Domino retro Diels-Alder/Diels-Alder reaction: An efficient protocol for the synthesis of highly functionalized bicyclo[2.2.2]octenones and bicyclo[2.2.2]octadienones

Article abstract of DOI:10.1039/b602928k

A novel and convenient approach, the domino retro Diels-Alder/Diels-Alder reaction sequence for highly stereo- and regioselective synthesis of various bicyclo[2.2.2]octenone and bicyclo[2.2.2]octadienone derivatives is presented. Thus, the masked o-benzoquinones (MOBs) 2a-e generated by the pyrolysis of the respective dimers 3a-e participated in this novel synthetic strategy with a variety of olefinic and acetylenic dienophiles at 220 °C to provide the title compounds in good to excellent yields. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602928k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Domino retro Diels–Alder/Diels–Alder reaction: an efficient protocol for the
synthesis of highly functionalized bicyclo[2.2.2]octenones and
bicyclo[2.2.2]octadienones
Santhosh Kumar Chittimalla, Hui-Yi Shiao and Chun-Chen Liao*
Received 27th February 2006, Accepted 27th March 2006
First published as an Advance Article on the web 4th May 2006
DOI: 10.1039/b602928k
A novel and convenient approach, the domino retro Diels–Alder/Diels–Alder reaction sequence for
highly stereo- and regioselective synthesis of various bicyclo[2.2.2]octenone and
bicyclo[2.2.2]octadienone derivatives is presented. Thus, the masked o-benzoquinones (MOBs) 2a–e
generated by the pyrolysis of the respective dimers 3a–e participated in this novel synthetic strategy with
a variety of olefinic and acetylenic dienophiles at 220 ◦C to provide the title compounds in good to
excellent yields.
are extensively studied.11 MOBs are highly reactive and are known
Introduction
for their facile dimerization.12 However, the bicyclo[2.2.2]octenone
The Diels–Alder (DA) reaction is clearly one of the most important
derivatives are provided by the in situ generated MOBs when
trapped with various dienophiles.12–14 The synthetic potential of
these functionally rich bridged cycloadducts as valuable starting
materials was demonstrated on several instances by using them
as key synthons in the total synthesis of various structurally
complex natural products.11 In the course of our extensive inves-
tigations on the DA reactions of MOBs, we found MOBs derived
from guaiacol, 5-methyl- and 6-methyl-2-methoxyphenols and 5-
carbomethoxy-2-methoxyphenol produced the cycloadducts in
low yields along with a considerable amount of dimers.12–14 To
circumvent this problem, we have developed a detour method by
introducing an easily removable bromo substitution at C-4 of these
2-methoxyphenols. Though the overall yields of the DA adducts
are better by this method, it consists of three synthetic operations14
(sequential bromination of 2-methoxyphenol, oxidation and cy-
cloaddition, and debromination). In the context of minimizing the
number of steps involved in this route and in the view to improve
the yield of the cycloadducts, an alternative method, the domino
rDA/DA strategy, is sought for the synthesis of these bicyclic
compounds.15 We present herein a full account of our investiga-
tions on this novel and convenient approach for highly stereo-
and regioselective synthesis of various bicyclo[2.2.2]octenone and
bicyclo[2.2.2]octadienone derivatives, employing the dimers 3a–e
as starting compounds.
and widely used of all processes in organic synthesis. With
the potential of forming carbon–carbon, carbon–heteroatom
and heteroatom–heteroatom bonds, the reaction is a versatile
synthetic tool for constructing simple and complex molecules.1,2
Aside from the DA reaction, the retro Diels–Alder (rDA) is an
important part of the armory of the synthetic chemist seeking
to make alkenes or 1,3-dienes.3,4 The cycloreversion occurs when
the diene and/or dienophile are particularly stable molecules
(i.e. formation of an aromatic ring, nitrogen, carbon dioxide,
acetylene, ethylene, nitriles, etc.) or when one of them can be
easily removed or consumed in a subsequent reaction. Retro
DA followed by a DA reaction is one of the examples of a
domino reaction. In recent years there has been a great deal of
interest in the exploration of new domino reactions due to their
various advantages such as formation of several bonds in one
operation and obviating the need of isolating the intermediates and
changing the reaction conditions.5 Furthermore, domino reactions
proved to be economically and ecologically favorable because
of the minimization of solvents, reagents, adsorbents and labor.
Domino rDA/DA reactions, while finding limited application
compared to simple rDA processes, have been incorporated into
numerous synthetic sequences. Recent examples where a domino
rDA/DA process was utilized as one of the key steps include the
taxane skeleton,6 the DCB carbon framework of phorbol,7 and a
clever and efficient total synthesis of pseudoptabersonine.8 Highly
reactive selenoaldehydes were regenerated by the rDA process
and trapped with 2-methoxyfuran via a DA reaction to give new
selenium-containing heterocycles which thereby formed penta-2,4-
dienoates in high yields with deposition of elemental selenium.9 A
novel [1,3]benzoxazino[2,3-b][1,3]benzoxazine was also prepared
by a domino cascade of tandem rDA/DA transformation.10
Recently, the DA reactions of 6,6-dialkoxycyclohexa-2,4-
dienones, generically known as masked o-benzoquinones (MOBs),
Results and discussion
Dimers 3a–e12,14b were synthesized in excellent yields by self-
dimerization of two MOBs via the DA reaction of a dienophilic
MOB and a dienic MOB when 2-methoxyphenols 1a–e in
methanol were treated with diacetoxyiodobenzene (DAIB) a
hypervalent iodine reagent as oxidizing agent (Scheme 1).
Our previous investigations on DA reactions of MOBs revealed
that 6,6-dimethoxycyclohexa-2,4-dienone (MOB 2a) is the most
unstable intermediate towards self-dimerization, leading to low
yields of desired DA adducts with concomitant formation of
dimer 3a.12,13 At the outset, dimer 3a was of interest to probe
Department of Chemistry, National Tsing Hua University, Hsinchu, Tai-
wan. E-mail: ccliao@mx.nthu.edu.tw; Fax: +886-3-5728123; Tel: +886-3-
5720874
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would be less. Subsequently 5 eq. of dienophiles 4 and 8 were
used in the reaction. To our surprise, DA adducts 18aN +
18aX (83% for dienophile 4); 22aN + 22aX (85% for dienophile
8) were produced in very good yields and easily purified by
column chromatography but the stereoisomers formed could
not be separated (entry 1 and 5 of Table 2). Though the present
strategy gave inseparable mixture of stereoisomers, it became
clear that both the electron-rich and electron-poor dienophiles
are compatible for this reaction (Scheme 2).
Scheme 1 Preparation of the dimers 3a–e.
Table 1 Standardization of domino rDA/DA reaction condition with
N-phenylmaleimide (9)
Yield (%)
Entrya
Temperature/◦C
Time/h
23a
Recovered 3a
Scheme 2 Domino rDA/DA approach for the synthesis of bicy-
clo[2.2.2]octenones and bicyclo[2.2.2]octadienones.
1
2
3
4
5
150
180
200
220
250
24
24
8
2
2
—
25
35
90
88
85
70
60
—
—
Recent studies on inverse electron-demand DA reactions,
dienophiles benzyl vinyl ether (6), vinyl phenyl sulfide (7) and
dihydrofuran (12) gave lower yields of cycloadducts with MOB 2a,
along with substantial amounts of dimer 3a.13 We envisaged the
possibility of using the present protocol with these dienophiles.
The dienophiles 6, 7 and 12 could afford the DA adducts in
81–87% total yields (entries 3, 4 and 13 of Table 2) with 8% of
stereoisomers 20aX and 21aX in the cases of dienophiles 6 and 7,
respectively. It is interesting to note entry 15 of Table 2; dimer 3a
and dicyclopentadiene (13) provided the DA adduct 27a in 81%
yield via the DA reaction of their in situ generated monomers
(MOB 2a and cyclopentadiene).
At this stage, we decided to apply this strategy to the dienophiles
cyclopentene (10) and 2,4-cyclohexadiene (11) which failed to
undergo DA reaction with MOB 2a in previous methods.17
Although a greater number of equivalents of dienophile 10 had to
be used, DA adduct 24a was achieved in considerable yield (35%,
entry 10 of Table 2). Dienophile 11 did not give the expected
product, instead DA adduct 25 was obtained in acceptable yield
(Fig. 2 and entry 10 of Table 2). The diagnostic analytical data
shown in Fig. 2 suggest the formation of compound 25. For an
externally added conjugated diene there are two possible reaction
pathways; (i) MOB can act as a diene while the added conjugated
diene acts as a dienophile or (ii) when added conjugated diene acts
as a diene, MOB acts as a dienophile.
a 5 equivalents of dienophile (with respect to the MOB generated) were
used.
the proposed reaction. We initiated our study by selecting N-
phenylmaleimide (NPM, 9) as the dienophile, an excellent trapping
agent in rDA reactions,3 to optimize the reaction conditions. After
much experimentation, entry 4 of Table 1 was found to be the most
suitable conditions for the success of this process. Accordingly,
MOB 2a generated in situ by the pyrolysis of dimer 3a in anhydrous
mesitylene in the presence of dienophile 9 in a sealed tube at 220 ◦C
furnished the DA adduct 23a in 90% yield. At this point it should
be noted that 23a could be attained in 45% yield following method
A (see the Experimental section) in addition also led to 48% of
dimer 3a.16 The reaction was very slow at lower temperatures and
large amounts of starting material remained unchanged even after
longer reaction times (Table 1). The in situ generated MOB has
two competing reactions, DA dimerization and formation of the
expected DA adduct. At low temperatures it appears that the rate
of DA dimerization is higher compared to the rate of DA reaction
between MOB and the added dienophile and the pre-equilibrium
of MOB dimer and MOB is slow.
The dramatic increase in the yield of 23a encouraged us to
apply this strategy to dienophiles, methyl acrylate (4, 25 eq.) and
styrene (8, 25 eq.) separately. Polymerization of these dienophiles
took place, making the purification of formed DA adducts from
the reaction mixtures difficult. At this instant it was predicted
that if lower molar ratios of these dienophiles are used, the
reaction might not be complete but purification of the products
formed should become easy as the amount of polymer formed
Our earlier reports on the DA reactions of MOBs with cyclopen-
tadiene gave a mixture of adducts (following both the reaction
pathways) in different ratios, depending on the substitution of
MOB.18 But at higher temperatures a more stable bicyclo[2.2.2]
system was obtained as a single product after Cope rearrangement
of the initially formed side product.18 This dual nature of MOB
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was observed both in inter- and intramolecular versions of DA
reactions.19,20 The current example, namely cyclohexadiene (11),
might be following the second reaction pathway or the adduct 25
is more stable than the other possible products under the reaction
conditions utilized.
bearing electron-donating and electron-withdrawing substituents.
Thus, our attention was turned to the dimers 3b–e. The study
was performed with a few selected dienophiles, namely 9, 13 and
15. When NPM (9) was treated separately with the dimers 3b–
e under similar conditions as for dimer 3a, DA adducts 23b–
e could be obtained in 81–96% yields (entries 6–9 of Table 2),
thus proving the generality of this protocol. Encouraged by this
result, when dicyclopentadiene (13) was used, DA adducts 27b–e
(entries 16–19 of Table 2) could be obtained in good yields via
DA reaction of in situ generated monomers, i.e. cyclopentadiene
and MOBs 2b–2e. Acetylenic dienophile 15 produced 29b–d in
excellent yields as shown in Table 3, whereas in previous methods21
the reaction led to the exclusive formation of the corresponding
self-dimerization products. Dienophile 9, which gave only 45%
of DA adduct with MOB 2e in method A, provided 81% in
this protocol. Similarly, dienophile 2,3-dihydrofuran (12) which
previously gave a 36% yield of 26e, could be improved to 50%.
Interestingly, when acetylenic dienophile DMAD (15) was used
in the reaction, no desired bicyclic compound could be isolated,
instead compound 3224 was obtained in 50% yield whose formation
is expected to come from the initially formed DA adduct as
depicted in Scheme 3. An uncharacterizable product was also
isolated along with compound 32. Attempts to isolate the DA
adduct at lower temperatures 180 ◦C and 200 ◦C failed, and
the reactions provided the same products, compound 32 and an
unknown compound, though the reaction was not complete with
large amounts of dimer still present.
The reaction was further exploited with acetylenic dienophiles
14–17 (Fig. 1) which are known to be less reactive in DA
reactions with MOBs. Generally, higher temperatures are required
to obtain DA adducts with acetylenic dienophiles. Thus, only
stable MOBs, which are less prone to self-dimerization, had to be
used in these reactions.21–23 On the other hand, the present strategy
could provide an easy access to the bicyclo[2.2.2]octadienones in
excellent yields. Initially, dimethylacetylenedicarboxylate (15) was
used in the reaction to produce 29a (92%, entry 2 of Table 3).
In contrast to phenylacetylene (16) and 1-hexyne (17), which
provided single regioisomers 30aN and 31aN, respectively, (entry
7, 8 of Table 3) ethyl propiolate (14) gave two regioisomers 28aN
and 28aX in an almost 1 : 1 ratio (entry 1 of Table 3). This may be
attributed to the profound electron-donating effect of phenyl in 16
and alkyl in 17 than the ethoxy carbonyl group in 14; the observed
behavior of these dienophiles is in accord with our previous
investigations.22,23 These results are particularly pertinent since
earlier attempts to synthesize these bicyclo[2.2.2]octadienones
were unsuccessful. Thus, our new approach looks to be superior
to the existing procedures for acetylenic dienophiles.
Having established the efficacy of this methodology with dimer
3a and a number of olefinic and acetylenic dienophiles, we
speculated this reaction could be generalized to other MOB dimers
Scheme 3 Domino rDA/DA followed by rDA providing 32.
The structures of all the new compounds were assigned on
1
the basis of their IR, H NMR and 13C NMR, DEPT, and low-
and high-resolution mass spectral analyses. For most of the high-
resolution mass spectra recorded in electron impact mode (70 eV),
the peaks corresponding to the molecular ion (M+) could not be
seen; instead the peaks corresponding to M+ −28 were observed,
indicating that the extrusion of CO resulted from facile fragmen-
tation. The 1H NMR of the known compounds 18aN–22aN, 23a,
23d, 26a, 26e, 27a–e and 32 were compared with those of the
authentic compounds.12,13,16–18,24 All the cycloadducts exhibited IR
absorptions at 1731–1742 cm−1 due to the characteristic features of
the carbonyl functional group adjacent to a,a-dimethoxyl groups
in the functionalized bicyclo[2.2.2]octenone skeleton.12–14,19 All the
compounds showed 13C resonance at about d 192.1–204.6 and d
89.2–95.0 revealing the presence of carbonyl and a quarternary
carbon bearing two methoxy groups.
Fig. 1 Dienophiles successfully employed in this study.
The regio- and stereochemistry of the new compounds were
confirmed by decoupling and NOE experiments. For instance,
in 20aX, saturation of both the –OMe gave rise to an increase
in the signal intensity of Hc (1.9%) while the saturation of Hc
Fig. 2 MOB 3a acting as dienophile.
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Table 3 Domino rDA/DA reactions of MOB dimers 3a–e with selected acetylenic dienophiles
Method A
Entrya
1
Dimer
Dienophile/eq.b
Reaction time/h
2
Adduct/yield (%)
Adduct/yield (%)
Equivalentsb
25
3a
28aN or 28aX/0c
2
3a
3b
3c
3d
3e
3a
3a
2
29a/0c
29b/0c
29c/0c
29d/0c
29e/0c
30aN/0c
31aN/0c
25
10
10
10
10
25
30
3
8
4
1.5
2
5
6
2
7d
8d
2
8
a A 0.25 M solution of dimer in mesitylene was used in the reaction. b Number of equivalents of dienophile used is with respect to the MOB generated.
c Exclusive formation of dimer of the corresponding MOB. d Reaction was conducted in the absence of solvent.
brought about a significant NOE effect in Hd (1.1%) and He (1.4%)
thus confirming the assigned regiochemistry. As the structure
of 20aN was already confirmed earlier, 20aX should be none
other than its stereoisomer, hence confirming the regio- and
stereochemistry. Similarly, in the case of 21aX, NOE studies could
provide the structure of this bicyclo[2.2.2]octenone (Fig. 2). For
28aN, the regiochemistry was confirmed by irradiating Hc to find
an enhancement in the signal intensity of Hd (1.6%). Likewise,
saturation of He in compound 28aX brought about a significant
NOE effect on Hd (1.3%), confirming the assigned regiochemistry.
The regiochemistry of 30aN and 31aN were also assigned in a
similar way on the basis of NOE studies. (Fig. 3). On the basis
of these analyses, the inseparable products 18aX and 22aX are
tentatively assigned as exo isomers of 18aN and 22aN, respectively.
The regioselectivity of these cycloadditions were very high in
many cases, and are in accord with our earlier results due to
the greater influence of the carbonyl functionality than the two
methoxy groups present on the MOB moiety.12,13 The selectivities
observed in the present study have literature precedents.11 The
results illustrated here are particularly notable due to their high
regio- and stereoselectivities, even in such harsh conditions. To
gain more insight into whether the formation of the stereoisomers
18aX, 20aX, 21aX and 22aX is a kinetically controlled or
thermodynamically controlled process, the following reactions
were carried out. We separately subjected 20aN and 21aN to the
standard rDA/DA reaction conditions (mesitylene, sealed tube,
220 ◦C) and did not observe any 20aX and 21aX as indicated
1
by the H NMR of crude reaction mixtures, suggesting that the
formation of isomers is a kinetically, rather than thermodynam-
ically, controlled process. Analogous experiments were executed
with 18aN and 22aN, which were synthesized by following the
previously reported procedures. Even in these cases, no 18aX
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methodology should prove to be of value in various synthetic
applications.
Experimental section
Unless stated otherwise, reagents were obtained from commercial
sources and used without further purification. All reactions were
performed under a nitrogen atmosphere in anhydrous solvents
which were dried prior to use following standard procedures.
Reactions were monitored with thin-layer chromatography carried
out on 0.25 mm E. Merck silica gel plates (60F-254) using 7%
ethanolic phosphomolybdic acid as developing agent. The product
composition of each reaction was determined from 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 spectra
were recorded at 400 and 100 MHz, respectively, in CDCl3 and
chemical shifts are reported in d (ppm) using solvent resonance
as the internal reference. Mass spectra were recorded by the NSC
Instrumentation Center at Hsinchu, Taiwan. Elemental analyses
were performed by the NSC Instrumentation Center at Taichung,
Taiwan.
Fig. 3 1H NMR studies of NOE (%) for 20aX, 21aX, 28aN, 28aX, 30aN
and 31aN.
1
and 22aX were observed in the H NMR of their crude reaction
mixtures.
Conclusions
General procedure for the preparation of the dimers 3a–e
In summary, a detailed investigation of the domino rDA/DA
reaction, a novel and efficient approach to synthesize bicy-
clo[2.2.2]octenones and bicyclo[2.2.2]octadienones, is presented.
Though the reaction works well with a series of electronically
and sterically distinct olefinic and acetylenic dienophiles (Fig. 1),
there were quiet a few dienophiles which could not undergo this
tandem rDA/DA reaction to provide the expected DA adducts.
The failure of the reaction with dienophiles cyclopentenone and
cyclohexenone can be attributed to their fixed s-trans configura-
tion; steric factors influence the reactivity of dienophiles like 4,4-
dimethylcyclopentene and 2,2-dimethyl-4-cyclopenta-1,3-dione.
The reaction of MOBs with monosubstituted acetylenes, com-
pared to the corresponding disubstituted ones [diphenylacetylene,
bis(trimethylsilyl)acetylene] may arise basically from the steric
effect. However, the effects of substituents on the relative reactivity
in the cases of mono- and di-substituted acetylenes is presumably
derived from electronic effects which may not be ruled out. Other
factors can be ascribed to the side reactions (polymerization,
decomposition) which resulted in messy 1H NMR readings.
The choice in the synthetic strategy of domino rDA/DA
methodology served 4 main purposes; (i) improving the yield
of DA adducts, (ii) utilization of a dimer which was a side
product in the DA reactions of MOBs, (iii) decreasing the number
of synthetic steps, (iv) decreasing the number of equivalents of
dienophiles, thus making it a cost effective method. Even though
the dienophiles 4–8 and 14 produced two stereoisomers in this
protocol, an increase in the yield of the endo-adduct, which is the
major reaction product, was observed and the two stereoisomers
in the cases of dienophiles 6, 7 and 14 could be easily separated
by column chromatography. Under these conditions 27a–e were
achieved in good yields, although previous method still offered
the best results. The results showed remarkable selectivity even at
that higher temperature. As a new direct and efficient method for
the preparation of highly functionalized bicyclo[2.2.2]octenones
and bicyclo[2.2.2]octadienones, we have discovered that this
To a solution of phenol (1 mmol) in dry methanol was added
at room temperature DAIB (1.2 mmol) previously dissolved in
methanol. The reaction mixture was left overnight to stir at am-
bient temperature. Solvent was removed with rotary evaporation
and then treated with saturated NaHCO3 and then ethylacetate
was used for the extraction. The crude product remaining after the
removal of solvent was recrystallised from ethyl acetate–hexane to
give the corresponding dimer.
General procedure for the domino rDA/DA reaction
To a solution of 0.25 mmol of the dimer in 1 ml of mesitylene in
a tube was added a specified equivalents of dienophile. The tube
was then sealed after degassing by freeze-thaw purge technique.
Reaction mixture was subjected to the appropriate temperature
for an appropriate time to give the corresponding products.
General procedure for method A
To a mixture of DAIB (2 mmol) and dienophile in MeOH (6 mL)
was added a 2-methoxyphenol (1 mmol) in MeOH (4 mL) during a
period of 1 h time with the aid of a syringe pump at rt. The reaction
mixture was stirred until the reaction was complete. Then, all the
volatiles were removed under reduced pressure and the residue was
subjected to purification by column chromatography on silica gel
using a mixture of ethyl acetate and hexanes as eluent to obtain
the cycloadducts.
The analytical data for compounds 3a,14b 3b,14b 3c,14b 3d,12 3e,12
18aN,12 19aN,12 20aN,13 22aN,13 26a,13 26e,13 and 3224 are identical
with those already reported in the literature.
Methyl (1R*,2R*,4S*)-8,8-dimethoxy-7-oxobicyclo[2.2.2]oct-5-
ene-2-carboxylate (18aX). Selected 1H NMR peaks dH
(400 MHz, CDCl3) (from the mixture) 2.11–2.14 (2 H, m, CH2),
3.16–3.19 (1 H, m, CHCO2Me), 3.31 (3 H, s, OCH3), 3.35 (3 H,
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s, OCH3), 3.67 (3 H, s, CO2CH3), 6.23 (1 H, ddd, J 1.6, 6.4,
1737, 1095, 1056, 764 and 691; dC(100 MHz, CDCl3) d 29.6 (CH2),
29.9 (CH2), 39.3 (CH), 49.9 (CH3), 50.2 (CH3), 55.0 (CH), 93.9
(C), 125.8 (CH), 126. 7(CH), 127.5 (CH), 127.7 (CH), 135.4 (CH),
144.2 (C), 201.7 (C); m/z (EI) 230.1339 (M+ − CO, C15H18O2
requires 230.1307) 230 (100), 155 (69), 128 (18), 91 (44), 75 (74),
59 (23), 51 (16).
=
=
8.0, CH CH), 6.29 (1 H, ddd, J 1.6, 6.4, 8.0, CH CH). The
following data is obtained for the mixture of endo and exo-isomers,
mmax(film)/cm−1 of the mixture 2952, 2836, 1744, 1737, 1093, 1061;
dC(100 MHz, CDCl3) 24.2 (CH2), 25.9 (CH2), 37.4 (CH), 38.3
(CH), 38.6 (CH), 41.5 (CH), 47.4 (CH), 49.7 (CH3), 49.9 (CH),
50.2 (CH3), 52.1 (CH3), 93.7 (C), 125.7 (CH), 129.2 (CH), 132.0
(CH), 135.3 (CH), 173.3 (C), 201.0 (C); m/z (EI) 212.1080 (M+ −
CO, C12H16O5 requires 212.1049) 211 (19), 201 (54), 195 (33), 183
(40), 180 (95), 173 (30), 167 (85), 166 (73).
(1R*,2R*,6R*,7R*)-9,9-Dimethoxy-4-phenyl-4-azatricyclo-
[5.2.2.02,6]undec-10-ene-3,5,8-trione (23a). Obtained as a white
◦
colored solid, mp 227–228 C; mmax(film)/cm−1 2975, 2839, 1781,
1735, 1718, 1598 and 1498; dH (400 MHz, CDCl3) 3.34 (3 H, s,
OCH3), 3.38 (1 H, dd, J 3.2, 8.4 Hz, CH–CH), 3.40 (3 H, s,
OCH3), 3.56 (1 H, dd, J 3.6, 8.4 Hz, CH–CH), 3.74 (1 H, ddd,
J 1.6, 3.2 and 6.4, CH–C(OMe)2), 3.79 (1 H, ddd, J 1.2, 3.6 and
(1R*,4S*,7R*)-7-(Benzyloxy)-3,3-dimethoxybicyclo[2.2.2]oct-
5-en-2-one (20aX). Obtained as a colorless oil; mmax(film)/cm−1
3102, 3023, 2944, 1742, 1057, 728 and 696; dH (400 MHz, CDCl3)
1.85 (1 H, ddd, J 3.6, 9.6 and 13.2, CH2), 1.97 (1 H, ddd, J 2.8,
6.4 and 13.2, CH2), 3.10 (1 H, m, CH–C(OMe)2), 3.31 (3 H, s,
OCH3), 3.34 (3 H, s, OCH3), 3.52 (1 H, ddd, J 1.2, 3.6 and 6.8,
CH–CO), 3.82 (1 H, ddd, J 3.6, 6.4 and 9.6, BnO–CH), 4.56 (1 H,
d, J 12.0, Ar–CH2–O), 4.61 (1 H, d, J 12.0, Ar–CH2–O), 6.02
=
6.4, CH–CO), 6.25 (1 H, ddd, J 1.6, 6.4 and 8.0, CH CH), 6.42
=
(1 H, ddd, J 1.2, 6.4 and 8.0, CH CH), 7.16 (2 H, dd, J 1.6 and
3.6, Ar–H), 7.42 (3 H, m, Ar–H); dC(100 MHz, CDCl3) 40.0 (CH),
40.7 (2 × CH), 48.8 (CH), 50.3 (2 × CH3), 92.9 (C), 126.3 (2 ×
CH), 127.0 (CH), 128.9 (CH), 129.2 (2 × CH), 131.5 (C), 133.1
(CH), 174.9 (C), 176.3 (C), 198.4 (C); m/z (EI) 299.1156 (M+ −
CO, C17H17NO4 requires 299.1157), 299 (M+ − CO, 72), 284 (76),
252 (100), 151 (6), 121 (13), 105 (36), 76 (11).
=
(1 H, ddd, J 1.6, 6.8 and 8.0, CH CH), 6.41 (1 H, ddd, J 1.2,
=
6.4 and 8.0, CH CH), 7.23–7.30 (5 H, m, Ar–H); dC(100 MHz,
CDCl3) 28.6 (CH2), 38.4 (CH), 49.8 (CH3), 50.0 (CH3), 53.2 (CH),
70.3 (CH2), 75.7 (CH), 94.4 (C), 125.6 (CH), 127.3 (CH), 127.6
(2 × CH), 128.3 (2 × CH), 136.3 (CH), 140.0 (C), 201.3 (C); m/z
(EI) 260.1468 (M+ − CO, C16H20O3 requires 260.1412) 260 (M+ −
CO, 7), 181(7), 105 (16), 91 (100), 79 (12), 77 (14), 69 (8), 59 (17).
(1R*,2R*,6S*,7R*)-9,9-Dimethoxy-7-methyl-4-phenyl-4-aza-
tricyclo[5.2.2.02,6]undec-10-ene-3,5,8-trione (23b). mmax(film)/cm−1
3067, 2978, 2944, 2837, 1779, 1741, 1714, 1598, 1498 and 1456;
dH (400 MHz, CDCl3) 1.57 (3 H, s, CH3), 2.98 (1 H, d, J 8.4,
CH–CH), 3.34 (3 H, s, OCH3), 3.40 (3 H, s, OCH3), 3.57 (1 H, dd,
J 3.2 and 8.4, CH–CH), 3.75–3.78 (1 H, m, CH–C(OMe)2), 5.92
(1S*,4R*,7R*)-3,3-Dimethoxy-7-(phenylsulfanyl)bicyclo[2.2.2]-
oct-5-en-2-one (21aN). Obtained as a light brown colored oil; dH
(400 MHz, CDCl3) 1.22 (1 H, ddd, J 2.8, 5.2 and 13.2, CH2), 2.53
(1 H, ddd, J 2.8, 8.0 and 13.2, CH2), 3.09 (1 H, m, CH–C(OMe)2),
3.23 (1 H, ddd, J 1.4, 2.4 and 6.2, CH–CO), 3.28 (3 H, s, OCH3),
3.29 (3 H, s, OCH3), 3.65 (1 H, ddd, J 2.4, 6.0 and 8.0, PhS–CH),
=
(1 H, dd, J 0.8 and 8.4, CH CH), 6.38 (1 H, dd, J 6.4, 8.0 Hz,
=
CH CH), 7.15–7.43 (5 H, m, Ar–H); dC(100 MHz, CDCl3) 14.7
(CH3), 40.2 (CH), 41.5 (CH), 44.7 (CH), 50.3 (2 × CH3), 51.2 (C),
92.7 (C), 126.4 (2 × CH), 128.9 (CH), 129.2 (2 × CH), 131.6 (C),
132.1 (CH), 132.7 (CH), 174.3 (C), 176.3 (C), 200.2 (C); m/z (EI)
313.1327 (M+ − CO, C18H19NO4 requires 313.1314), 313 (24), 298
(28), 266 (19), 264 (100).
=
6.15 (1 H, dddd, J 1.2, 1.4, 6.2 and 8.0, CH CH), 6.48 (1 H,
=
ddd, J 1.4, 6.2 and 8.0, CH CH), 7.26–7.36 (5 H, m, Ar–H);
dC(100 MHz, CDCl3) 28.3 (CH2), 38.4 (CH), 41.5(CH), 49.8
(CH3), 50.0 (CH3), 52.3 (CH), 93.7 (C), 126.1 (CH), 127.3 (CH),
129.0 (2 × CH), 131.5 (2 × CH), 134.6 (CH), 135.6 (C), 200.9 (C).
(1R*,2R*,6R*,7S*)-9,9-Dimethoxy-11-methyl-4-phenyl-4-aza-
tricyclo[5.2.2.02,6]-undec-10-ene-3,5,8-trione (23c). mmax(film)/cm−1
2972, 2946, 2837, 1779, 1738, 1713, 1498, 1384, 1189 and 1138;
dH (400 MHz, CDCl3) 1.85 (3 H, s, CH3), 3.34 (3 H, s, OCH3),
3.34 (1 H, m, CH–CH), 3.39 (3 H, s, OCH3), 3.40 (1 H, d, J
3.2 Hz, CH–CH), 3.60 (1 H, m, CH–C(OMe)2), 3.68 (1 H, dd, J
(1S*,4S*,7R*)-3,3-Dimethoxy-7-(phenylsulfanyl)bicyclo[2.2.2]-
oct-5-en-2-one (21aX). Obtained as a light brown colored oil;
mmax(film)/cm−1 3060, 2963, 2944, 2360, 1741, 1057, 740, 691; dH
(400 MHz, CDCl3) 1.91 (1 H, ddd, J 2.4, 7.2 and 14.0, CH2), 2.04
(1 H, ddd, J 3.2, 5.2 and 14.0, CH2), 3.15 (2 H, ddd, J 1.6, 2.8
and 4.4, CH–C(OMe)2 and CH–CO), 3.31 (3 H, s, OCH3), 3.34
(1 H, ddd, J 3.2, 5.2 and 7.2, PhS–CH), 3.40 (3 H, s, OCH3), 6.08
=
1.6, 6.8 Hz, CH–CO), 6.00 (1 H, m, CH CCH3), 7.12–7.47 (5
H, m, Ar–H); dC(100 MHz, CDCl3) 20.8 (CH3), 40.5 (CH), 40.6
(CH), 40.7 (CH), 50.1 (CH3), 50.4 (CH3), 53.9 (CH), 93.3 (C),
124.6 (CH), 126.3 (2 × CH), 129.0 (CH), 129.3 (2 × CH), 131.6
(C), 137.3 (C), 175.0 (C), 176.6 (C), 198.3 (C); m/z (EI) 313.1331
(M+ − CO, C18H19NO4 requires 313.1314) 313 (32), 298 (41), 268
(18), 267 (100), 194 (10).
=
(1 H, ddd, J 1.6, 6.4 and 8.0, CH CH), 6.45 (1 H, ddd, J 1.6, 6.4
=
and 8.0, CH CH) 7.26–7.32 (3 H, m, Ar–H), 7.45–7.47 (2 H, m,
Ar–H); dC(100 MHz, CDCl3) 27.5 (CH2), 38.7 (CH), 43.5 (CH),
49.7 (CH3), 49.9 (CH3), 52.4 (CH), 66.1 (C), 94.1 (C), 127.8 (CH),
128.3 (CH), 129.1 (2 × CH), 133.3 (2 × CH), 136.0 (CH), 200.7
(C); m/z (EI) 262.1069 (M+ − CO, C15H18O2S requires 262.1028)
231 (3), 153 (100), 121 (38), 79 (33), 77 (41), 75 (75), 47 (23), 28
(48).
(1R*,2R*,6R*,7R*)-9,9-Dimethoxy-10-methyl-4-phenyl-4-aza-
tricyclo[5.2.2.02,6]-undec-10-ene-3,5,8-trione (23d). Obtained as a
white solid, mp 165–166 ◦C; (found: C, 66.61; H, 5.91; N, 3.98,
C19H19 NO5 requires C, 66.85; H, 5.61; N, 4.10%): mmax(film)/cm−1
2945, 2824, 1765, 1742, 1713, 1062 and 754; dH (400 MHz, CDCl3)
1.92 (3 H, d, J 1.6, CH3), 3.60 (6 H, s, 2 × OCH3), 3.36 (1 H, dd, J
3.6 and 8.6, CH–CH), 3.52 (1 H, dd, J 3.4 and 8.6, CH–CH), 3.61
(1 H, dd, J 1.8 and 3.6, CH–C(OMe)2), 3.63 (1 H, dd, J 3.4 and
(1R*,4S*,7R*)-3,3-Dimethoxy-7-phenylbicyclo[2.2.2]oct-5-en-
1
2-one (22aX). Selected H NMR dH (400 MHz, CDCl3) (from
the mixture) 2.01 (1 H, dt, J 3.6, 12.8 and 12.8, CH2), 2.15 (1 H,
=
dd, J 6.4 and 14.0, CH2), 6.34 (1 H, t, J 7.6, CH CH), 6.44 (1 H,
=
=
t, J 7.2, CH CH). The following data is obtained for the mixture
6.0 Hz, CH–CO), 5.82 (1 H, ddq, J 1.6, 6.0 and 1.8, CH CCH3),
of endo and exo-isomers, mmax(film)/cm−1 3065, 3031, 2968, 2944,
2274 | Org. Biomol. Chem., 2006, 4, 2267–2277
7.12–7.15 (2 H, m, Ar–H), 7.38–7.45 (3 H, m, Ar–H); dC(100 MHz,
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CDCl3) 21.8 (CH3), 39.9 (CH), 41.1 (CH), 45.4 (CH), 48.8 (CH),
50.1 (CH3), 50.7 (CH3), 93.1 (C), 118.1 (CH), 126.2 (2 × CH),
128.8 (CH), 129.2 (2 × CH), 131.6 (C), 144.1 (C), 175.2 (C), 176.2
(C), 198.5 (C); m/z (EI) 313.1314 (M+ − CO, C18H19NO4 requires
313.1314) 313 (M+ − CO, 85), 298 (33), 266 (100), 135 (10), 119
(21), 91 (20), 59 (9)
(1R*,2R*,6S*,7R*)-9,9-Dimethoxytricyclo[5.2.2.02,6]undeca-4,
10-dien-8-one (27a). Obtained as a colorless oil; mmax(film)/cm−1
3052, 2841, 1737, 1094 and 1052; dH (400 MHz, CDCl3) 1.97
=
(1 H, dm, J 17.2, CH2–CH CH), 2.54 (1 H, dm, J 17.2, CH2–
=
CH CH), 2.90 (1 H, m, CH–CH), 2.97 (1 H, m, CH–C(OMe)2),
3.12 (1 H, ddd, J 1.6, 2.8 and 6.0, CH–CO), 3.19 (1 H, m,
CH–CH), 3.30 (s, 3 H, –OCH3), 3.35 (3 H, s, –OCH3), 5.41
Methyl (1R*,2R*,6R*,7S*)-10,10-dimethoxy-3,5,11-trioxo-4-
=
(1 H, m, CH2–CH CH), 5.65 (1 H, ddd, J 2.4, 6.0 and 3.6,
phenyl-4-azatricyclo[5.2.2.02,6]undec-8-ene-8-carboxylate
(23e).
=
=
=
CH2–CH CH), 6.04 (1 H, m, CH CH), 6.24 (1 H, m, CH CH);
dC(100 MHz, CDCl3) 33.7 (CH), 38.4 (CH2), 43.7 (CH), 49.4
(CH), 49.6 (CH3), 50.2 (CH3), 52.0 (CH), 94.7 (C), 127.7 (CH),
130.0 (CH), 131.8 (CH), 133.1 (CH), 203.4 (C); m/z (EI) 220.1100
(M+, C13H16O3 requires 220.1099), 192 (M+ − CO, 100), 177 (7),
161 (78), 127 (9), 117 (39), 96 (8), 75 (20).
mmax(film)/cm−1 1716 and 1748; dH (400 MHz, CDCl3) 3.33 (3 H, s,
OCH3), 3.42 (3 H, s, OCH3), 3.47 (1 H, dd, J 3.2 and 8.0,
CH–CH), 3.58 (1 H, dd, J 3.2 and 8.0, CH–CH), 3.76 (3 H, s,
CO2CH3), 3.98 (1 H, dd, J 3.2 and 8.0, CH–C(OMe)2), 4.33
(1 H, dd, J 2.0 and 1.6, CH–CO), 7.07 (1 H, dd, J 1.6 and
=
8.0, CH CCO2CH3), 7.30–7.44 (5 H, m, Ar–H); dC(100 MHz,
(1S*,2R*,3S*,7R*)-9,9-Dimethoxy-7-methyltricyclo-[5.2.2.02,6]-
undeca-4,10-dien-8-one (27b). mmax(film)/cm−1 3050, 2945, 2908,
1733, 1454, 1241, 1158, 1145, 1056 and 988; dH (400 MHz,
CDCl3) 39.6 (CH), 40.6 (CH), 41.5 (CH), 48.1 (CH), 50.2 (CH3),
50.2 (CH3), 52.5 (CH3), 92.4 (C), 126.2 (2 × CH), 128.9 (CH),
129.2 (2 × CH), 130.9 (C), 131.2 (C), 140.9 (CH), 162.6 (C), 173.7
(C), 175.5 (C), 197.2 (C); m/z (EI) 385.1172 (M+, C20H19O7N
requires 385.1162), 357 (M+ − 28, 29), 311 (19), 310 (100), 179
(11), 163 (38).
=
CDCl3) 1.20 (3 H, s, CH3), 1.97–2.02 (1 H, m, CH2–CH CH),
=
2.49–2.56 (1 H, m, CH2–CH CH), 2.81–2.85 (1 H, m, CH–CH),
2.89–2.96 (1 H, m, CH–CH), 3.10–3.13 (1 H, m, CH–C(OMe)2),
3.29 (3 H, s, OCH3), 3.34 (3 H, s, –OCH3), 5.49–5.52 (1 H, m,
(1R*,2R*,6S*,7R*)-9,9-Dimethoxytricyclo[5.2.2.02,6]undeca-10-
en-8-one (24a). Obtained as a colorless oil; mmax(film)/cm−1 2918,
1731 and 1415; dH (400 MHz, CDCl3) 1.20 (3 H, m), 1.64 (1 H,
broad dd, J 6.0), 1.82 (2 H, m), 2.46 (1 H, ddd, J 2.4, 8.0 and 9.6),
2.57 (1 H, ddd, J 2.8, 9.6 and 10.0), 3.08 (2 H, m), 3.28 (3 H, s,
OCH3), 3.30 (3 H, s, OCH3), 6.09 (1 H, dddd, J 1.2, 2.4, 6.0 and
=
=
CH CH), 5.68–5.70 (2 H, m, CH CH), 6.18–6.22 (1 H, t, J
=
6.4, CH CH); dC(100 MHz, CDCl3) 15.5 (CH3), 35.2 (CH), 38.7
(CH2), 43.2 (CH), 49.7 (CH3), 50.3 (CH3), 52.3 (C), 54.7 (CH),
94.5 (C), 128.7 (CH), 131.3 (CH), 133.2 (CH), 134.0 (CH), 204.6
(C); m/z (EI) 234.1243 (M+, C14H18O3 requires 234.1256), 234 (5),
225 (14), 208 (15), 207 (15), 206 (100).
=
=
8.0, CH CH), 6.32 (1 H, ddd, J 0.8, 5.2 and 8.0, CH CH);
dC(100 MHz, CDCl3) 26.8 (CH2), 31.4 (CH2), 31.7 (CH2), 38.3
(CH), 41.2 (CH), 42.8 (CH), 49.6 (CH3), 50.3 (CH3), 52.9 (CH),
94.1 (C), 127.7 (CH), 134.5 (CH), 203.8 (C); m/z (EI) 194.1341
(M+ − CO, C12H18O2 requires 194.1307) 194 (87), 163 (35), 147
(25), 119 (81), 91 (100), 77 (39), 59 (30), 51 (21).
(1S*,2R*,6S*,7R*)-9,9-Dimethoxy-11-methyltricyclo[5.2.2.02,6]-
undeca-4,10-dien-8-one (27c). Obtained as a white solid; (found:
C, 70.84, H, 7.76, C14H18O4 requires C, 71.15, H, 7.74%):
mmax(film)/cm−1 3046, 2951, 2842, 1734, 1442, 1148, 1095, 1055,
978, 833, 790 and 698; dH (400 MHz, CDCl3) 1.74 (3 H, d, J
(1R*,2R*,6S*,7R*)-9,9-Dimethoxytricyclo[5.2.2.02,6]undec-10-
en-8-one (24d). Obtained as a colorless oil; mmax(film)/cm−1 2952
(m), 2861 (w), 1733 (s), 1642 (w), 1050 (m) cm−1; dH (400 MHz,
CDCl3) 0.95–1.05 (1 H, m), 1.12–1.34 (2 H, m), 1.58–1.67 (1 H,
m), 1.74–1.84 (2 H, m), 1.87 (3 H, s, CH3), 2.39 (1 H, dd, J 9.6,
18.8 Hz), 2.51 (1 H, ddd, J 2.8, 10.0, 12.8 Hz), 2.83 (1 H, t, J
2.0 Hz), 2.93 (1 H, dd, J 2.4, 6.4 Hz), 3.28 (3 H, s, OCH3), 3.29
=
1.6 Hz, CH3), 2.04 (1 H, dm, J 17.2 Hz, CH2–CH CH), 2.54
=
(1 H, dm, J 17.2 Hz, CH2–CH CH), 2.89 (1 H, m, CH–CH),
2.94 (1 H, t, J 2.4 Hz, CH–CO), 3.03 (1 H, dd, J 2.8, 6.4 Hz,
CH–C(OMe)2), 3.25 (1 H, m, CH–CH), 3.33 (3 H, s, –OCH3),
3.37 (3 H, s, –OCH3), 5.40 (1 H, m, CH CH), 5.67 (1 H, ddd,
J 2.0, 4.4 and 5.6 Hz, CH CH), 5.85 (1 H, dm, J 6.4 Hz,
CH C–CH3); dC(100 MHz, CDCl3) 21.4 (CH3), 33.5 (CH), 38.2
(CH2), 43.0 (CH), 49.0 (CH), 49.6 (CH3), 49.9 (CH3), 57.4 (CH),
94.8 (C), 123.3 (CH), 129.3 (CH), 132.9 (CH), 136.6 (C), 203.2
(C); m/z (EI) 234.1255 (M+, C14H18O3 requires 234.1256), 206
(M+ − 28, 99), 191 (13), 175 (100), 159 (6), 153 (10), 131 (30), 117
(14), 91 (5), 75 (33).
=
=
=
=
(3 H, s, OCH3), 5.64 (1 H, d, J 6.0 Hz, CH); dC(100 MHz,
CDCl3) 23.5 (CH3), 27.0 (CH2), 30.9 (CH2), 31.4 (CH2), 38.2
(CH), 39.9 (CH), 47.7 (CH), 49.5 (CH3), 50.5 (CH3), 52.1 (CH),
94.3 (C), 118.7 (CH), 144.3 (C), 204.2 (C); m/z (EI) 236.1425 (M+,
C14H20O3 requires 236.1412) 236 (98), 208 (20), 176 (43), 151 (61).
(1R*,2S*,7R*,8R*)-3,3-Dimethoxytricyclo[6.2.2.02,7]dodeca-5,9-
dien-4-one (25). Obtained as a white solid; (found: C, 71.93; H,
7.92, C14H18O3 requires C, 71.77; H, 7.74%): mmax(film)/cm−1 3021,
2937, 2866 and 1704; dH (400 MHz, CDCl3) 1.36–1.43 (1 H, m),
1.51–1.65 (3 H, m), 2.49 (2 H, t, J 7.2), 2.64 (1 H, br m), 2.85–2.90
(1 H, br m), 2.97 (3 H, s, OCH3), 3.25 (3 H, s, OCH3), 5.80 (1 H,
(1S*,2R*,6S*,7R*)-9,9-Dimethoxy-10-methyltricyclo[5.2.2.02,6]-
undeca-4,10-dien-8-one (27d). mmax(film)/cm−1 3048, 2949, 2842,
1735, 1444, 1230, 1139, 1087, 1051, 979, 824 and 719; dH
(400 MHz, CDCl3) 1.91 (3 H, d, J 1.6, CH3), 1.92 (1 H, dm, J
=
=
16.8, CH2–CH CH), 2.55 (1 H, dm, J 16.8, CH2–CH CH),
2.89 (1 H, m, CH–CH), 2.96 (1 H, t, J 2.4, CH–C(OMe)2), 3.04
(1 H, dd, J 6.8 and 2.4, CH–CO), 3.20 (1 H, m, CH–CH), 3.35
=
=
t, J 7.6, CH CH), 5.84 (1 H, dd, J 1.2 and 10.0, CH CH), 6.04
=
=
(1 H, t, J 7.2, CH CHCO), 6.44 (1 H, dd, J 4.0 and 10.0 Hz,
(3 H, s, –OCH3), 3.36 (3 H, s, –OCH3), 5.39 (1 H, m, CH CH),
=
=
CH CHCO); dC(100 MHz, CDCl3) 23.6 (CH2), 27.6 (CH2), 30.7
5.60 (1 H, dm, J 6.8, CH CCH3), 5.68 (1 H, ddd, J 6.0, 4.4 and
=
(CH), 35.7 (CH), 42.7 (CH), 44.8 (CH), 48.4 (CH3), 49.9 (CH3),
99.4 (C), 127.4 (CH), 132.7 (CH), 133.1 (CH), 150.9 (CH), 194.6
(C); m/z (EI) 234.1241 (M+, C14H18O3 requires 234.1256), 234
(73), 206 (28), 154 (100), 131.0 (45), 127 (21), 123 (45), 111 (45).
2.4 Hz, CH CH); dC(100 MHz, CDCl3) 23.6 (CH3), 33.7 (CH),
37.6 (CH2), 48.2 (CH), 48.6 (CH), 49.6 (CH3), 50.5 (CH3), 51.9
(CH), 94.9 (C), 118.4 (CH), 129.9 (CH), 132.9 (CH), 141.7 (C),
203.7 (C); m/z (EI) 234.1260 (M+, C14H18O3 requires 234.1256),
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206 (M+-28, 100), 191 (19), 175 (42), 153 (12), 131 (95), 117 (30),
105 (8), 91 (26), 75 (30).
Dimethyl
(1R*,4R*)-8,8-dimethoxy-1-methyl-7-oxobicyclo-
[2.2.2]octa-2,5-diene-2,3-dicarboxylate (29b). Obtained as
a
colorless oil; mmax(film)/cm−1 2978, 2946, 2836, 1735, 1703,
1646, 1455, 1159 and 1056; dH (400 MHz, CDCl3) 1.41 (3 H, s,
CH3), 3.27 (3 H, s, OCH3), 3.29 (3 H, s, OCH3), 3.74 (3 H, s,
CO2CH3), 3.77 (3 H, s, CO2CH3), 4.52 (1 H, dd, J 1.6 and 6.8,
(1R*,2R*,6S*,7R*)-9,9-dimethoxy-11-methyoxy-carbonyltricy-
clo[5.2.2.02,6]undeca-4,10-dien-8-one (27e). mmax(film)/cm−1 2947,
1740, 1719, 1630, 1441, 1283, 1235, 1136 and 1099; dH (400 MHz,
=
=
CD3COCD3) 2.02 (1 H, d, J 17.6, CH2–CH CH), 2.57 (1 H, d, J
CH–C(OMe)2), 6.04 (1 H, dd, J 2.0, 6.8 Hz, CH CHCH3),
=
=
17.6, CH2–CH CH), 2.96 (1 H, d, J 0.8, CH–CH), 3.24 (3 H, s,
6.50 (1 H, t, J 6.8 Hz, CH CHCH3); dC(100 MHz, CDCl3)
–OCH3), 3.28 (1 H, m, CH–CH), 3.36 (3 H, s, –OCH3), 3.50
(1 H,dd, J 6.8 and 2.8, CH–C(OMe)2), 3.63 (1 H, dd, J 2.8 and
2.0, CH–CO), 3.70 (3 H, s, CO2CH3), 5.42 (1 H, m, CH CH),
5.64 (1 H, m, CH CH), 7.26 (1 H, ddd, J 6.8, 2.0 and 0.8,
CH C(CO2Me)); dC(100 MHz, CD3COCD3) 34.4 (CH), 38.9
(CH2), 45.6 (CH), 49.9 (CH3), 50.2 (CH), 50.4 (CH3), 52.1 (CH3),
52.3 (CH), 95.0 (C), 130.4 (CH), 131.9 (C), 134.0 (CH), 142.8
(CH), 164.8 (C), 202.2 (C); m/z (EI) 278.1151 (M+, C15H18O5
requires 278.1154), 250 (M+ − CO, 100), 219 (84), 203 (16), 191
(26), 185 (12), 159 (17), 127 (17), 115 (42).
12.0 (CH3), 43.6 (CH), 49.9 (CH3), 50.6 (CH3), 52.3 (CH3), 52.5
(CH3), 57.0 (C), 89.7 (C), 133.5 (CH), 133.6 (CH), 146.0 (2 × C),
162.9 (C), 166.0 (C), 193.5 (C); m/z (EI) 310.1050 (M+, C15H18O7
requires 310.1053), 310 (5), 283 (8), 282 (19), 280 (5), 279 (22).
=
=
=
Dimethyl
(1R*,4R*)-7,7-dimethoxy-5-methyl-8-oxobicyclo-
[2.2.2]octa-2,5-diene-2,3-dicarboxylate (29c). Obtained as
a
colorless oil; mmax(film)/cm−1 2999, 2954, 2915, 2840, 1738, 1731,
1725, 1659, 1632, 1435 and 1266; dH (400 MHz, CDCl3) 1.93
(3 H, s, CH3), 3.28 (3 H, s, OCH3), 3.31 (3 H, s, OCH3), 3.78
(3 H, s, CO2CH3), 3.79 (3 H, s, CO2CH3), 4.06 (1 H, d, J 1.6,
CH–C(OMe)2), 4.24 (1 H, d, J 6.4, CH–CO), 6.04–6.07 (1 H, m,
Ethyl
(1R*,4R*)-8,8-dimethoxy-8-oxobicyclo[2.2.2]octa-2,5-
colorless oil;
=
CH CCH3); dC(100 MHz, CDCl3) 19.1 (CH3), 45.8 (CH), 49.9
diene-2-carboxylate (28aN). Obtained as
a
(CH3), 50.9 (CH3), 52.6 (2 × CH3), 60.8 (CH), 89.7 (C), 125.1
(CH), 136.6 (C), 139.5 (C), 139.8 (C), 165.0 (C), 165.2 (C), 192.5
(C); m/z (EI) 310.1035 (M+, C15H18O7 requires 310.1053), 310 (5),
282 (23), 279 (4).
mmax(film)/cm−1 3016, 2901, 1737, 1710 and 1050; dH (400 MHz,
CDCl3) 1.27 (3 H, t, J 7.2, CO2CH2CH3), 3.27 (3 H, s, OCH3),
3.30 (3 H, s, OCH3), 4.11 (2 H, dt, J 6.8 and 1.6, CO2CH2CH3),
4.20 (1 H, ddd, J 1.2, 7.2 and 8.4, CH–C(OMe)2), 4.53 (1 H, td,
=
J 6.8 and 2.0, CH–CO), 6.41 (1 H, dt, J 6.0 and 1.6, CH CH),
Dimethyl
(1R*,4R*)-8,8-dimethoxy-5-methyl-7-oxobicyclo-
=
6.50 (1 H, dt, J 7.2 and 1.6, CH CH), 7.30 (1 H, dd, J 1.6 and
[2.2.2]octa-2,5-diene-2,3-dicarboxylate (29d). Obtained as
a
7.2, CH CCO2Et); dC(100 MHz, CDCl3) 14.1 (CH3), 44.8 (CH),
colorless oil; mmax(film)/cm−1 3050, 2945, 2910, 1740, 1734,
1721, 1654, 1615, 1422 and 1272; dH (400 MHz, CDCl3) 1.91
(3 H, s, CH3), 3.19 (3 H, s, OCH3), 3.26 (3 H, s, OCH3), 3.70
(3 H, s, CO2CH3), 3.71 (3 H, s, CO2CH3), 4.06 (1 H, d, J 5.6,
CH–C(OMe)2)), 4.08 (1 H, d, J 2.4, CH–CO), 5.93–5.95 (1 H,
=
49.9 (CH3), 50.4 (CH3), 53.6 (CH), 61.1 (CH2), 89.8 (C), 129.9
(CH), 132.2 (CH), 134.5 (C), 142.1 (CH), 163.5 (C), 193.8 (C);
m/z (EI) 224.1082 (M+ − CO, C12H16O4 requires 224.1049), 224
(7), 193 (10), 151 (6), 105 (69), 91 (9), 77 (27), 74 (44), 59 (100).
=
m, CH CCH3); dC(100 MHz, CDCl3) 20.1 (CH3), 50.2 (CH3),
Ethyl
(1R*,4R*)-7,7-dimethoxy-8-oxobicyclo[2.2.2]octa-2,5-
colorless oil;
50.5 (CH3), 50.9 (CH), 52.3 (CH3 × 2), 54.9 (CH), 89.4 (C), 120.2
(CH), 138.0 (C), 138.4 (C), 144.4 (C), 164.6 (C), 165.0 (C), 192.2
(C); m/z (EI) 310.1049 (M+, C15H18O7 requires 310.1053) 310
(10), 283 (18), 279 (25).
diene-2-carboxylate (28aX). Obtained as
a
mmax(film)/cm−1 3018, 2905, 1737, 1713 and 1052; dH (400 MHz,
CDCl3) 1.29 (3 H, t, J 6.8, CO2CH2CH3), 3.29 (3 H, s, OCH3),
3.32 (3 H, s, OCH3), 4.11 (1 H, dt, J 1.6, 6.0 and 7.6, CH–CO),
4.22 (2 H, ddd, J 2.8, 6.8 and 10.0, CO2CH2CH3), 4.56 (1 H,
td, J 2.0 and 4.0, CH–C(OMe)2), 6.40 (1 H, dt, J 1.6, 5.6 and
(1R*,4R*)-3,3-Dimethoxy-6-phenylbicyclo[2.2.2]octa-5,7-dien-
2-one (30aN). Obtained as a colorless oil; mmax(film)/cm−1 3100,
3022, 2944, 1737 and 1071; dH (400 MHz, CDCl3) 3.34 (3 H, s,
OCH3), 3.36 (3 H, s, OCH3), 4.20 (1 H, m, CH–C(OMe)2)), 4.47
(1 H, m, CH–CO), 6.56 (3 H, m, CH CH and CH CPh), 7.27
(1 H, td, J 7.2 and 1.2, Ar–H), 7.33 (3 H, m, 3 × Ar–H), 7.47 (1 H,
t, J 3.6, Ar–H); dC(100 MHz, CDCl3) 44.3 (CH), 50.1 (CH3), 50.2
(CH3), 57.2 (CH), 90.8 (C), 118.9 (CH), 125.4 (2 × CH), 127.9
(CH), 128.3 (2 × CH), 128.6 (CH), 133.3 (C), 133.4 (CH), 134.9
(C), 195.3 (C); m/z (EI) 228.1181 (M+ − CO, C15H16O2 requires
228.1150), 228 (5), 197 (35), 154 (49), 153 (32), 115 (7.16), 77 (17),
74 (71), 59 (100).
=
=
7.2 Hz, CH CH), 6.53 (1 H, dt, J 1.6, 7.2 and 8.0, CH CH),
7.30 (1 H, dd, J 2.0 and 6.0, CH CCO2Et); dC(100 MHz, CDCl3)
=
=
=
14.1 (CH3), 43.9 (CH), 50.4 (2 × CH3), 55.2 (CH), 61.0 (CH2),
89.8 (C), 128.1 (CH), 133.8 (CH), 137.4 (C), 138.3 (CH), 163.9
(C), 193.9 (C); m/z (EI) 224.1044 (M+ − CO, C12H16O4 requires
224.1049), 224 (8), 151.1 (8), 105 (77), 91 (10), 77 (34), 74 (42), 59
(100), 51 (9).
Dimethyl (1R*,4R*)-7,7-dimethoxy-8-oxobicyclo[2.2.2]octa-2,5-
diene-2,3-dicarboxylate (29a). Obtained as a light yellow colored
oil; mmax(film)/cm−1 2953, 2846, 1737, 1718, 1645 and 1071; dH
(400 MHz, CDCl3) 3.31 (6 H, s, 2 X–OCH3), 3.78 (3 H, s,CO2CH3),
3.80 (3 H, s, CO2CH3), 4.32 (1 H, dd, J 1.6 and 5.2, CH–C(OMe)2),
(1R*,4R*)-6-Butyl-3,3-dimethoxybicyclo[2.2.2]octa-5,7-dien-2-
one (31aN). Obtained as a colorless oil; mmax(film)/cm−1 3069,
2965, 2930 and 1738; dH (400 MHz, CDCl3) 0.86 (3 H, t, J 7.2,
CH3), 1.25 (2 H, dd, J 6.8 and 14.4, nBu), 1.38 (2 H, dd, J 7.2 and
14.4, Bu), 2.20 (2 H, apparent tt, J 1.6 and 6.8 Hz, Bu), 3.29
(3 H, s, OCH3), 3.30 (3 H, s, OCH3), 3.78 (1 H, td, J 2.0 and 5.6,
CH–CO), 3.85 (1 H, m, CH–C(OMe)2)), 5.94 (1 H, ddd, J 1.2,
3.2 and 4.8, CH C- Bu), 6.41 (2 H, m, CH CH); dC(100 MHz,
CDCl3) 13.8 (CH3), 22.0 (CH2), 29.2 (CH2), 33.2 (CH2), 43.6
=
4.41 (1 H, dd, J 2.4 and 6.0, CH–CO), 6.51 (2 H, m, CH CH);
n
n
dC(100 MHz, CDCl3) 46.2 (CH), 50.0 (CH3), 50.6 (CH3), 52.2
(CH3), 52.5 (CH3), 53.0 (CH), 58.6 (C), 89.2 (C), 128.7 (CH),
133.0 (CH), 137.1 (C), 139.0 (C), 164.9 (C), 192.1 (C); m/z (EI)
268.0940 (M+ − CO, C13H16O6 requires 268.0947), 268 (57), 221
(68), 210 (89), 178 (92), 135 (70), 105 (81), 92 (82), 76 (61).
n
=
=
2276 | Org. Biomol. Chem., 2006, 4, 2267–2277
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(CH), 49.9 (CH3), 50.1 (CH3), 58.8 (CH), 91.0 (C), 124.4 (CH),
130.1 (CH), 133.3 (CH), 143.7 (C), 195.5 (C); m/z (EI) 236.1408
(M+, C14H20O3 requires 236.1412), 236 (2), 208 (20), 178 (13), 151
(65), 119 (4), 105 (8), 102 (11).
6 J. D. Winkler, H. S. Kim and S. Kim, Tetrahedron Lett., 1995, 36, 687.
7 V. K. Singh and B. Samanta, Tetrahedron Lett., 1999, 40, 1807.
8 W. A. Carroll and P. A. Grieco, J. Am. Chem. Soc., 1993, 115, 1164.
9 (a) A. Zhou, M. Segi and T. Nakajima, Tetrahedron Lett., 2003, 44,
1179; (b) M. Segi, A. J. Zhou and M. Honda, Phosphorus, Sulfur Silicon
Relat. Elem., 2005, 180, 1045.
10 Z. GoldSchmidt, S. Levinger and H. E. Gottlieb, Tetrahedron Lett.,
1994, 39, 7273.
Acknowledgements
11 (a) C.-C. Liao, in Modern Methodology in Organic Synthesis, ed.
T. Sheno, Kodansha, Tokyo, 1992, pp. 409–424; (b) S. Quideau and
L. Pouyse´gu, Org. Prep. Proced. Int., 1999, 31, 617; (c) V. Singh, Acc.
Chem. Res., 1999, 32, 324; (d) C.-C. Liao and R. K. Peddinti, Acc.
Chem. Res., 2002, 35, 856; (e) D. Magdziak, S. J. Meek and T. R. R.
Pettus, Chem. Rev., 2004, 104, 1383; (f) C.-C. Liao, Pure Appl. Chem.,
2005, 77, 1221.
Financial support from the National Science Council of Taiwan
is gratefully acknowledged. Thanks are due to Ms Hsiao-Chien,
Wu and Mr Chia-Ming, Chang for carrying out a couple of
experiments. We sincerely thank Dr N. R. Villarante for helpful
discussions.
12 C.-C. Liao, C.-S. Chu, T.-H. Lee, P. D. Rao, S. Ko, L.-D. Song and
H.-C. Hsiao, J. Org. Chem., 1999, 64, 4102.
13 (a) S.-Y. Gao, Y.-L. Lin, P. D. Rao and C.-C. Liao, SYNLETT, 2000,
421; (b) S.-Y. Gao, S. Ko, Y.-L. Lin, R. K. Peddinti and C.-C. Liao,
Tetrahedron, 2001, 57, 297; (c) S.-Y. Gao, Masters thesis, National Tsing
Hua University, Hsinchu, Taiwan, 2000.
14 (a) C.-H. Lai, Y.-L. Shen and C.-C. Liao, SYNLETT, 1997, 1351;
(b) C.-H. Lai, Y.-L. Shen, M.-N. Wang, N. S. K. Rao and C.-C. Liao,
J. Org. Chem., 2002, 67, 6493.
15 (a) S. K. Chittimalla and C.-C. Liao, SYNLETT, 2002, 565; (b) D.
Gabrilidis, C. Kalogiros and L. P. Hadjiarapolou, SYNLETT, 2004,
2566.
References
1 (a) W. Carruthers, Cycloaddition Reactions in Organic Synthesis,
Pergamon, Oxford, 1990; (b) W. Oppolzer, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, New York,
1991, vol. 5, ch. 4.1, pp. 316–399; (c) A. G. Fa˘llis and Y.-F. Lu, Advances
in Cycloadditions, Jai Press Inc., Greenwich, CT, 1993, vol. 3, ch. 2,
pp. 1–66; (d) F. Fringuelli and A. Taticchi, The Diels–Alder Reaction:
Selected Practical Methods, Wiley, Chichester, UK, 2002.
2 (a) B. M. Trost, Science, 1991, 254, 1471; (b) B. M. Trost, Angew. Chem.,
Int. Ed., 1995, 34, 259; (c) E. J. Corey, Angew. Chem., Int. Ed., 2002,
41, 1650; (d) K. C. Nicolaou, S. A. Snyder, T. Montagnon and G. E.
Vassilikogiannakis, Angew. Chem., Int. Ed., 2002, 41, 1668; (e) E. M.
Stocking and R. M. Williams, Angew. Chem., Int. Ed., 2003, 42, 3078.
3 (a) B. Rickborn, Org. React., 1998, 52, 1–393; (b) B. Rickborn, Org.
React., 1998, 53, 223–629.
4 (a) F. L. Funk and K. P. C. Vollhardt, Chem. Soc. Rev., 1980, 9, 41;
(b) P. Magnus, T. Gallagher, P. Brown and P. Pappalardo, Acc. Chem.
Res., 1984, 17, 35; (c) J. L. Charlton, M. M. Alauddin and G. H.
Penner, Can. J. Chem., 1986, 64, 793; (d) G. Capozzi, P. Fratini, S.
Menichetti and C. Nativi, Tetrahedron, 1996, 52, 12233; (e) R. Block
and G. Mandville, Recent Res. Dev. Org. Chem, 1998, 2, 441.
5 L. F. Tietze, Chem. Rev., 1996, 96, 115.
16 J. Chuang and C.-C. Liao, unpublished results.
17 (a) Method A was utilized; (b) all of the procedures described in ref. 13
were utilized.
18 D.-S. Hsu, P. D. Rao and C.-C. Liao, Chem. Commun., 1998, 1795.
19 (a) C.-H. Chen, P. D. Rao and C.-C. Liao, Chem. Commun., 1998, 155;
(b) C.-H. Chen, R. K. Peddinti, N. S. K. Rao and C.-C. Liao, J. Org.
Chem., 2004, 69, 5365.
20 (a) P.-Y. Hsu and C.-C. Liao, Chem Commun., 1997, 1085; (b) P.-Y. Hsu,
R. K. Peddinti and S. K. Chittimalla, J. Org. Chem., 2005, 23, 9156.
21 A.-C. Chen and C.-C. Liao, unpublished results.
22 C.-C. Liao and H.-S. Lin, J. Chin. Chem. Soc., 1983, 30, 69.
23 C.-C. Liao and H.-S. Lin, J. Chin. Chem. Soc., 1986, 33, 73.
24 B. Daniel and R. Mordecai, J. Am. Chem. Soc., 1976, 98, 1599.
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