.1 Hz), 5.47 (1H, d, J ) 8.8
Hz), 7.46 (2H, t, J ) 7.3 Hz), 7.57 (1H, t, J ) 7.2 Hz), 8.02
(2H, d, J ) 7.1 Hz); HRMS calcd for C16H16O7Na 343.0784
(NaM+), found 343.0787 (NaM+).
(1R,2R,3S,4R)-4-O-Acet yl-5-(b en zoyloxym et h yl)-3-O-
(ter t-bu tyl-dim eth ylsilyl)-5-cycloh exen e-1,2,3,4-tetr ol (33).
To a solution of compound 32 (517 mg, 1.0 mmol) in CH2Cl2
(25 mL) was added 2 mL of 50% aqueous TFA. The mixture
was stirred vigorously at room temperature for 6 h and poured
into an aqueous solution of NaHCO3 (10 mL, 5% w/v). The
aqueous phase was extract with CH2Cl2 (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL),
dried (MgSO4), and filtered. Concentration of the filtrate
followed by flash chromatography (Et2O-hexane, 2:1) provided
the title compound 33 (331 mg, 80%) as a white solid with
95% conversion: mp 79-80 °C (Et2O-hexane); Rf ) 0.43
(Et2O-hexane, 3:1); [R]26D -66.7 (c ) 1.5, CHCl3); IR (thin film)
(b) F r om 43. Following the same procedure as for R-en-
doperoxide rearrangement of 37, â-endoperoxide 43 (32 mg,
0.1 mmol) gave a quantitative yield of â-bisepoxide 38 as a
white solid, after flash chromatography (Et2O-hexane, 4:1).
Silyla ted r-Bisep oxid e 39. Following the same procedure
as for 5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II) me-
diated rearrangement of 35, the R-endoperoxide 36 (11 mg,
0.03 mmol) gave R-bisepoxide 39 (11 mg, 100%) as a colorless
oil, after fractionation by flash chromatography (Et2O-hexane,
3450, 1724 cm-1 1H NMR δ 0.16 (6H, s), 0.87 (9H, s), 2.01
;
1:2): Rf ) 0.32 (Et2O-hexane, 1:1); [R]22 -48.1 (c ) 0.8,
(3H, s), 2.68 (1H, d, J ) 11.6 Hz), 2.91 (1H, d, J ) 9.2 Hz),
3.87 (1H, ddd, J ) 2.2, 4.7, 9.2 Hz), 4.08 (1H, t, J ) 2.5 Hz),
4.15 (1H, m), 4.81 (2H, s), 5.45 (1H, d, J ) 3.4 Hz), 6.34 (1H,
d, J ) 4.8 Hz), 7.42 (2H, t, J ) 6.5 Hz), 7.58 (1H, t, J ) 5.9
Hz), 8.06 (2H, d, J ) 7.0 Hz); MS m/z (relative intensity) 437
D
CHCl3); IR (thin film) 1726 cm-1; 1H NMR δ 0.07 (3H, s), 0.09
(3H, s), 0.87 (9H, s), 2.17 (3H, s), 3.25 (1H, d, J ) 4.0 Hz),
3.40 (1H, d, J ) 2.7 Hz), 3.48 (1H, dd, J ) 2.8, 4.0 Hz), 4.22
(2H, m), 4.46 (1H, d, J ) 12.3 Hz), 5.18 (1H, d, J ) 9.8 Hz),

1554 J . Org. Chem., Vol. 63, No. 5, 1998
Shing and Tam
7.47 (2H, t, J ) 7.3 Hz), 7.60 (1H, t, J ) 7.2 Hz), 8.01 (2H, d,
J ) 7.1 Hz); HRMS calcd for C22H30O7SiNa 457.1653 (NaM+),
found 457.1606 (NaM+).
d, J ) 7.3 Hz). The more polar R-endoperoxide 44 was
obtained (2.6 mg, 32%) as a colorless oil: Rf ) 0.33 (EtOAc-
hexane, 1:1); 1H NMR δ 2.06 (3H, s), 3.34 (1H, br s), 3.60 (1H,
br s), 4.57 (1H, d, J ) 12.6 Hz), 4.66 (1H, d, J ) 12.8 Hz), 4.81
(2H, m), 6.43 (1H, d, J ) 8.4 Hz), 6.81 (1H, dd, J ) 6.5, 8.3
Hz),7.45 (2H, t, J ) 7.4 Hz), 7.56 (1H, t, J ) 7.2 Hz), 8.04
(2H, d, J ) 7.1 Hz).
r-Bisep oxid e 40. Following the same procedure as for the
R-endoperoxide rearrangement of 37, R-endoperoxide 44 (21
mg, 0.07 mmol) gave a quantitative yield of R-bisepoxide 40
as a white solid, after flash chromatography (Et2O-hexane,
4:1): mp 131-133 °C; Rf ) 0.50 (EtOAc-hexane, 4:1); [R]22
D
Cycloh exen e Ep oxid e 45. A solution of the R-endoper-
oxide 43 (32 mg, 0.1 mmol) in benzene (10 mL) was added 5
drops of trimethyl phosphite. The reaction was reflux for 12
h and poured into saturated aqueous NH4Cl (10 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL), and
the combined organic extracts were washed with brine (10
mL), dried (MgSO4), and filtered. Concentration of the filtrate
followed by flash chromatography (EtOAc-hexane, 1:2) pro-
vided the oxirane 45 (26 mg, 85%) as a white solid: mp 88-
-47.7 (c ) 0.9, CHCl3); IR (thin film) 3430, 1722 cm-1; 1H NMR
δ 2.08 (3H, s), 2.65 (1H, d, J ) 12.3 Hz), 3.32 (1H, dd, J ) 3.8,
4.9 Hz), 3.59 (1H, dd, J ) 2.7, 3.7 Hz), 3.64 (1H, d, J ) 2.8
Hz), 4.11 (1H, dt, J ) 4.7, 11.0 Hz), 4.26 (1H, d, J ) 12.6 Hz),
4.61 (1H, d, J ) 12.7 Hz), 5.37 (1H, d, J ) 4.5 Hz),7.43 (2H, t,
J ) 7.4 Hz), 7.58 (1H, t, J ) 7.2 Hz), 8.03 (2H, d, J ) 7.1 Hz);
HRMS calcd for C16H16O7Na 343.0784 (NaM+), found 343.0797
(NaM+).
(3R,4R)-4-O-Acet yl-5-(b en zoyloxym et h yl)cycloh exa -
1,5-d ien e-3,4-d iol (41). A solution of diene 12 (100 mg, 0.25
mmol) in CH3CN (10 mL) was added a drop of 48% aqueous
HF. The solution was stirred vigorously at room temperature
for 6 h and poured into a pad of silica gel. Removal of the
solvents under reduced pressure followed by flash chromatog-
raphy (Et2O-hexane, 2:1) afforded the alcohol 41 (64 mg, 80%)
89 °C; Rf ) 0.34 (EtOAc-hexane, 1:1); [R]20 +57.7 (c ) 0.4,
D
1
CHCl3); IR (thin film) 3441, 1725 cm-1; H NMR δ 2.22 (3H,
s), 3.55 (1H, t, J ) 3.3 Hz), 4.36 (1H, d, J ) 12.0 Hz), 4.42
(1H, s), 5.36 (1H, d, J ) 12.0 Hz), 5.97 (2H, m), 7.46 (2H, t, J
) 6.4 Hz), 7.60 (1H, t, J ) 7.1 Hz), 8.03 (2H, d, J ) 7.1 Hz);
HRMS calcd for C16H16O6 305.1025 (MH+), found 305.1027
(MH+).
as a colorless oil: Rf ) 0.31 (Et2O-hexane, 2:1); [R]24 -150
D
Cycloh exen e Ep oxid e 46. Following the same procedure
as for reductive rearrangement of 45, R-endoperoxide 44 (32
mg, 0.1 mmol) gave 84% of 46 as a colorless oil, after
fractionation by flash chromatography (Et2O-hexane, 2:1): Rf
(c ) 0.3, CHCl3); {lit.2 [R]24 -150 (c ) 1.2, CHCl3)}; IR (thin
D
film) 3417, 1728 cm-1; 1H NMR δ 2.06 (3H, s), 2.35 (1H, br s),
4.48 (1H, m), 4.90 (2H, dd, J ) 13.4, 17.4, Hz), 5.73 (1H, dd,
J ) 7.1 Hz), 6.03 (2H, ddd, J ) 3.7, 9.5, 12.5 Hz), 6.22 (1H,
m), 7.44 (2H, t, J ) 6.4 Hz), 7.54 (1H, t, J ) 7.5 Hz), 8.04 (2H,
d, J ) 8.3 Hz).
) 0.40 (EtOAc-hexane, 1:1); [R]20 -104.4 (c ) 0.9, CHCl3);
D
1
IR (thin film) 3520, 1738 cm-1; H NMR δ 2.06 (3H, s), 2.18
(1H, s br), 3.58 (1H, d, J ) 4.0 Hz), 4.06 (1H, dd, J ) 3.8, 6.0
Hz), 4.25 (1H, d, J ) 12.6 Hz), 4.85 (1H, d, J ) 12.6 Hz), 5.62
(1H, d, J ) 2.0 Hz), 6.32 (2H, m), 7.47 (2H, t, J ) 6.4 Hz),
7.59 (1H, t, J ) 7.1 Hz), 8.06 (2H, d, J ) 7.1 Hz); HRMS calcd
for C16H16O6 305.1025 (MH+), found 305.1033 (MH+).
â-En d op er oxid e 43 a n d r-En d op er oxid e 44. Following
the same procedure as for the endoperoxidation of 12, diene
41 (8.2 mg, 0.02 mmol) gave a mixture of â- and R-endoper-
oxides as colorless oils, after fractionation by flash chroma-
tography (Et2O-hexane, 1:1): The less polar â-endoperoxide
43 was obtained (4.0 mg, 48%) as a colorless oil: Rf ) 0.40
(EtOAc-hexane, 1:1); 1H NMR δ 2.21 (3H, s), 3.30 (1H, d, J )
2.4 Hz), 4.08 (1H, s), 4.21 (1H, d, J ) 1.4 Hz), 4.55 (1H, d, J
) 12.2 Hz), 4.64 (1H, d, J ) 12.2 Hz), 4.77 (1H, t, J ) 4.5 Hz),
6.77 (2H, m), 7.47 (2H, m), 7.60 (1H, t, J ) 7.3 Hz), 8.03 (2H,
Ack n ow led gm en t. This research was supported by
the Croucher Foundation.
J O970907O