Generation, stability, dimerization, and Diels-Alder reactions of masked o-benzoquinones. Synthesis of substituted bicyclo[2.2.2]octenones from 2- methoxyphenols

Article abstract of DOI:10.1021/jo9901891

Diels-Alder reactions of labile and readily dimerizing masked o- benzoquinones, i.e., substituted 6,6-dimethoxy-2,4-cyclohexadienones with electron-deficient dienophiles that resulted in the development of an efficient and reliable one-pot method for the

Full text of DOI:10.1021/jo9901891

4102
J . Org. Chem. 1999, 64, 4102-4110
Gen er a tion , Sta bility, Dim er iza tion , a n d Diels-Ald er Rea ction s of
Ma sk ed o-Ben zoqu in on es. Syn th esis of Su bstitu ted
Bicyclo[2.2.2]octen on es fr om 2-Meth oxyp h en ols
Chun-Chen Liao,* Chrong-Shyua Chu, Tsung-Ho Lee, Polisetti Dharma Rao, San Ko,
Ling-Duan Song, and Huey-Chin Shiao
Department of Chemistry, National Tsing Hua University Hsinchu, Taiwan 300
Received February 1, 1999
Diels-Alder reactions of labile and readily dimerizing masked o-benzoquinones, i.e., substituted
6,6-dimethoxy-2,4-cyclohexadienones with electron-deficient dienophiles that resulted in the
development of an efficient and reliable one-pot method for the preparation of highly functionalized
bicyclo[2.2.2]octenones, are described. Oxidation of 2-methoxyphenols 8, 9, 11, 13, and 14 with
(diacetoxy)iodobenzene in methanol afforded the corresponding masked o-benzoquinones 1, 2, 4,
6, and 7, which are not stable enough to be isolated and are found to dimerize under reaction
conditions in a highly regio- and stereoselective manner to provide the Diels-Alder dimers 22, 23,
25, 27, and 28 respectively. On the other hand, masked o-benzoquinones 3 and 5, derived from
phenols 10 and 12, respectively, were found to be quite labile and provided a complex mixture of
products. However, masked o-benzoquinones 1-7, when generated in the presence of dienophiles
such as methyl acrylate, methyl methacrylate, and methyl vinyl ketone, underwent highly regio-
and stereoselective intermolecular Diels-Alder reactions to furnish variously substituted bicyclo-
[2.2.2]octenones 15-21(a -c). While the Diels-Alder reactions of masked o-benzoquinone 5 were
found to be low-yielding, masked o-benzoquinones 1-4, 6, and 7 provided the desired adducts in
good to high yields. Attempts are made to explain the observed regio- and stereoselectivity of these
Diels-Alder reactions in terms of frontier molecular orbital theory.
In tr od u ction
and oxadi-π-methane rearrangement.9 On the other
hand, 2,4-cyclohexadienones themselves are very impor-
tant compounds from both synthetic and biological points
of view.10-12 They were recently identified as a potential
new class of receptor tyrosine kinase inhibitors.11 They
can in principle participate in (i) cycloaddition reac-
tions,7,10 (ii) nucleophilic, electrophilic, and radical addi-
tion reactions,13 and (iii) photochemical reactions.14 De-
spite their vast potential, they are a relatively underutil-
ized class of compounds.
The Diels-Alder reaction has become one of the most
frequently used reactions in organic synthesis since it
provides easy access to a wide variety of cyclic com-
pounds.1-4 The art of utilizing the Diels-Alder reaction
in the synthesis of natural products lies in the design
and preparation of suitable dienes and dienophiles.5 A
large variety of dienes and dienophiles bearing an array
of functionalities have been used to construct different
types of ring structures.6 Nevertheless, Diels-Alder
reaction of 2,4-cyclohexadienones with activated alkenes
has been used as one of the methods for the synthesis of
bicyclo[2.2.2]octenones,7,8 which have wide range of ap-
plications in the synthesis of natural products.5 In
addition, bicyclo[2.2.2]octenones undergo interesting and
useful photochemical reactions, viz., 1,3-acyl migration
Although not extensively, the Diels-Alder chemistry
of cyclohexadienones I-VII (Figure 1) has been studied
and used in the total synthesis of natural products.7,10,15-21
(7) (a) Alder, K.; Flock, F. H.; Lessenich, H. Chem. Ber. 1957, 90,
1709. (b) Metlesics, W.; Wessely, F.; Budzikiewicz, H. Monatsh. Chem.
1958, 89, 102. (c) Yates, P.; Stevens, K. E. Tetrahedron 1981, 37, 4401.
(d) Schultz, A. G.; Dittami, J . P.; Lavieri, F. P.; Salowey, C.; Sundarara-
man, P.; Szymula, M. B. J . Org. Chem. 1984, 49, 4429. (e) Hirao, K.;
Unno, S.; Miura, H.; Yonemitsu, O. Chem. Pharm. Bull. 1977, 25, 3354.
(8) For the preparation of bicyclo[2.2.2]octenones using other meth-
ods, see, for example: (a) Ranganathan, S.; Ranganathan, D.; Me-
hrotra, A. K. Synthesis 1977, 289. (b) Hung, S.-C.; Liao, C.-C.
Tetrahedron Lett. 1991, 32, 4011. (c) Hung, S.-C.; Liao, C.-C. J . Chem.
Soc., Chem. Commun. 1993, 1457. (d) Hung, S.-C.; Liao, C.-C. J . Chin.
Chem. Soc. 1994, 41, 817. (e) Uyehara, T.; Kabasawa, Y.; Kato, T.
Tetrahedron Lett. 1985, 26, 2343. (f) Yates, P.; Burnell, D. J .; Freer,
V. J .; Sawyer, J . F. Can. J . Chem. 1987, 65, 69.
* To whom correspondence should be addressed. Fax: + 886-3-
5711082. E-mail: ccliao@faculty.nthu.edu.tw.
(1) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990.
(2) Advances in Cycloaddition; Curran, D. P., Ed.; J AI Press:
Greenwich, 1990; Vols. 1-3.
(3) For a recent review on intermolecular Diels-Alder reaction,
see: Oppolzer, W. Combining C-C π-bonds. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, Chapter 4.1.
(4) For some reviews on intramolecular Diels-Alder reaction, see:
(a) Roush, W. R. Combining C-C π-bonds. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, Chapter 4.4. (b) Craig, D. Chem. Soc. Rev.
1987, 187. (c) Fallis, A. G. Can. J . Chem. 1984, 62, 183. (d) Ciganek,
E. Org. React. 1984, 32, 1.
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Products Synthesis Through Pericyclic Reactions; ACS Monograph no.
180; American Chemical Society: Washington, DC, 1983. (b) Ho, T.-
L. Carbocyclic Ring Construction in Terpene Synthesis; VCH: Wein-
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Rearrangements in Ground and Excited States; de Mayo, P., Ed.;
Academic Press: New York, 1980; Vol. 3, p 167.
(10) For
a comprehensive review covering the literature on all
aspects of cyclohexadienones through 1965, see: Warring, A. J . In
Advances in Alicyclic Chemistry; Hart, H., Karabatsos, G. J ., Eds.;
Academic Press: New York, 1966; Vol. 1, p 129.
(11) Waldman, H.; Hinterding, K.; Herrlich, P.; Rahmsdorf, H. J .;
Knebel, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 1541.
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(6) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction;
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10.1021/jo9901891 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/04/1999

Synthesis of Substituted Bicyclo[2.2.2]octenones
J . Org. Chem., Vol. 64, No. 11, 1999 4103
F igu r e 2.
Prior to our entry into this area,26 relatively little
Diels-Alder chemistry of masked o-benzoquinones has
been reported.19-21 Deslongchamps and co-workers have
used Diels-Alder reaction of a masked o-benzoquinone
as one of the key steps in their synthesis of ryanodol.20a,b
Andersson reported dimers of some simple MOBs of type
VII and studied Diels-Alder reactions of 5,6,6-trimethoxy-
2,4-cyclohexadienone with dimethyl acetylenedicarboxy-
late and substituted maleic anhydrides.21 For the past
decade or so, we have been interested in exploiting the
synthetic potential of masked o-benzoquinones in general
and their Diels-Alder chemistry in particular.22,23,26-28
In the begining, our efforts were mainly focused on
synthesis of stable MOBs and their photo- and Diels-
Alder chemistry with the emphasis laid on unraveling
their basic nature.26 Spirolactone moiety, which needs
additional synthetic steps and results in mixtures of
diastereomeric products, was employed as the mask in
those studies. Consequently, our attention was shifted
to MOBs VII, which are achiral and easily accessible. It
was soon realized that MOBs VII have a very high
propensity to dimerize. As a result, attempts were made
to trap rather than isolate them. This change in direction
has brought remarkable success, and over the years we
have made a systematic study of Diels-Alder chemistry
of in situ generated unstable MOBs. We herein present
a detailed account of our investigations on the generation,
stability, and dimerization of masked o-benzoquinones
1-7 derived from 2-methoxyphenols 8-14 and their
Diels-Alder reactions with electron-deficient dienophiles
to facilitate the synthesis of various bicyclo[2.2.2]-
octenones 15-21 (Figure 2).28
F igu r e 1. Various types of 2,4-cyclohexadienones.
The use of cyclohexadienones I-IV in a general way is
constrained in that their preparation requires strategic
placement of substituents, which cannot be removed
easily. On the other hand, 2,4-cyclohexadienones of type
V-VII, which may also be called as o-quinone monoac-
etals or masked o-benzoquinones (MOBs), could be ideal
compounds for use in Diels-Alder reactions because the
unavoidable acetal group, being positioned next to a keto
group, could be removed by reduction if not required or
modified into a desired functionality at a latter stage with
relative ease.22,23 However, lack of efficient methods for
their preparation and their high propensity to dimerize
are main deterrents for their use in organic synthesis.24,25
(13) (a) Danishefsky, S. J .; Shair, M. D. J . Org. Chem. 1996, 61, 16.
(b) Coleman, R. S.; Grant, E. B. J . Am. Chem. Soc. 1995, 117, 10889.
(c) Mitchell, A. S.; Russell, R. A. Tetrahedron Lett. 1993, 34, 545. (d)
Banwell, M. G.; Collis, M. P. J . Chem. Soc., Chem. Commun. 1991,
1343. (e) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987,
43, 5095. (f) Gammill, R. B. Tetrahedron Lett. 1985, 26, 1385.
(14) (a) Liao, C.-C.; Wei, C.-P. Tetrahedron Lett. 1991, 32, 2531 (b)
Schaffner, K.; Demuth, M. In Rearrangements in Ground and Excited
States; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 3, p
328 and references therein. (c) Morris, M. R.; Warring, A. J . J . Chem.
Soc. C 1971, 3269. (d) Warring, A. J .; Morris, M. R.; Islam, M. M. J .
Chem. Soc. C 1971, 3274.
(15) (a) Brown, T. L.; Curtin, D. Y.; Fraser, R. R. J . Am. Chem. Soc.
1958, 80, 4339. (b) Miller, B. J . Am. Chem. Soc. 1965, 87, 5115. (c)
Miller, B. J . Org. Chem. 1970, 35, 4262. (d) Bertrand, M.; Tesseire,
P.; Pelerin, G. Tetrahedron Lett. 1980, 21, 2051. (e) Frater, G. Helv.
Chim. Acta 1974, 57, 172. (c) Fukamiya, N.; Kato, M.; Yoshikoshi, A.
J . Chem. Soc., Perkin Trans. 1 1973, 1843.
(16) Schultz, A. G.; Puig, S. J . Org. Chem. 1985, 50, 916.
(17) (a) Singh, V.; Pratap, S. Synlett 1994, 542. (b) Singh, V.; Pratap,
S.; Porinchu, M. Tetrahedron Lett. 1997, 38, 2911.
Resu lts
Oxidation of 2-methoxy-4-methylphenol (8) in metha-
nol using (diacetoxy)iodobenzene (DAIB)23,29 at 0 °C
produced MOB 1 exclusively as shown by 1H NMR
spectrum of the reaction mixture. Attempts to isolate 1
in a pure state resulted in the production of its dimer,
22.25 Instead of isolating 1, an excess (25 equiv) of methyl
acrylate (MA) was added to the oxidation reaction
mixture of 8 and the reaction was allowed to proceed at
0 °C. The reaction was found to be rather sluggish, and
(18) (a) Wessely, F.; Lauterbach-Keil, G.; Schmid, F. Monatsh. Chem.
1950, 81, 811. (b) Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81,
1055 and other papers in this series. (c) Carman, R. M.; Owsia, S.;
Van Dongen, J . M. A. M. Aust. J . Chem. 1987, 40, 333. (d) Singh, V.;
Deota, P. T.; Bedekar, A. V.; J . Chem. Soc., Perkin Trans. 1 1992, 903.
(19) (a) Wessely, F.; Kotlan, J .; Sinwel, F. Monatsh. Chem. 1952,
83, 902. (b) Wessely, F.; Budzikiewicz, H.; Metlesics, W. Monatsh.
Chem. 1959, 90, 121.
(20) (a) Berney, D. J . F.; Deslongchamps, P. Can. J . Chem. 1969,
47, 515. (b) Deslongchamps, P.; Belanger, A.; Berney, D. J . F.;
Borschberg, H.-J .; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama,
H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.;
Maffrand, J .-P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-
Laurent, L.; Saintonge, R.; Soucy, P. Can. J . Chem. 1990, 68, 115 and
127. (c) Sethi, S. P.; Atwal, K. S.; Masini-Bettolo, R. M.; Tsai, T. Y. R.;
Wiesner, K. Can. J . Chem. 1980, 58, 1889. (d) Coleman, R. S.; Grant,
E. B. J . Org. Chem. 1991, 56, 1357.
(26) (a) Liao, C.-C.; Lin, H.-S. J . Chin. Chem. Soc. 1983, 30, 69. (b)
Liao, C.-C.; Lin, H.-S. Proc. Nat. Sci. Council (ROC) 1983, B7, 413. (c)
Hsu, Y.-H.; Kuo, L.-C.; Liao, C.-C.; Lin, H.-S.; Uang, B.-J . J . Chin.
Chem. Soc. 1984, 31, 63. (d) Hsu, Y.-H.; Kuo, L.-C.; Liao, C.-C. J . Chin.
Chem. Soc. 1984, 31, 199. (e) Kuo, L.-C.; Liao, C.-C. J . Chin. Chem.
Soc. 1984, 31, 263. (f) Liao, C.-C.; Lin, H.-S. J . Chin. Chem. Soc. 1986,
33, 73. (g) Liao, C.-C. In Modern Methodology in Organic Synthesis;
Shono, T., Ed.; Kodansha: Tokyo, 1992; 409 and references therein.
(27) (a) Lee, T.-H., Liao, C.-C., Liu, W.-C. Tetrahedron Lett. 1996,
37, 5897. (b) Hsiu, P.-Y.; Liao, C.-C. Chem. Commun. 1997, 1085. (c)
Lai, C.-H.; Lin, S.-Y.; Liao, C.-C. Synlett 1997, 1351. (d) Rao, P. D.;
Chen, C.-H.; Liao, C.-C. Chem. Commun. 1998, 155. (e) Hsu, D.-S.;
Rao, P. D.; Liao, C.-C. Chem. Commun. 1998, 1795. (f) Chen, C.-H.;
Rao, P. D.; Liao, C.-C. J . Am. Chem. Soc. 1998, 120, 13254.
(28) Chu, C.-S. Lee, T.-H., Liao, C.-C. Synlett 1994, 635.
(21) (a) Andersson, G.; Berntsson, P. Acta Chem. Scand. B 1975,
29, 948. (b) Andersson, G. Acta Chem. Scand. B 1976, 30, 64. (c)
Andersson, G. Acta Chem. Scand. B 1976, 30, 403.
(22) Liao, C.-C.; Wei, C.-P. Tetrahedron Lett. 1989, 30, 2255.
(23) Hwang, J .-T., Liao, C.-C. Tetrahedron Lett. 1991, 32, 6583.
(24) In general, the existing methods provide 2,4-cyclohexadienones
I-VI in moderate yields, especially those that rely on Wessely
oxidation, which lacks selectivity and produces mixtures of products.
(25) (a) Vannerberg, N. G.; Brasen, S. Acta Chem. Scand. 1970, 24,
1894. (b) Karlsson, B.; Kierkegaard, P.; Pilotti, A.-M.; Wiehager, A.-
C.; Lindgren, B. O. Acta Chem. Scand. 1973, 27, 1428. (c) Karlsson,
B.; Pilotti, A.-M.; Wiehager, A.-C.; Lindgren, B. O. Acta Chem. Scand.
1973, 27, 2945 and 2955. (d) Kende, A. S.; MacGregor, P. J . Am. Chem.
Soc. 1961, 83, 4197.
(29) (a) Tamura, Y.; Yakura, T.; Harnata, J . I.; Kita, Y. J . Org. Chem.
1987, 52, 3927. (b) Yahura, T.; Tohma, H.; Kikchi, K.; Kita, Y. Synthesis
1989, 126.

4104 J . Org. Chem., Vol. 64, No. 11, 1999
Liao et al.
Sch em e 1
Sch em e 2
Sch em e 3
Ta ble 1. In ter m olecu la r Diels-Ald er Rea ction s of
Ma sk ed o-Ben zoqu in on es 1-7 w ith MA, MMA, a n d MVK
entry
phenol
MOB
dienophile
product
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
8
1
MA
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
21c
88
75
80
85
90
86
89
87
90
74
78
87
45
33
34
76
60
84
86
84
88
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
MA
9
10
11
12
13
14
2
3
4
5
6
7
obtained via oxidation of acetovanillone (10) under
similar conditions was found to be quite reactive and
provided a complex mixture of products but not the dimer
24. However, MOBs 2 and 3 furnished the expected
products 16a -c and 17a -c in excellent yields when MA,
MMA, and MVK were employed as dienophiles (Scheme
1).
Under usual conditions, MOB 4, derived from methyl
syringate (11), reacted smoothly with MA, MMA, and
MVK to furnish adducts 18a -c in good yields. These
cycloadditions of 4 also proceeded with excellent regio-
and stereoselectivity. MOB 4 was found to be comparable
to MOB 2 in Diels-Alder reactivity. However, MOB 4
dimerized quite rapidly to provide the dimer 25 when
generated in the absence of dienophile (Scheme 2). On
the other hand, MOB 5 generated from phenol 12 was
found to be labile and furnished the desired products
19a -c in very low yields in the reactions with MA, MMA,
and MVK under the usual conditions. Dimer 26 was not
discernible from any of the above reactions or from
oxidation of 12 in the absence of dienophile.
MMA
MVK
it produced substantial amounts of the Diels-Alder
dimer 22 with some desired product 15a . It was quite
clear that the concentration of 1 in the reaction mixture
should be reduced to avoid dimerization. To achieve this,
a high dilution technique was employed. To maintain an
appropriate concentration all through the course of
reaction, a syringe pump was employed for the addition
of phenol. The temperature was elevated to room tem-
perature to increase the rate of Diels-Alder reaction.
Accordingly, MOB 1 was generated in the presence of
MA during 8 h by adding a solution of 8 in methanol
using a syringe pump to a mixture of DAIB and MA in
methanol at room temperature. These changes in reac-
tion conditions provided the desired results. No trace of
1
the dimer 22 could be detected in the H NMR spectrum
The cycloaddition reactions of MOB 6, generated from
methyl isovanillate (13), were found to be rather sluggish
when performed at room temperature and furnished a
substantial amount of dimer 27. However, MOB 6 reacted
in a highly regio- and stereoselective manner at reflux
temperature with MA, MMA, and MVK to provide
bicyclo[2.2.2]octenones 20a -c in good yields (Scheme 3).
MOB 6 also exhibited a high propensity to dimerize.
Attempted oxidation of vanillin in the presence of MA
at room temperature resulted in the production of a
of the crude reaction mixture. The reaction furnished a
single Diels-Alder adduct 15a in 74% isolated yield after
column chromatography. These conditions were extended
to other dienophiles such as methyl methacrylate (MMA)
and methyl vinyl ketone (MVK) to afford adducts 15b
and 15c in good yields (Scheme 1, Table 1).
The MOB 2, generated from methyl vanillate (9) via
oxidation with DAIB, was found to be highly reactive,
and in the absence of dienophile it dimerized quite
rapidly to produce dimer 23. On the other hand, MOB 3

Synthesis of Substituted Bicyclo[2.2.2]octenones
J . Org. Chem., Vol. 64, No. 11, 1999 4105
Sch em e 4
indicating rapid fragmentation resulting in the extrusion
of CO. For the majority of these compounds, a satisfactory
elemental analysis could be obtained.
Discu ssion
Gen er a tion a n d Sta bility of MOBs. Oxidation of
2-methoxyphenols in methanol by oxidants such as
periodic acid21 and thallium trinitrate (TTN)32 is known
to produce, among other products, 6,6-dimethoxy-2,4-
cyclohexadienones and the corresponding dimers. In the
initial stages of our studies, MOBs VII were generated
in situ from 2-methoxyphenols by oxidation with TTN
in methanol, and the yields of Diels-Alder reactions of
thus generated MOBs were moderate.22 This could be due
to less stability of MOBs under the reaction conditions.
Meanwhile, oxidation of phenols by organic hypervalent
iodine reagents had come in for use.29 Attracted by the
mildness of this oxidation, we switched over to (diac-
etoxy)iodobenzene (DAIB) and bis(trifluoroacetoxy)iodo-
benzene (BTIB).23,27b These two reagents were found to
be quite efficient. The oxidation had been spontaneous
even at 0 °C (5-10 min), and the yields of MOBs were
quite high as reflected by the yields of Diels-Alder
adducts. Thus generated MOBs, except 5, were found to
be stable enough to undergo dimerization or Diels-Alder
reactions with added dienophiles under the oxidation
reaction conditions. However, due to problem of dimer-
ization or high reactivity, the isolation of these MOBs in
pure form was not possible.
complex reaction mixture. Consequently, the aldehyde
group was protected as an acetal,30 and MOB 7 was
generated in the presense of MA and anhydrous NaHCO3
under the usual conditions. The MOB 7 was found to be
less reactive and quite stable at room temperature in
methanol. The best results were obtained when the MOB
7 was generated by the addition of phenol 14 in one
portion to the mixture of DAIB and MA in methanol and
the reaction was allowed to proceed until the MOB 7
reacted completely. This procedure was extended to MMA
and MVK. The adducts 21a -c were obtained in good
yields (Scheme 4). No trace of dimer 28 was observed in
any of the reactions performed at room temperature. The
stability of 7 has attracted our attention. However,
attempts to isolate it in pure form were unsuccessful.
The observed regioselectivity is in line with literature
precedents.7d,15d,20c,31d However, it was thoroughly exam-
ined in each case using proton-proton decoupling experi-
ments. The structures of all the new compounds were
Dim er iza tion a n d Diels-Ald er Rea ctivity. In the
absence of dienophiles as well as in the presence of less
reactive dienophiles, MOBs readily undergo dimerization
in a highly regio- and stereoselective manner (Schemes
1-4). This is not a regular feature of all types of 2,4-
cyclohexadienones. In fact, many 2,4-cyclohexadienones
of types IV-VI or Schultz’s 2,4-cyclohexadienones II are
stable enough to be isolated in moderate yields and
require relatively harsh conditions to undergo Diels-
Alder reactions with added dienophiles.7d,18-20 Appar-
ently, the dimethoxy acetal group plays some role in
increasing the reactivity as well as the propensity to
dimerize. The reasons for this higher tendency of MOBs
to dimerize could be reduced steric effects and increased
secondary orbital overlap between the diene and un-
shared pair of electrons of the oxygen atom of the
methoxy group of MOB acting as dienophile (Figure
3).33,34
1
determined by their IR, H and 13C NMR, and low- and
high-resolution mass spectral analyses. The assigned
relative configuration of the epimeric carbon C7 in all
these adducts is based on previously confirmed structures
of compounds 16a 22 and 20b.31 The significant feature
1
that could be seen in the H NMR spectra is the W-type
or allylic coupling between the vinylic protons and
corresponding allylic protons on the bridgehead carbons.
In the low-resolution mass spectra recorded in electron
impact mode (12 or 70 eV) the peak corresponding to the
molecular ion (M+) could not be detected in general. Only
the peak corresponding to M+ - 28 could be seen,
However, the substituents present on other carbons of
MOBs also have a profound influence on dimerization.
MOBs 2, 4, and 6 undergo facile dimerization when
compared to MOBs 1 and 7. Expectedly, the parent MOB
29 (Figure 3) was found to dimerize quite readily, making
its intermolecular Diels-Alder reactions with electron-
deficient dienophiles inefficient.27e,35 The MOBs isolated
by us or others thus far are either strategically or highly
(30) Bozell, J . J .; Hames, B. R.; Dimmel, D. R. J . Org. Chem. 1995,
60, 2398.
(31) (a) Compound 20b was stereoselectively transformed into
compound i using oxadi-π-methane rearrangement as one of the key
steps. The structure of i was unambiguously determined by its single-
crystal X-ray diffraction analysis, and the details will be published
elsewhere.31b (b) Chu, C.-S.; Liao, C.-C. Unpublished results. (c) Quite
recently, Yamauchi and co-workers have studied Diels-Alder reactions
of a 2,4-cyclohexadienone with methyl methacrylate, methacrolein, and
methyl propen-2-yl ketone and reported identical regio- and stereose-
lectivities as described herein.31d (d) Katayama, S.; Hiramatsu, S.; Aoe,
K.; Yamauchi, M. J . Chem. Soc., Perkin Trans. 1 1997, 561.
(32) McKillop, A.; Perry, D. H.; Edwards, M.; Antus, S.; Farkas, L.;
Nogradi, M.; Taylor, E. C. J . Org. Chem. 1976, 41, 282.
(33) Auksi, H.; Yates, P. Can. J . Chem. 1981, 59, 2510.
(34) (a) Houk, K. N. Tetrahedron Lett. 1970, 2621. (b) Ginsburg, D.
Tetrahedron 1983, 39, 2095. (c) Fox, M. A.; Cardona, R.; Kiwiet, N. J .
J . Org. Chem. 1987, 52, 1469. (d) Guner, O. F.; Ottenbrite, R. M.;
Shillady, D. D.; Alston, P. V. J . Org. Chem. 1988, 53, 1129. (e)
Loncharich, R. J .; Brown, F. K.; Houk, K. N. J . Org. Chem. 1989, 54,
1129.
(35) Lai, C.-H.; Liao, C.-C. Unpublished results.

4106 J . Org. Chem., Vol. 64, No. 11, 1999
Liao et al.
Ta ble 2. En er gies of F MOs of MOBs 1-7, MA, a n d MVK
Obta in ed by Sem iem p ir ica l P M3 a n d a b In itio RHF /
3-21G* Level Ca lcu la tion s
compd
FMO
PM3
3-21G
1
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
-9.9179
-0.8748
-10.3082
-1.2899
-10.1925
-1.2763
-9.3278
-0.7856
-9.6192
-0.8503
-10.3225
-1.3340
-9.8372
-0.9020
-11.0665
-0.0833
-10.7234
-0.0561
-9.1671
1.9099
-9.5140
1.3586
-9.6321
1.1981
-8.7543
1.6312
-8.5393
2.2056
-9.5289
1.1110
-9.0949
1.7428
2
F igu r e 3. Dimerization of MOB 29. Possible secondary
interactions responsible for higher propensity of MOBs to
dimerize.
3
4
5
6
7
MA
MVK
-10.7733
3.0393
-10.5074
2.7259
results clearly indicate that if the substituent attached
to C4 of MOB is an electron-withdrawing group as in 2,
the reactivity is much higher compared to when the
substituent at C4 is an electron-donating group as in
MOB 1 (Figure 4).
Regio- a n d Ster eoselectivity. These cycloaddition
reactions of MOBs appear to have followed all the ground
rules of Diels-Alder reactions. To explain this high
selectivity in all respects, an attempt was made to
correlate the energies and coefficients of the frontier
molecular orbitals.36 HOMOs and LUMOs of MOBs 1-7,
MA, and MVK were calculated using both semiempirical
(PM3) method and ab initio RHF (3-21G*) procedures.37,38
The geometries were fully optimized by the AM1 semiem-
pirical method39 and used as the starting point for
optimization at PM3 and 3-21G* levels. The energy levels
derived from these calculations are summarized in Table
2.
In the majority of the cases examined, the difference
in the energy gaps (DDE) for the two possible interactions
remained around 0.5 eV. If these small differences are
considered as preference for either interaction, the energy
gaps indicate the preference for normal-electron-demand
interaction, i.e., HOMOdiene/LUMOdienophile in the case of
reactions of MOBs 1, 4, 5, and 7 with dienophiles MA
and MVK, while for the reactions of MOBs 2, 3, and 6
with both the dienophiles inverse-electron-demand inter-
actions are preferred.40 Figure 5 illustrates the FMO
interactions of Diels-Alder reactions of MOBs 1 and 2
with MVK. However, in two cases the predictions made
by the two methods are different (Table 3).
F igu r e 4.
substituted or have very bulky substituents.13,21,26 Based
on experience, it may be concluded that the presence of
electron-withdrawing groups at C4 of MOB increase the
propensity of MOB to dimerize and the substituents that
are electron releasing in nature exert an opposite effect.
The presence of bulky substituents at C4 of MOBs also
reduce their propensity to dimerize (Figure 4).13c
A
similar conclusion was reached by Andersson from his
own observations.21b
To prevent or reduce dimerization, the MOBs were
generated in situ in very low concentrations by a very
slow and regulated addition of phenol to a mixture of
DAIB and an excess of dienophile in methanol. Under
such reaction conditions, the dienophile is present in
large excess (thousands of times) to MOB. As a result,
the accumulation of MOB could be avoided in cases where
the MOBs exhibited sufficient reactivity toward added
dienophiles.
Despite the fact that the MOBs are electron-defficient
dienes, they readily undergo both normal and inverse-
electron-demand Diels-Alder reactions with electron-
deficient dienophiles at room temperature and atmo-
spheric pressure if generated in the presence of dienophiles
(vide infra). However, different MOBs have exhibited
different degrees of reactivity in their cycloaddition
reactions with a given dienophile to produce highly
substituted bicyclo[2.2.2]octenones. In addition, the com-
petition between self-dimerization and Diels-Alder reac-
tion with added dienophiles always exists except in case
of MOB 7. For example, the MOB 2 and 3 exhibited
excellent reactivity in Diels-Alder reactions and pro-
duced only the desired bicyclo[2.2.2]octenones in very
good yields at room temperature. On the other hand,
MOBs 1 and 4-7 were found to be relatively less reactive.
Obviously, these differences in reactivity are a result of
nature, position, and size of the substituents. Although
the relative reactivities are not rigorously assessed, our
The relative magnitudes of HOMO and LUMO coef-
ficients of MOBs 1-7, MA and MVK derived from ab
initio calculations performed at the 3-21G* level are listed
(36) (a) Fukui, K. Acc. Chem. Res. 1971, 4, 57. (b) Houk, K. N. Acc.
Chem. Res. 1975, 8, 361. (c) Alston, P. V.; Ottenbrite, R. M.; Guner, O.
F.; Shillady, D. D. Tetrahedron 1986, 42, 4403.
(37) PM3 calculations were performed using PC Spartan Plus.38a
(a) PC Spartan, v 1.5, Wave Function, Inc., 18401 Von Karman, Suite
370, Irvine, CA 92715.
(38) RHF/3-21G* calculations were performed using PC Spartan
Plus.39a (a) PC Spartan, v 1.5, Wave Function, Inc., 18401 Von Karman,
Suite 370, Irvine, CA 92715.
(39) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.
(40) (a) Fleming, I. Frontier Orbitals and Organic Chemical Reac-
tions; Wiley: New York, 1975. (b) Sauer, J .; Sustmann, R. Angew.
Chem., Int. Ed. Engl. 1980, 19, 779.

Synthesis of Substituted Bicyclo[2.2.2]octenones
J . Org. Chem., Vol. 64, No. 11, 1999 4107
The extremely high stereoselectivity observed in these
cycloaddition reactions clearly indicates overwhelming
endo preference at the transition state. This high endo
preference may be explained by invoking secondary
orbital interactions between the carbonyl group in the
dienophile and C3’s of MOBs. Our calculations clearly
indicate the possibility for such interactions. The ab initio
RHF/3-21G* level calculations provided large coefficients
for C3’s of both HOMOs and LUMOs of MOBs. The large
C3 coefficient could involve in secondary orbital overlap
with large coefficients in the carbonyl group of dieno-
philes and thereby participate in stabilizing the endo
transition state (Figure 6). In fact, on similar lines
regioselectivity can also be explained. However, it is wise
to examine other factors before any conclusion could be
reached. In fact, studies directed at evaluation of solvent
effect and transition-state calculations are in progress
and will form the basis of a future publication.
Con clu sion
F igu r e 5. FMO interactions for the Diels-Alder reactions of
MOBs 1 and 2 with MVK. The values shown on solid lines
are derived by ab initio RHF/3-21G* level calculations, and
those shown on dotted lines are derived by PM3 semiempirical
calculations.
In conclusion, these studies resulted in the develop-
ment of a reliable method for the regio- and stereoselec-
tive preparation of a variety of bicyclo[2.2.2]octenones.
The present methodology makes use of inexpensive
2-methoxyphenols and DAIB for the generation of a
variety of highly reactive 2,4-cyclohexadienones in a
simple and practical manner. Furthermore, these studies
also helped in assessing the nature of this class of 2,4-
cyclohexadienones especially with regard to their stabil-
ity, propensity to dimerize, and Diels-Alder reactivity.
This methodology has already been used as one of the
key steps in the stereoselective synthesis of a variety of
compounds including polysubstituted cyclohexane deriva-
tives,43 cis-decalins,27a bicyclo[4.2.2]decenones,27a tricyclo-
[3.3.0.02,8]octenones,43,44 and bicyclo[4.2.0]octenones44 and
in the total synthesis of a clerodane diterpenic acid45 and
forsythide aglucone dimethyl ester.22
Ta ble 3. En er gy Ga p s (eV): F MO In ter a ction s of MOBs
1-7 w ith MA a n d MVK
energy gaps to MA
energy gaps to MVK
HOMOMOB- HOMOMA- HOMOMOB- HOMOMVK
-
MOB method LUMOMA LUMOMOB LUMOMVK LUMOMOB
1
2
3
4
5
6
7
PM3
3-21G*
PM3
3-21G*
PM3
3-21G*
PM3
3-21G*
PM3
3-21G*
PM3
3-21G*
PM3
3-21G*
9.8617
11.8929
10.2521
12.2399
10.1363
12.3580
9.2717
11.4802
9.5631
11.2652
10.2663
12.2548
9.9786
9.8487
12.4173
9.4335
11.8660
9.4471
11.7055
9.9378
12.1387
9.8731
12.7131
9.3894
11.6184
9.7469
9.8346
12.2064
10.2249
12.5533
10.1092
12.6714
9.2445
11.7936
9.5360
11.5787
10.2392
12.5683
9.9514
10.1917
12.6831
9.7766
12.1319
9.7902
11.9713
10.2809
12.4045
10.2162
12.9789
9.7325
11.8842
10.0990
12.5615
Exp er im en ta l Section
11.9944
12.2957
12.3079
Gen er a l P r oced u r es. Unless stated otherwise, reagents
were obtained from commercial sources and used without
further purification. Methyl acrylate, methyl methacrylate,
and methyl vinyl ketone were distilled from hydroquinone
prior to use. All reactions were performed under a nitrogen
atmosphere in anhydrous solvents, which were dried prior to
use following standard procedures. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm E.
Merck silica gel plates (60F-254) using 7% ethanolic phospho-
molybdic acid as developing agent. The product composition
of each reaction was determined by the 1H NMR (400 MHz)
spectrum of the crude reaction mixture. Standard column
chromatography was performed using 230-400 mesh silica gel
obtained from E. Merck. Melting points are uncorrected. IR
spectra were recorded as films on NaCl plates. 1H and 13C
NMR spectra were recorded at 300 or 400 MHz and 75 or 100
MHz, respectively, in CDCl3, and chemical shifts are reported
in δ (ppm) using solvent resonance as the internal reference.
Mass spectra were recorded by the NSC Instrumentation
Center at Hsinchu, Taiwan. Elemental analyses were per-
formed by the NSC Instrumentation Center at Taichung,
Taiwan.
in Table 4. While in the case of MOBs 1 and 6 the
regioselectivity observed and predicted by calculations
are the same, in other cases the predictions differed from
observed regioselectivity. In fact, in the majority of the
cases the relative magnitudes of C2 and C5 coefficients
of both HOMO and LUMO of MOBs are very close.
Similarly, C1 and C2 coefficients of HOMOs of MA and
MVK are also very close. It is therefore clear that these
calculations based on molecular orbitals of isolated
reactants are just not enough to explain the exclusive
formation of ortho adducts. It is pertinent to mention that
the Diels-Alder reactions of dienes and alkenes termi-
nally substituted with electron-demanding groups could
not be explained in terms of simple FMO theory and no
general solutions for such anamolies are available.
However, Alston invoked secondary orbital interactions
and Houk introduced the schizophrenic behavior of
substituents to explain similar anomalies of regioselec-
tivity.41,42
(43) Lee, T.-H.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1999, in
press.
(44) Song, L.-D. Master Thesis, National Tsing Hua University,
Hsinchu, Taiwan, 1993.
(41) Alston, P. V.; Ottenbrite, R. M.; Shillady, D. D. J . Org. Chem.
1973, 38, 4075 and references therein.
(42) Houk, K. N.; Domelsmith, L. N.; Strozier, R. W.; Patterson, R.
T. J . Am. Chem. Soc. 1978, 100, 6531 and references therein.
(45) Liu, W.-C.; Liao, C.-C. Synlett 1998, 912.

4108 J . Org. Chem., Vol. 64, No. 11, 1999
Ta ble 4. Coefficien ts (Ci) of HOMOs a n d LUMOs of MOBs 1-7, MA, a n d MVKa
Liao et al.
HOMO
C3
LUMO
C3
compd
CO
C1
C2
C4
C5
∆Cib
CO
C1
C2
C4
C5
∆Cib
1
2
3
4
5
6
7
0.090
0.111
0.138
0.069
0.058
0.086
0.103
0.194
0.209
0.012
0.012
0.006
0.002
0.005
0.016
0.014
0.294
0.292
0.239
0.257
0.267
0.231
0.216
0.237
0.253
0.311
0.301
0.172
0.197
0.194
0.247
0.229
0.187
0.188
0.036
0.052
0.211
0.196
0.192
0.158
0.169
0.212
0.202
0.266
0.231
0.234
0.222
0.255
0.258
0.248
0.027
-0.027
-0.032
-0.009
0.040
0.022
-0.005
0.017
0.189
0.156
0.169
0.165
0.195
0.180
0.181
0.192
0.224
0.180
0.142
0.154
0.156
0.193
0.158
0.169
0.286
0.265
0.184
0.155
0.143
0.174
0.207
0.219
0.178
0.197
0.162
0.220
0.176
0.185
0.136
0.180
0.200
0.209
0.237
0.246
0.137
0.145
0.140
0.158
0.154
0.095
0.142
0.181
0.243
0.236
0.230
0.162
0.151
0.195
-0.003
0.089
0.092
0.056
-0.045
-0.068
0.017
-0.089
-0.103
MA
MVK
0.009
a
b
Obtained from 3-21G* calculations and only absolute values are given. ∆Ci ) C5 - C2 for MOBs 1-7 and ∆Ci ) C2 - C1 for MA and
MVK.
1
IR (film) 2936, 1724 cm-1; H NMR (400 MHz, CDCl3) δ 1.25
(s, 3H), 1.74 (dd, J ) 13.6, 2.1 Hz, 1H), l.83 (d, J ) 1.5 Hz,
3H), 2.26 (dd, J ) l3.6, 3.4 Hz, 1H), 2.83 (dd, J ) 3.4, 2.1 Hz,
1H), 3.22 (d, J ) 6.3 Hz, 1H), 3.29 (s, 3H), 3.30 (s, 3H), 3.63
(s, 3H), 5.69 (dd, J ) 6.3, l.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 21.15, 25.42, 31.17, 43.66, 46.62, 49.41, 50.49, 52.34,
56.12, 94.19, 119.40, 145.32, 176.44, 202.49; MS (EI, 12 eV)
m/z (relative intensity) 268 (M+, 1), 240 (M+ - CO, 100); HRMS
(EI) calcd for C14H20O5 (M+) 268.1311, found 268.1310. Anal.
Calcd for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.65; H,
7.51.
(1R *,4S *,7S *)-3,3-Dim e t h oxy-7-e t h a n oyl-5-m e t h yl-
bicyclo[2.2.2]oct-5-en -2-on e (15c). This was prepared from
phenol 8 and methyl vinyl ketone in 80% yield as a colorless
solid: mp 61-62 °C (from ethyl acetate-hexanes); IR (film)
2927, 1724 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.62 (ddd, J )
12.9, 6.6, 2.6 Hz, 1H), 1.79 (d, J ) 1.2 Hz, 3H), 1.99-2.12 (m,
1H), 2.05 (s, 3H), 2.85 (dd, J ) 2.6, 2.3 Hz, 1H), 2.94 (ddd, J
) 8.9, 6.6, 1.7 Hz, 1H), 3.22 (s, 3H), 3.24 (s, 3H), 3.26 (dd, J )
5.7, 1.7 Hz, 1H), 5.55 (dd, J ) 5.7, 1.2 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 20.94, 22.62, 28.18, 43.51, 47.00, 49.16, 49.66,
50.43, 94.11, 117.03, 145.45, 201.21, 205.99; MS (EI, 12 eV)
m/z (relative intensity) 238 (M+, 1), 210 (M+ - CO, 100); HRMS
(EI) calcd for C13H18O4 (M+) 238.1205, found 238.1205. Anal.
Calcd for C13H18O4: C, 65.53; H, 7.61. Found: C, 65.46; H,
7.60.
F igu r e 6. Possible endo transition states of Diels-Alder
reactions of MOBs 1 and 2 with MVK.
Gen er a l P r oced u r e for Diels-Ald er Rea ction s. P r o-
ced u r e A. F or th e Rea ction s of P h en ols 8-13. To a
mixture of DAIB (6 mmol) and a dienophile (125 mmol) in
anhydrous methanol (30 mL) was added a solution of a
2-methoxyphenol (5 mmol) in MeOH (70 mL) during 8 h using
a syringe pump at room temperature (in the case of phenol 6
at reflux) under a nitrogen atmosphere. The stirring was
continued for a further 2 h. Then solvent, excess dienophile,
and other volatile products were stripped off under reduced
pressure. After the 1H NMR spectrum of the residue was
recorded, it was subjected to purification by column chroma-
tography on silica gel using 15-40% ethyl acetate in hexanes
as eluent.
P r oced u r e B. F or th e Rea ction s of Va n illin Der iva tive
14. Unlike in procedure A, the phenol 14 (5 mM) in MeOH
(25 mL) was added in one portion to a mixture of DAIB (6
mM), anhydrous NaHCO3 (15 mM), and dienophile (125 mM)
in MeOH (25 mL), and stirring was continued at room
temperature until MOB 7 disappeared (TLC). Then solvent
and excess dienophile were removed under reduced pressure.
The residue was suspended in ether (50 mL) and washed with
brine. The organic layer was dried and concentrated. After the
1H NMR spectrum of the residue was recorded, it was
subjected to purification by column chromatography on silica
gel using 20% ethyl acetate in hexanes as eluent.
(1R*,4S*,7S*)-3,3-Dimethoxy-7-methoxycarbonyl-5-meth-
ylbicyclo[2.2.2]oct-5-en -2-on e (15a ). This was prepared
from phenol 8 and methyl acrylate in 88% yield as a colorless
solid: mp 67-68 °C (from ethyl acetate-hexanes); IR (film)
2956, 1738 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.70 (ddd, J )
13.3, 6.1, 3.0 Hz, 1H), 1.85 (d, J ) 1.5 Hz, 3H), 2.15 (ddd, J )
13.3, 10.0, 3.0 Hz, 1H), 2.88 (m, 1H), 2.94 (ddd, J ) 10.0, 6.1,
1.8 Hz, 1H), 3.25 (s, 3H), 3.28 (s, 3H), 3.34 (dd, J ) 6.3, 1.8
Hz, 1H), 3.66 (s, 3H), 5.64 (m, 1H); 13C NMR (300 MHz, CDCl3)
δ 21.06, 23.88, 39.00, 43.45, 49.64, 50.45, 52.10, 93.93, 117.40,
145.91, 173.45, 201.00; MS (EI, 12 eV) m/z (relative intensity)
226 (M+ - CO, 100); HRMS (EI) calcd for C13H18O5 (M+)
254.1154, found 254.1154. Anal. Calcd for C13H18O5: C, 61.40;
H, 7.14. Found: C, 61.38; H, 7.14.
(1R*,4S*,7S*)-3,3-Dim eth oxy-5,7-bis(m eth oxycar bon yl)-
bicyclo[2.2.2]oct-5-en -2-on e (16a ). This was prepared from
methyl vanillate (9) and methyl acrylate in 85% yield as a
colorless liquid: IR (film) 2950, 1740, 1730, 1710 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 1.68 (ddd, J ) 13.2, 6.0, 2.9 Hz,
1H), 2.35 (ddd, J ) 13.2, 10.2, 2.9 Hz, 1H), 3.07 (ddd, 10.2,
3.3, 1.9 Hz, 1H), 3.25 (s, 3H), 3.31 (s, 3H), 3.61 (m, 1H), 3.63
(s, 3H), 3.74 (s, 3H), 3.75 (m, 1H), 7.06 (dd, J ) 6.3, 1.9 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 24.81, 38.25, 39.16, 50.05,
50.24, 50.80, 52.00, 52.40, 93.19, 135.32, 138.11, 164.07,
172.77, 199.70; MS (EI, 12 eV) m/z (relative intensity) 270 (M+
- CO, 100); HRMS (EI) calcd for C13H18O6 (M+ - CO)
270.1103, found 270.1105.
(1R*,4S*,7S*)-3,3-Dim eth oxy-5,7-bis(m eth oxycar bon yl)-
7-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (16b). This was pre-
pared from methyl vanillate (9) and methyl methacrylate in
90% yield as a colorless liquid: IR (film) 2975, 1727 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.31 (s, 3H), 1.93 (dd, J ) 18.1, 2.2
Hz, 1H), 2.19 (dd, J ) 18.1, 3.1 Hz, 1H), 3.26 (s, 3H), 3.34 (s,
3H), 3.48 (d, J ) 6.5 Hz, 1H), 3.64 (s, 3H), 3.74 (s, 3H), 3.65-
3.71 (m, 1H), 7.09 (dd, J ) 6.5, 1.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 24.92, 31.58, 38.03, 46.29, 49.32, 49.77, 51.58,
52.21, 56.93, 93.17, 137.27, 137.36, 164.22, 175.67, 200.98; MS
(EI, 20 eV) m/z (relative intensity) 284 (M+ - CO, 70), 252
(8), 225 (100); HRMS calcd for C14H20O6 (M+ - CO) 284.1260,
found 284.1260.
(1R *,4S *,7S *)-3,3-D i m e t h o x y -7-e t h a n o y l-5-m e t h -
oxyca r bon ylbicyclo[2.2.2]oct-5-en -2-on e (16c). This was
prepared from methyl vanillate (9) and methyl vinyl ketone
in 86% yield as a colorless liquid: IR (film) 2947, 1741, 1714,
(1R*,4S*,7S*)-3,3-Dim et h oxy-7-m et h oxyca r b on yl-5,7-
d im eth ylbicyclo[2.2.2]oct-5-en -2-on e (15b). This was pre-
pared from phenol 8 and methyl methacrylate in 75% yield as
a colorless solid: mp 37-38 °C (from ethyl acetate-hexanes);
1
1671 cm-1; H NMR (400 MHz, CDCl3) δ 1.52 (ddd, J ) 13.1,
6.8, 3.0 Hz, 1H), 2.09 (s, 3H), 2.36 (ddd, J ) 13.1, 10.2, 3.0

Synthesis of Substituted Bicyclo[2.2.2]octenones
J . Org. Chem., Vol. 64, No. 11, 1999 4109
Hz, 1H), 3.13 (m, 1H), 3.24 (s, 3H), 3.31 (s, 3H), 3.54 (dd, J )
6.2, 1.3 Hz, 1H), 3.72 (s, 3H), 3.75 (m, 1H), 7.05 (dd, J ) 6.2,
1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.08, 28.12, 38.22,
47.48, 50.04, 50.23, 51.94, 93.33, 135.82, 136.92, 164.05,
200.11, 205.10; MS (EI, 70 eV) m/z (relative intensity) 254 (M+
(1R *,4S *,7S *)-1,3,3-Tr im e t h oxy-7-e t h a n oyl-5-m e t h -
oxyca r bon ylbicyclo[2.2.2]oct-5-en -2-on e (18c). This was
prepared from methyl syringate (11) and methyl vinyl ketone
in 87% yield as a colorless solid: mp 93-94 °C (from ethyl
1
acetate-hexanes); IR (film) 2959, 1757, 1717 cm-1; H NMR
- CO, 9), 252 (8), 43 (100); HRMS calcd for C13H18O5 (M+
-
(400 MHz, CDCl3) δ 1.63 (ddd, J ) 13.0, 6.2, 2.9 Hz, 1H), 2.20
(s, 3H), 2.20-2.28 (m, 1H), 3.23-3.29 (m, 1H), 3.29 (s, 3H),
3.38 (s, 3H), 3.56 (s, 3H), 3.78-3.82 (m, 1H), 3.82 (s, 3H), 7.20
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 25.72, 31.73, 37.71, 49.49,
49.70, 50.01, 51.93, 54.75, 86.62, 92.74, 134.52, 135.24, 163.39,
198.25, 206.32; MS (EI, 12 eV) m/z (relative intensity) 284 (M+
- CO, 48), 43 (100); HRMS (El) calcd for C15H20O7 (M+)
312.1209, found 312.1210. Anal. Calcd for C15H20O7: C, 57.69;
H, 6.45. Found: C, 57.67; H, 6.47.
CO) 254.1154, found 254.1148.
(1R*,4S*,7S*)-3,3-Dim et h oxy-5-et h a n oyl-7-m et h oxy-
ca r bon ylbicyclo[2.2.2]oct-5-en -2-on e (17a ). This was pre-
pared from acetovanillone (10) and methyl acrylate in 89%
yield as a yellowish liquid: IR (film) 2951, 1738 (br), 1673 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.55 (ddd, J ) 13.2, 6.4, 2.8 Hz,
1H), 2.32 (s, 3H), 2.39 (ddd, J ) 13.2, 10.4, 2.8 Hz, 1H), 3.13
(ddd, J ) 10.4, 6.4, 1.8 Hz, 1H), 3.23 (s, 3H), 3.32 (s, 3H), 3.64
(dd, J ) 6.8, 1.8 Hz, 1H), 3.65 (s, 3H), 3.94 (m, 1H), 7.05 (dd,
J ) 6.8, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.65,
24.80, 35.98, 39.19, 50.04, 50.11, 50.70, 52.30, 93.10, 135.53,
146.20, 172.90, 194.10, 199.78; MS (EI, 70 eV) m/z (relative
intensity) 254 (M+ - CO, 74), 195 (100); HRMS calcd for
(1R*,4S*,7S*)-1,3,3-Tr im eth oxy-7-m eth oxyca r bon yl-5-
m eth ylbicyclo[2.2.2]oct-5-en -2-on e (19a ). This was pre-
pared from phenol 12 and methyl acrylate in 45% yield as a
colorless solid: mp 73-74 °C (from ethyl acetate-hexanes);
1
IR (film) 2956, 1741 cm-1; H NMR (300 MHz, CDCl3) δ 1.67
C
13H18O5 (M+ - CO) 254.1154, found 254.1162.
(ddd, J ) 12.9, 6.3, 2.9 Hz, 1H), 1.97 (s, 3H), 2.26 (ddd, J )
12.9, 9.9, 2.9 Hz, 1H), 2.92 (m, 1H), 3.10-3.14 (m, 1H), 3.32
(1R*,4S*,7S*)-3,3-Dim et h oxy-5-et h a n oyl-7-m et h oxy-
(s, 3H), 3.36 (s, 3H), 3.57 (s, 3H), 3.69 (s, 3H), 5.79 (s, 1H); 13
C
ca r bon yl-7-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (17b). This
was prepared from acetovanillone (10) and methyl methacryl-
ate in 87% yield as a yellowish liquid: IR (film) 2953, 1737
(br), 1674 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.33 (s, 3H), 1.96
(dd, J ) 14.0, 2.0 Hz, 1H), 2.06 (dd, J ) 14.0, 3.6 Hz, 1H),
2.29 (s, 3H), 3.21 (s, 3H), 3.34 (s, 3H), 3.50 (d, J ) 6.4 Hz,
1H), 3.65 (s, 3H), 3.85 (m, 1H), 7.05 (dd, J ) 6.4, 2.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 24.65, 25.27, 31.94, 36.27, 46.80,
49.71, 50.04, 52.48, 57.22, 93.31, 137.57, 145.40, 175.63,
194.32, 201.02; MS (EI, 70 eV) m/z (relative intensity) 268 (M+
- CO, 49), 209 (100); HRMS calcd for C14H20O5 (M+ - CO)
268.1311, found 268.1312.
NMR (75 MHz, CDCl3) δ 20.99, 26.62, 42.38, 42.90, 49.62,
50.44, 51.91, 53.92, 84.42, 93.88, 118.77, 143.04, 173.04,
198.84; MS (EI, 12 eV) m/z (relative intensity) 256 (M+ - 28,
18), 209 (100); HRMS (EI) calcd for C14H20O6 (M+) 284.1260,
found 284.1252.
(1R*,4S*,7S*)-1,3,3-Tr im et h oxy-7-m et h oxyca r b on yl-
5,7-d im eth ylbicyclo[2.2.2]oct-5-en -2-on e (19b). This was
prepared from phenol 12 and methyl methacrylate in 33% yield
as a colorless solid: mp 41-42 °C (from ethyl acetate-
hexanes); IR (film) 2957, 1736 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 1.21 (s, 3H), 1.78 (dd, J ) 13.4, 2.9 Hz, 1H), 1.90 (s,
3H), 2.00 (dd, J ) 13.4, 2.9 Hz, 1H), 2.81 (m, 1H), 3.28 (s, 3H),
3.29 (s, 3H), 3.44 (s, 3H), 3.59 (s, 3H), 5.91 (s, 1 H); 13C NMR
(100 MHz, CDCl3) δ 20.40, 21.07, 35.12, 42.89, 49.29, 49.38,
50.29, 51.99, 54.57, 88.19, 93.62, 118.78, 142.15, 174.95,
200.23; MS (EI, 12 eV) m/z (relative intensity) 298 (M+, 1),
270 (M+ - CO, 71), 223 (100); HRMS (EI) calcd for C15H22O6
298.1416, found 298.1429.
(1R*,4S*,7S*)-1,3,3-Tr im et h oxy-7-et h a n oyl-5-m et h yl-
bicyclo[2.2.2]oct-5-en -2-on e (19c). This was prepared from
phenol 12 and methyl vinyl ketone in 34% yield as a colorless
liquid: IR (film) 2952, 1728 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.68 (ddd, J ) 13.1, 6.3, 3.0 Hz, 1H), 1.97 (s, 3H), 2.05 (ddd,
J ) 13.1, 9.6, 3.0 Hz, 1H), 2.21 (s, 3H), 2.92 (m, 1H), 3.18 (dd,
J ) 9.6, 6.3 Hz, 1H), 3.33 (s, 3H), 3.34 (s, 3H), 3.52 (s, 3H);
5.77 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.19, 24.99, 31.81,
43.16, 49.29, 49.57, 50.54, 54.24, 85.35, 93.81, 116.88, 143.73,
199.66, 207.73; MS (EI, 12 eV) m/z (relative intensity) 240 (M+
- 28, 41), 193 (100); HRMS (EI) calcd for C13H20O4 (M+ - CO)
240.1362, found 240.1369.
(1R*,4S*,7S*)-3,3-Dim eth oxy-6,7-bis(m eth oxycar bon yl)-
bicyclo[2.2.2]oct-5-en -2-on e (20a ). This was prepared from
methyl isovanillate (13) and methyl acrylate in 76% yield as
a colorless liquid: IR (film) 2953, 1732 (br) cm-1; 1H NMR (400
MHz, CDCl3) δ 1.74 (ddd, J ) 13.2, 5.6, 2.8 Hz, 1H), 2.25 (ddd,
J ) 13.2, 10.0, 2.8 Hz, 1H), 3.07 (ddd, J ) 10.0, 5.6, 2.0 Hz,
1H), 3.27 (s, 3H), 3.32 (s, 3H), 3.32 (m, 1H), 3.63 (s, 3H), 3.74
(s, 3H), 4.05 (apparent t, J ) 2.0 Hz, 1H), 7.36 (dd, J ) 6.8,
2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 23.41, 38.60, 39.22,
49.17, 49.64, 50.37, 51.90, 52.23, 93.20, 129.48, 143.43, 163.69,
172.61, 199.56; MS (EI, 70 eV) m/z (relative intensity) 270 (M+
- 28, 100); HRMS (EI) calcd for C14H18O7 (M+) 298.1053, found
298.1045.
(1R*,4S*,7S*)-3,3-Dim eth oxy-5,7-dieth an oylbicyclo[2.2.2]-
oct-5-en -2-on e (17c). This was prepared from acetovanillone
(10) and methyl vinyl ketone in 90% yield as a yellowish
1
liquid: IR (film) 2947, 1741, 1714, 1671 cm-1; H NMR (400
MHz, CDCl3) δ 1.36 (ddd, J ) 13.2, 6.8, 2.8 Hz, 1H), 2.11 (s,
3H), 2.29 (s, 3H), 2.42 (ddd, J ) 13.2, 10.4, 2.8 Hz, 1H), 3.19
(m, 1H), 3.22 (s, 3H), 3.33 (s, 3H), 3.56 (dd, J ) 6.8, 1.6 Hz,
1H), 3.94 (m, 1H), 7.05 (dd, J ) 6.8, 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 24.14, 24.54, 28.08, 35.91, 47.60, 50.08,
93.24, 136.48, 144.96, 194.14, 200.33, 205.46; MS (EI, 70 eV)
m/z (relative intensity) 238 (M+ - CO, 13), 195 (100); HRMS
calcd for C13H18O4 (M+ - CO) 238.1205, found 238.1202.
(1R *,4S *,7S *)-1,3,3-T r im e t h o x y -5,7-b is (m e t h o x y -
ca r bon yl)bicyclo[2.2.2]oct-5-en -2-on e (18a ). This was pre-
pared from methyl syringate (11) and methyl acrylate in 74%
yield as a colorless solid: mp 124-125 °C (from ethyl acetate-
hexanes); IR (film) 2961, 1734 cm-1 1H NMR (400 MHz,
;
CDC13) δ 1.65 (ddd, J ) 13.0, 6.3, 2.9 Hz, 1H), 2.43 (ddd, J )
13.0, 10.1, 2.9 Hz, 1H), 3.17 (ddd, J ) 10.1, 6.3, 1.2 Hz, 1H),
3.32 (s, 3H), 3.37 (s, 3H), 3.61 (s, 3H), 3.69 (s, 3H), 3.79 (m,
1H), 3.83 (s, 3H), 7.22 (d, J ) 1.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 27.17, 37.60, 43.27, 49.89, 50.02, 51.98, 52.07, 54.42,
85.71, 92.94, 135.06, 136.12, 163.54, 172.28, 197.84; MS (EI,
12 eV) m/z (relative intensity) 300 (M+ - CO, 83), 285 (100);
HRMS (EI) calcd for C14H20O7 (M+ - CO) 300.1209, found
300.1203. Anal. Calcd for C15H20O8: C, 54.87; H, 6.14. Found:
C, 54.88; H, 6.15.
(1R*,4S*,7S*)-1,3,3-Tr im eth oxy-5,7-bis(m eth oxyca r bo-
n yl)-7-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (18b). This was
prepared from methyl syringate (11) and methyl methacrylate
in 78% yield as a colorless solid: mp 86-87 °C (from ethyl
acetate-hexanes); IR (film) 2966, 1731 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.30 (s, 3H), 1.95-2.05 (m, 2H), 3.31 (s, 3H),
3.40 (s, 3H), 3.58 (s, 3H), 3.66 (s, 3H), 3.73 (dd, J ) 2.7, 2.0
Hz, 1H), 3.83 (s, 3H), 7.43 (d, J ) 2.0 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 20.28, 35.86, 37.57, 49.65, 49.92, 50.14, 52.04,
52.32, 55.20, 89.45, 92.75, 134.02, 137.15, 163.85, 174.26,
199.08; MS (EI, 12 eV) m/z (relative intensity) 314 (M+ - CO,
71), 299 (100); HRMS (EI) calcd for C15H22O7 (M+ - CO)
314.1366, found 314.1367. Anal. Calcd for C16H22O8: C, 56.l3;
H, 6.48. Found: C, 56.11; H, 6.49.
(1R*,4S*,7S*)-3,3-Dim eth oxy-6,7-bis(m eth oxycar bon yl)-
7-m eth ylbicyclo[2.2.2]oct-5-en -2-on e (20b). This was pre-
pared from methyl isovanillate (13) and methyl methacrylate
in 60% yield as a colorless liquid: IR (film) 2960, 1740, 1730,
1720 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H), 1.83 (dd,
J ) 13.9, 2.2 Hz, 1H), 2.27 (dd, J ) 13.9, 3.6 Hz, 1H), 3.25 (m,
1H), 3.26 (s, 3H), 3.32 (s, 3H), 3.58 (s, 3H), 3.72 (s, 3H), 3.87
(d, J ) 1.5 Hz, 1H), 7.27 (dd, J ) 8.7, 1.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 24.94, 31.12, 39.51, 46.19, 49.56, 50.45,

4110 J . Org. Chem., Vol. 64, No. 11, 1999
Liao et al.
51.98, 52.40, 55.56, 93.61, 131.70, 143.37, 163.80, 175.49,
200.60; MS (EI, 12 eV) m/z (relative intensity) 284 (M+ - CO,
100).
98.27, 122.01, 126.20, 142.54, 152.04, 193.13, 201.68; MS (EI,
70 eV) m/z (relative intensity) 336 (M+, 2), 308 (100); HRMS
(EI) calcd for C18H24O6 (M+) 336.1573, found 336.1577.
Dim er 23. This was obtained in 85% yield during attempted
isolation of MOB 2, which was generated by adding DAIB (1.1
mM) to a solution of phenol 9 in MeOH (10 mL) at room
temperature: mp 129-131 °C (from ethyl acetate-hexanes);
IR (film) 2952, 1735, 1719 cm-1; 1H NMR (400 MHz, CDCl3) δ
3.03 (s, 3H), 3.24 (s, 3H), 3.40 (s, 3H), 3.46 (s, 3H), 3.47 (d, J
) 6.8 Hz, 1H), 3.75 (s, 3H), 3.77 (m, 1H), 3.80 (s, 3H), 4.02 (m,
1H), 6.00 (d, J ) 10.4 Hz, 1H), 6.55 (dd, J ) 10.4, 1.2 Hz, 1H),
6.85 (dd, J ) 6.8, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
39.95, 42.97, 48.55, 49.31, 49.97, 50.99, 52.23, 53.43, 54.74,
57.44, 93.75, 97.39, 128.50, 136.00, 137.13, 143.80, 163.14,
171.44, 192.50, 198.36; MS (EI, 70 eV) m/z (relative intensity)
409 (M+ - CH3, 11), 396 (M+ - CO, 57), 59 (100); HRMS (EI)
calcd for C20H24O10 (M+) 424.1370, found 424.1378.
(1R*,4S*,7S*)-3,3-Dim et h oxy-7-et h a n oyl-6-m et h oxy-
ca r bon ylbicyclo[2.2.2]oct-5-en -2-on e (20c). This was pre-
pared from methyl isovanillate (13) and methyl vinyl ketone
in 84% yield as a colorless solid: mp 69-70 °C (from ethyl
acetate-hexanes); mp 69-70 °C; IR (film) 2950, 1740, 1730,
1
1720 cm-1; H NMR (400 MHz, CDCl3) δ 1.85 (ddd, J ) 13.3,
5.5, 3.0 Hz, 1H), 2.03 (ddd, J ) 13.3, 9.5, 2.7 Hz, 1H), 2.19 (s,
3H), 3.11 (ddd, J ) 9.5, 5.5, 2.0 Hz, 1H), 3.27 (s, 3H), 3.33 (m,
1H), 3.36 (s, 3H), 3.72 (s, 3H), 4.06 (dd, J ) 2.0, 1.7 Hz, 1H),
7.31 (dd, J ) 7.1, 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
21.25, 28.32, 39.46, 46.68, 49.04, 49.73, 50.60, 52.08, 93.58,
128.77, 143.61, 163.85, 200.00, 205.01; MS (EI, 70 eV) m/z
(relative intensity) 254 (M+ - CO); HRMS (EI) calcd for
C
14H18O6 (M+) 282.1103, found 282.1087. Anal. Calcd for
C14H18O6: C, 59.57; H, 6.43. Found: C, 59.57; H, 6.43.
(1R*,4S*,7S*)-3,3-Dim eth oxy-7-m eth oxycar bon yl-5-(2,5-
d ioxa cyclop en tyl)bicyclo[2.2.2]oct-5-en -2-on e (21a ). This
was prepared from phenol 14 and methyl acrylate in 86% yield
as a colorless solid: reaction time 60 h; mp 121-123 °C (from
Dim er 25. This was obtained in 78% yield during attempted
isolation of MOB 4, which was generated by adding DAIB (1.1
mM) to a solution of phenol 11 in MeOH (10 mL) at room
temperature: mp 153-154 °C (from ethyl acetate-hexanes);
IR (film) 1726 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.05 (s, 3H),
3.26 (s, 3H), 3.39 (s, 3H), 3.58-3.59 (m, 6H), 3.66 (s, 3H), 3.72
(s, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 3.85 (s, 1H), 5.73 (s, 1H),
6.99 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 38.94, 44.80, 48.64,
49.12, 50.43, 51.28, 52.51, 53.29, 55.63, 55.89, 58.25, 92.02,
92.94, 97.79, 109.77, 134.48, 138.14, 151.25, 162.78, 172.18,
187.93, 197.89; MS (EI, 70 eV) m/z (relative intensity) 456 (M+
- 28, 53); HRMS (EI) calcd for C22H28O12 (M+) 484.1581, found
484.1577.
1
ethyl acetate-hexanes); IR (film) 2955, 1740, 1730 cm-1; H
NMR (300 MHz, CDCl3) δ 1.73 (ddd, J ) 13.1, 6.1, 2.9 Hz,
1H), 2.33 (ddd, J ) 13.1, 10.0, 3.5 Hz, 1H), 3.06 (ddd, J ) 10.0,
6.1, 2.0 Hz, 1H), 3.27 (dd, J ) 3.5, 2.9 Hz, 1H), 3.33 (s, 3H),
3.34 (s, 3H), 3.55 (dd, J ) 6.5, 2.0 Hz, 1H), 3.68 (s, 3H), 3.90-
4.10 (m, 4H), 5.43 (s, 1H), 6.19 (d, J ) 6.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 25.24, 38.17, 39.17, 49.76, 49.96, 52.22,
64.75, 64.83, 93.56, 102.01, 122.80, 144.95, 173.14, 200.44; MS
(EI, 70 eV) m/z (relative intensity) 284 (M+ - CO, 30), 253
(100); HRMS (EI) calcd for C15H20O7 (M+) 312.1209, found
312.1208. Anal. Calcd for C15H20O7: C, 57.69, H, 6.45. Found:
C, 57.71, H, 6.41.
Dim er 27. This was obtained in 82% yield during attempted
isolation of MOB 6, which was generated by adding DAIB (1.1
mM) to a solution of phenol 13 (1 mM) in MeOH (10 mL) at
room temperature: mp 104-106 °C (from ethyl acetate-
(1R *,4S *,7S *)-3,3-Dim e t h oxy-7-m e t h oxyca r b on yl-7-
m eth yl-5-(2,5-d ioxa cyclop en tyl)bicyclo[2.2.2]oct-5-en -2-
on e (21b). This was prepared from phenol 14 and methyl
methacrylate in 84% yield as a colorless solid: reaction time
72 h; mp 97-98 °C (from ethyl acetate-hexanes); IR (film)
hexanes); IR (film) 2955, 1725 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 2.92 (s, 3H), 3.08 (s, 3H), 3.17 (dd, J ) 7.0, 1.5 Hz,
1H), 3.22 (dd, J ) 6.0, 3.1 Hz, 1H), 3.28 (s, 3H), 3.33 (s, 3H),
3.53 (s, 3H), 3.70 (m, 1H), 3.74 (s, 3H), 3.83 (m, 1H), 6.61 (d,
J ) 1.0 Hz, 1H), 6.94 (dd, J ) 6.8, 1.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 38.00, 38.06, 40.72, 48.92, 49.72, 50.10, 50.38,
51.41, 51.92, 52.64, 94.13, 98.33, 132.09, 132.54, 140.41,
144.18, 163.12, 164.61, 193.63, 200.10; MS (EI, 70 eV) m/z
(relative intensity) 424 (M+, 11), 396 (100); HRMS (EI) calcd
for C20H24O10 (M+) 424.1370, found 424.1386.
Dim er 28. This was obtained in 69% yield during attempted
isolation of MOB 7, which was generated by adding DAIB (1.1
mM) to a solution of phenol 14 (1 mM) in MeOH (10 mL) at
room temperature: IR (film) 2987, 1737, 1706 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.04 (s, 3H), 3.15 (t, J ) 1.8 Hz, 1H), 3.27
(s, 3H), 3.32 (d, J ) 6.8 Hz, 1H), 3.38 (s, 3H), 3.39 (s, 3H),
3.58 (t, J ) 1.2 Hz, 1H), 3.78-3.92 (m, 7H), 4.11-4.15 (m, 1H),
5.21 (d, J ) 0.8 Hz, 1H), 5.23 (s, 1H), 5.99 (ddd, J ) 7.1, 2.1,
1.1 Hz, 1H), 6.02 (d, J ) 10.4 Hz, 1H), 6.35 (dd, J ) 10.4, 1.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 39.84, 41.85, 48.16,
48.42, 49.77, 51.16, 51.56, 53.70, 64.19, 64.55, 64.99, 66.06,
94.49, 97.46, 101.35, 104.76, 125.43, 129.22, 142.91, 146.73,
191.94, 199.12; MS (EI, 70 eV) m/z (relative intensity) 421 (M+
- OMe, 13), 350 (100); HRMS (EI) calcd for C22H28O10 (M+)
452.1683, found 452.1691.
1
2975, 1725 cm-1; H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H),
1.89 (dd, J ) 13.6, 2.8 Hz, 1H), 2.27 (dd, J ) 13.6, 3.6 Hz,
1H), 3.20 (m, J ) 3.6, 2.8, 1.6 Hz, 1H), 3.34 (s, 3H), 3.35 (s,
3H), 3.40 (d, J ) 6.8 Hz, 1H), 3.67 (s, 3H), 3.90-4.00 (m, 4H),
5.41 (d, J ) 0.8 Hz, 1H), 6.22 (ddd, J ) 6.8, 1.6, 0.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 25.04, 32.07, 38.19, 46.60, 49.37,
49.70, 52.20, 56.06, 64.45, 64.58, 93.55, 101.83, 124.40, 144.19,
175.75, 201.52; MS (EI, 70 eV) m/z (relative intensity) 298 (M+
- CO, 75), 267 (100); HRMS (EI) calcd for C16H22O7 (M+)
326.1366, found 326.1360. Anal. Calcd for C16H22O7: C, 58.89,
H, 6.79. Found: C, 58.84, H, 6.73.
(1R*,4S*,7S*)-7-E t h a n oyl-3,3-d im et h oxy-5-(2,5-d ioxa -
cyclop en tyl)bicyclo[2.2.2]oct-5-en -2-on e (21c). This was
prepared from phenol 14 and methyl vinyl ketone in 88% yield
as a colorless solid: reaction time 20 h; mp 104-105 °C (from
1
ethyl acetate-hexanes); IR (film) 2975, 1738 cm-1; H NMR
(400 MHz, CDCl3) δ 1.61 (ddd, J ) 12.8, 6.4, 3.2 Hz, 1H), 2.12
(s, 3H), 2.27 (ddd, J ) 12.8, 9.6, 3.2 Hz, 1H), 3.07 (ddd, J )
9.6, 6.4, 2.0 Hz, 1H), 3.26 (m, 1H), 3.32 (s, 3H), 3.33 (s, 3H),
3.47 (dd, J ) 6.4, 2.0 Hz, 1H), 3.80-4.00 (m, 4H), 5.37 (d, J )
0.8 Hz, 1H), 6.16 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 24.31,
28.22, 38.13, 47.26, 49.16, 49.93, 64.70, 64.82, 93.71, 101.99,
123.01, 144.65, 200.77, 205.56; MS (EI, 70 eV) m/z (relative
intensity) 281 (M+ - CH3, 5), 73 (100); HRMS (EI) calcd for
Ack n ow led gm en t. We thank the National Science
Council (NSC) of the Republic of China for financial
support of our research. P.D.R. thanks NSC for post-
doctoral fellowship.
C
C
15H20O6 (M+) 296.1260, found 296.1180. Anal. Calcd for
15H20O6: C, 60.80, H, 6.80. Found: C, 60.83, H, 6.84.
Dim er 22. This was obtained in 72% yield during attempted
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and DEPT spectra of compounds 15-21(a -c). This material
is available free of charge via the Internet at http://pubs.acs.org.
isolation of MOB 1, which was generated by adding DAIB (1.1
mM) to a solution of phenol 8 in MeOH (10 mL) at room
temperature:21a 13C NMR (75 MHz, CDCl3) δ 20.94, 26.00,
44.25, 44.92, 44.99, 48.25, 49.59, 49.88, 50.14, 59.30, 94.54,
J O9901891