Microwave-based reaction screening: Tandem retro-Diels-Alder/Diels-Alder cycloadditions of o-quinol dimers

Article abstract of DOI:10.1021/jo201658y

We have accomplished a parallel screen of cycloaddition partners for o-quinols utilizing a plate-based microwave system. Microwave irradiation improves the efficiency of retro-Diels-Alder/Diels-Alder cascades of o-quinol dimers which generally proceed in

Full text of DOI:10.1021/jo201658y

Article
pubs.acs.org/joc
Microwave-Based Reaction Screening: Tandem Retro-Diels−Alder/
Diels−Alder Cycloadditions of o-Quinol Dimers
Suwei Dong,† Katharine J. Cahill,‡ Moon-Il Kang,§ Nancy H. Colburn,§ Curtis J. Henrich,§
Jennifer A. Wilson,§ John A. Beutler,§ Richard P. Johnson,*,‡ and John A. Porco, Jr.*,†
†Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
Boston, Massachusetts 02215, United States
‡Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, United States
§Laboratory of Cancer Prevention and Molecular Targets Laboratory, Center for Cancer Research, NCI-Frederick, Frederick,
Maryland 21702, United States
S
* Supporting Information
ABSTRACT: We have accomplished a parallel screen of cycloaddition partners for o-quinols utilizing a plate-based microwave
system. Microwave irradiation improves the efficiency of retro-Diels−Alder/Diels−Alder cascades of o-quinol dimers which
generally proceed in a diastereoselective fashion. Computational studies indicate that asynchronous transition states are favored
in Diels−Alder cycloadditions of o-quinols. Subsequent biological evaluation of a collection of cycloadducts has identified an
inhibitor of activator protein-1 (AP-1), an oncogenic transcription factor.
thermal susceptors or “sensitizers”, including graphite6 and
INTRODUCTION
■
silicon carbide (SiC),7 has been shown to further improve the
o-Quinols are highly reactive 2,4-cyclohexadienones and have
been proposed as precursors for a number of natural products.
efficiency of thermal transformations, as these materials can
reach high temperature under microwave irradiation in spite of
the nature of reaction solvents.8 Recently, Kappe and co-
workers have reported the development of sintered SiC
microtiter plates for performing parallel synthesis in a
multimode microwave reactor.9 Considering the reactivity of
o-quinol dimers and the available literature precedents, we
wished to utilize SiC plates in a high-throughput reaction
partner assessment.10 In the current study, a broad panel of
reaction partners in the retro-[4 + 2]/[4 + 2] cascade of o-
quinol dimers have been evaluated under microwave conditions
in an effort to study the scope and limitations of this
methodology, to obtain both bicyclo[2.2.2]octenone and cis-
decalin frameworks, and to understand the factors determining
regio- and diastereoselectivity. To explain the observed
reactivities and diastereoselectivities, in particular the regiose-
lectivity for cycloadditions, computational studies of Diels−
Alder reactions between o-quinols and select dienophiles/
dienes were also conducted.11 In this paper, we report the
results of this study as well as biological screening of the
resulting collection of complex cycloadducts.
o-Quinol dimers are common building blocks for preparation of
bicyclo[2.2.2]octenones via retro-Diels−Alder reaction fol-
lowed by a Diels−Alder cycloaddition with external dien-
ophiles.1 We recently reported the synthesis of the natural
product chamaecypanone C (1)2 involving a retro-Diels−
Alder/Diels−Alder cascade of 2,4-cyclohexadienone (o-quinol)
dimer 2 and diaryl enone 3 under thermal, oxidative conditions
(Scheme 1). [4 + 2] cycloaddition of the derived o-quinol
monomer 4 and 2,4-diaryl cyclopentadienone 5 was found to
proceed in a highly regio- and diastereoselective manner. This
result, along with reactions with a few dienophiles, prompted us
to further evaluate cycloadditions of 4 and related o-quinols
with a range of reaction partners, in order to better understand
the mode of reactivity for dienophiles as well as diaster-
eoselectivity with respect to the o-quinol.
Retro-[4 + 2]/[4 + 2] reactions of dimers derived from o-
quinols and masked o-benzoquinones (MOBs) have been
utilized for the preparation of reactive 2,4-cyclohexadienones en
route to bicyclo[2.2.2]octenones.1,3,4 However, most reported
examples involve thermolysis at high temperatures for extended
reaction times. In some cases, sealed tubes have been used at
temperatures up to 220 °C,3b where safety issues may become a
concern. In comparison to conventional heating, microwave
heating has been proven to be efficient in many cases, leading
to a dramatic reduction in reaction time.5 In particular, use of
Received: August 10, 2011
Published: September 26, 2011
© 2011 American Chemical Society
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Scheme 1. Synthesis of (+)-Chamaecypanone C Utilizing a Retro-[4 + 2]/[4 + 2] Cascade
results of the reaction screening indicated that dimer 2 was
completely consumed in all cases. Of the 57 reactions, 12
afforded products corresponding to [4 + 2] adducts between
the o-quinol and alkene reaction partners, and other reactions
afforded product 8 (Scheme 2), likely generated from a
dienone−phenol rearrangement of intermediate 4.15 The
formation of 8 is in accordance with thermal degradation
results reported in the literature for dimer 216 and suggests that
the corresponding reaction partners are unreactive in the
cycloaddition event.
RESULTS AND DISCUSSION
■
Reaction Optimization. We first evaluated reactions
between the readily accessible dimer (−)-212 and N-phenyl-
maleimide (6) under microwave conditions in various solvents
(Table 1).13 Although reactions went to completion within 30
Table 1. Optimization of the Microwave-Mediated Retro-[4
+ 2]/[4 + 2] Cascade
As shown in Table 2, o-quinol 4 may react with activated
alkenes, including the normal-demand dienophiles MVK (9a),
indene (9b), and 4-methoxystyrene (9c), the inverse-demand
dienophiles dihydrofuran (DHF; 9d) and vinylene carbonate
(9e), and the alkynes dimethyl acetylenedicarboxylate (DMAD,
9f) and phenylacetylene (9g). In all cases, Diels−Alder
cycloaddition between o-quinol 4 and dienophiles 9 proceeded
in a highly diastereoselective fashion with [4 + 2] adducts 10a−
g isolated in moderate to excellent yields. Structure elucidation
of products using 2D NMR experiments or X-ray crystallog-
raphy confirmed that endo-[4 + 2] cycloadducts were the
predominate products isolated from the reactions,13 which is in
accordance with both experimental results and theoretical
calculations in literature that secondary orbital overlap is
believed to govern endo selectivity.17 Facial selectivity could be
explained by either steric or hyperconjugation effects according
to our computational studies (vide infra).
a
b
entry
solvent
DMF
conditions
time (min)
conv (%)
cd
,
1
2
3
A
A
A
A
B
30
30
30
15
90
>99 (90)
d
DMA
>99 (92)
mesitylene
mesitylene
mesitylene
>99 (98)
>99 (98)
>99 (97)
e
4
f
5
a
Reaction conditions: (A) 3.0 equiv of 6, SiC chip, μW, 188 °C (IR
temperature); (B) 3.0 equiv of N-phenylmaleimide (6), 150 °C.
Conversion based on UPLC analysis. Isolated yield of product 7 in
parentheses. Aqueous workup required. Reaction conducted at 180
°C (IR temperature) under microwave irradiation. Reaction reported
b
c
d
e
f
in ref 2.
In the cases of reaction with dienes (11, Table 3), o-quinol 4
was found to react as either a 4π or 2π reaction partner to
afford the bicyclooctenone derivative 12 or cis-decalin product
13. Reaction with the 1-phenyl-substituted 1,3-butadiene 11a
(entry 1) cleanly afforded a mixture of bicyclooctenones endo-
12aα and exo-12aβ in a 4:1 ratio favoring the endo adduct.
When the 2-substituted 1,3-butadiene β-myrcene (11b, entry
2) was used in the reaction, cis-decalin 13b was found to be the
major product.18 Considering the result that a mixture of two
compounds was generated at lower reaction temperature (150
°C),2 cycloadduct 13b should be thermodynamically more
favored in comparison to its bicyclooctenone isomer
obtunone.19 Similarly, reaction with 2,3-disubstituted 1,3-
butadiene 11c (entry 3) produced cis-decalin 13c as the
major product in excellent yield (94%). While reaction with
cyclopentadiene dimer 11d (entry 4) generated cycloadduct
12d as the sole product in almost quantitative isolated yield, use
of cyclohexadiene 11e (entry 5) as a reaction partner led to a
more complex product mixture. Structure elucidation con-
firmed that compounds 12e and 13e were the major products
in this instance, along with a small amount of the rearranged
bicyclooctene 14 (approximately 10%).
min in either DMF (entry 1) or DMA (entry 2) to afford
cycloadduct 7, we noticed that use of mesitylene as solvent
afforded cleaner reactions (entry 3). Further experiments
(entry 4) indicated that reactions could be completed within 15
min (μW, 180 °C) in comparison to use of conventional
heating (entry 5), which required approximately 90 min for
completion.2
Screening of Reaction Partners. Utilizing the optimized
microwave conditions, 57 reaction partners were evaluated in a
reaction screen (Figure 1).13 A number of alkene partners were
selected on the basis of retro-[4 + 2]/[4 + 2] cycloadditions of
o-quinol dimers and MOB dimers reported in the literature.1,3
Representative dipolarophiles and dienes were also included.
Reactions were conducted on a 0.009 mmol scale using 3.0 mg
of dimer (−)-2 as substrate, 10 equiv of the corresponding
reaction partner, and 100 μL of mesitylene under microwave
irradiation at 180 °C (IR temp). After 60 min, reaction
mixtures were filtered through a silica gel plug, concentrated,
and evaluated using ultrahigh-performance liquid chromatog-
raphy (UPLC)-MS, which allows for short analytical run times
(approximately 3 min).14 On the basis of UPLC-MS data,
reactions showing major peaks in the HPLC trace were scaled
up (0.06 mmol, 20 mg of substrate) using a SiC chip as passive
heating element in a single-mode microwave reactor.13 The
In order to probe possible interconversion between adducts
12e and 13e, pure compound 12e was resubjected to the
reaction conditions (μW, SiC, mesitylene, 180 °C, 15 min).
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Figure 1. Reaction partners for retro-[4 + 2]/[4 + 2] cascade.
Scheme 2. Dienone−Phenol Rearrangement of o-Quinol 4
suggest that Diels−Alder cycloaddition of o-quinols is an
electronically and sterically demanding process. These obser-
vations are also in accordance with examples of 2,4-cyclo-
hexadienones reported in the literature.1,3
To further evaluate the scope of the microwave-assisted
protocol, o-quinol dimers (+)-15,12 16,24 17, and 1825 were
subjected to optimized reaction conditions (μW, SiC,
mesitylene, 170 °C, 15 min, Table 4). In all cases, good to
excellent isolated yield of the desired cycloadducts 19−25 were
obtained as single diastereomers.
Computational Studies. Previously computational mod-
eling has been employed mainly in studies of MOBs as dienes
in [4 + 2] cycloadditions.3a,26 Quideau and co-workers have
also utilized calculations to study the dimerization of o-
quinols.27 We wished to further study Diels−Alder cyclo-
additions of o-quinols and dienophiles/dienes computationally
to further understand the energetics and regio- and stereo-
chemical features of the cycloadditions.
Product analysis indicated that a mixture of cycloadducts 12e,
13e, and 14 was generated in a 2:1:1 ratio. An extended
reaction time (1 h) or elevated temperature (200 °C) did not
change the ratio, in which case further decomposition was
observed. It is plausible that compounds 12e and 13e may
interconvert through Cope rearrangement20 (Figure 2, pathway
a) or via a retro-[4 + 2] reaction of 12e followed by
recombination of o-quinol and cyclohexadiene (pathway b). To
further understand this process, trapping experiments were
conducted as shown in Scheme 3. In both experiments, no
crossover Diels−Alder cycloadduct was observed; reactions
afforded either a mixture of 12e/13e/14 from 12e or recovered
starting materials from cycloadduct 7. These results support an
intramolecular [3,3]-sigmatropic rearrangement mechanism for
the interconversion of cycloadducts 12e and 13e.21
The generation of product 14 may be explained by thermal
α-ketol rearrangement of hydroxy enone 13e (Figure 2,
pathway c).22 A similar ring contraction has been observed in
a related α-methyl-α-hydroxylcyclohexanone system under
basic conditions.23 However, use of related basic conditions
(LiHMDS/THF or Al2O3/hexanes) did not effect ketol
rearrangement of 13e.
On the basis of the results from our reaction screen and
follow-up product analyses, we noticed that activated alkenes or
alkynes are more reactive in the reaction with the model o-
quinol. Moreover, cis-alkenes in general showed better reactivity
than trans-alkenes and 1,1-disubstituted and trisubstituted
alkenes. Acyclic 1,3-dienes were found to react as 4π
components only if they lacked substitution at the C1 or C4
positions and displayed reactivity as 2π components in the
cases of less substituted alkenes. Taken together, these results
In our studies, B3LYP calculations28 first showed (Table 5,
entry 1) that cycloreversion of dimer 2 is modestly
endothermic, with forward and reverse barriers of 23.9 and
12.3 kcal/mol, respectively. The lowest energy transition state
has C2 symmetry; similar results have been described for related
cycloadditions.25 Predicted reaction energetics support a low
transient concentration of dienone 4. Cycloaddition of 4 with
9a,d,b as representative dienophiles is predicted in each case
(entries 2−4) to have a low reaction barrier, with exothermicity
favorable to a unidirectional process. For each of these
reactions, we optimized all eight potential transition states;
the observed product was correctly assigned by theory in all
cases. In every favored cycloaddition, the shorter transition-
state bond connects to C-5 of dienone 4 (Figure 3). Two failed
reactants, 27 and 28, showed unexpectedly higher reaction
barriers (entries 6 and 7) in comparison to structural analogues
9a,b. It is noteworthy that the barriers for two reaction modes
of myrcene (11b, entry 5) are nearly equal, consistent with the
experimental product distribution (ca. 1:1) at lower reaction
temperature (150 °C).2 The lower energy 13b was the sole
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a
Table 2. Retro-[4 + 2]/[4 + 2] Reactions To Afford
Bicyclo[2.2.2]octenones
Table 3. Retro-[4 + 2]/[4 + 2] Cycloadditions with Dienes
a
a
Reaction conditions: dimer (−)-2, dienophile, SiC chip, mesitylene,
b
μW, 180 °C, 15 min. Single diastereomer isolated unless otherwise
noted. Isolated yield after column chromatography. Approximately
9% of an inseparable minor product observed by H NMR (ca. 10:1
c
d
1
a
Reaction conditions: dimer (−)-2, diene, SiC chip, mesitylene, μW,
isomeric ratio).
b
180 °C, 15 min. Isolated yield after column chromatography.
c
Approximately 5% of an inseparable minor product was observed by
product generated from the reaction at higher temperature
(180 °C; cf. Table 3, entry 2), presumably from cycloadduct 26
via Cope rearrangement.
1H NMR analysis (ca. 19:1 isomeric ratio).
The observed ensemble of selectivity and the correlation
between theory and experiment are striking. In all cases,
cycloaddition stereochemistry favors the usual Alder endo rule,
with additional facial selectivity syn to the less sterically
demanding hydroxyl group. Hyperconjugative effects (Cie-
plak−Fallis model)29 from the methyl group in the transition
state may also contribute to facial selectivity.25,30 Dienone 4 has
a high-lying HOMO (−6.9 eV) and a low-lying LUMO (−2.3
eV) and as a consequence reacts with both electron-rich and
electron-poor dienophiles. In every case, the preferred
regiochemistry follows initial bonding to C5 of the dienone,
which maximizes resonance stabilization in the asynchronous
Figure 2. Cope rearrangement vs a retro-[4 + 2]/[4 + 2] process.
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Scheme 3. Trapping Experiment
Table 5. B3LYP/6-31G(d) Reaction Energetics
Table 4. Retro-[4 + 2]/[4 + 2] Cascade Using Other o-
a
Quinol Precursors
TS4 the arene has a more optimal π−π interaction with the 4π
partner, while in TS7 the dihydronaphthalene (28) aromatic
ring is oriented nearly perpendicular to the cyclohexadienone
ring, presumably to minimize steric interactions, thereby raising
TS energetics by 5.1 kcal/mol in comparison to the indene case
(cf. Table 5, entries 4 and 7). In addition to the sterics and
electronics of dienophiles, these results suggest that secondary
orbital overlap of dienophiles with o-quinols may be another
important factor determining dienophile reactivity.
Competition between cycloreversion, [3,3]-sigmatropic
shifts20,21 and secondary dienone−phenol32 or α-ketol22
rearrangements add complexity to these results. For example,
DFT calculations show that (−)-2 should undergo a degenerate
and homochiral Cope rearrangement with a barrier of 22.4
kcal/mol which should compete with cycloreversion. Figure 4
summarizes the predicted energetics for the dienone 4 + 1,3-
cyclohexadiene potential surface. No transition state for [4 + 2]
cycloaddition leading directly to 13e (TS9) was identified with
DFT calculations. Repeated attempts to locate TS9 instead
optimized to TS8, which leads to 12e. On the basis of these
predictions, the most likely pathway to 13e is through a Cope
rearrangement of 12e which has a predicted barrier of 29.6
kcal/mol. According to their relative energetics, Cope
a
Reaction conditions: dimer, dienophile, SiC chip, mesitylene, μW,
b
c
170 °C, 15 min. Single diastereomer isolated. Isolated yield after
silica gel chromatography.
transition state. In general, reactions with lower barriers showed
more asynchronous transition-state structures.31
In a side by side comparison of MVK (9a) and cyclo-
pentenone 27, electronically similar dienophiles, the MVK π
system shows better secondary orbital overlap in transition
states in reactions with o-quinol 4 (Figure 3, TS2). In contrast,
the exo CO double bond of cyclic ketone 27 does not align
well with the o-quinol in the transition state (TS6). Similarly, in
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Scheme 4. DFT Results for α-Ketol Rearrangement
Pathways
energetics. Adventitious proton catalysis seems most compat-
ible with our experimental results. For the most favorable case,
B3LYP/6-31+G(d) calculations predict that deprotonated 13e
should undergo an exothermic rearrangement with a barrier of
only 13.1 kcal/mol. The apparent conflict of this result with our
LiHMDS-catalyzed experiments (vide infra) was resolved by
showing that rearrangement of lithiated 13e is now
endothermic by 3.5 kcal/mol because O−Li−O bridging
creates product strain.
Figure 3. Examples of transition-state structures.
Rearrangement of 4 to 8 can proceed by similarly diverse
mechanisms.22,32 DFT computations for the methyl migration
step (Scheme 5) showed low barriers for ionic pathways. Once
again, our experimental results are consistent with trace acid
catalysis.
Biological Studies. Both enantiomers of synthesized
bicyclo[2.2.2]octenones and cis-decalins were subjected to
screening at 20 μM for inhibition in three biological assays at
the National Cancer Institute (NCI): AP-1 (activator protein-1,
an oncogenic transcription factor),33 TRAIL (tumor necrosis
factor-α-related apoptosis-inducing ligand) sensitization,34 and
HIF-2 (hypoxia inducible factor 2).35 Compound (−)-31
(Figure 5, inset) showed selective inhibition against AP-1 at 4
μM concentration with luciferase reporter assays in HEK293
cells. TPA (12-O-tetradecanoylphorbol-13-acetate) induced
AP-1 activity was repressed by more than 50% after
pretreatment with the compound at 8 μM. However, the
compound did not show inhibition of NF-κB (nuclear factor
kappa B) or SRE (serum response element) dependent
transcription at the same concentration (Figure 5). SRE was
also used as a proliferation control which can measure cytotoxic
activity for the compound. Thus, this result suggests that
compound (−)-31 targets the events needed for AP-1
activation selectively, rather than other transcription factors
such as HIF-2, NF-κB, and SRE. As AP-1 is required for tumor
promotion and progression,36 identification of novel and
specific AP-1 inhibitors such as bicyclooctenone (-)-31 may
be beneficial for cancer prevention and therapy. Although
further experiments in the NCI 60-cell screen at 10 μM showed
that (−)-31 did not pass the threshold for further evaluation of
cell growth inhibition, analogues of compound 31 may be
pursued in future studies for SAR analysis.
Figure 4. DFT results for cycloaddition and Cope rearrangement.
rearrangement of 12e should be favored over cycloreversion.
Our trapping experiments (Scheme 3) supported only a [3,3]-
sigmatropic rearrangement for interconversion of 12e and 13e,
consistent with computations.
The rearrangement of 13e to 14 can proceed by thermal
isomerization of neutral 13e or through catalysis by acid, base,
or lithiation. Computational results are summarized in Scheme
4. The predicted thermal barrier (41.1 kcal/mol) is too high to
be operative. Protonation, deprotonation, or lithiation of 13e all
decrease the predicted barrier significantly and affect product
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Scheme 5. DFT Results for Dienone−Phenol Rearrangement
library. Further studies involving retro-Diels−Alder/Diels−
Alder cascade processes to produce natural products and
analogues are currently in progress and will be reported in
future publications.
EXPERIMENTAL SECTION
■
Optimization of the Retro-[4 + 2]/[4 + 2] Reaction. A 10 mL
microwave tube with a silicon carbide chip was charged with dimer 2
(10.0 mg, 0.030 mmol) and N-phenylmaleimide (6; 15.6 mg, 0.150
mmol).13 A 0.5 mL amount of solvent was added under an argon
atmosphere and the reaction was irradiated in a microwave reactor
(stir off) at the indicated temperature (cf. Table 1). Reactions in DMF
(entry 1) and DMA (entry 2) were directly submitted to UPLC-MS
analysis, and crude reaction mixtures were diluted with EtOAc, washed
with water and brine, and dried over MgSO4. The organic fraction was
concentrated, dried in vacuo, and purified by silica gel column
chromatography. Reactions in mesitylene were stopped after the
indicated reaction time, and the crude mixture was passed through a
short silica gel plug, flushed using hexanes to remove mesitylene, and
finally flushed with EtOAc to elute both the product and excess
maleimide 6. The organic fraction was concentrated, dried in vacuo,
analyzed by UPLC-MS, and purified by silica gel column
chromatography to afford cycloadduct 7.
Figure 5. (−)-31 shows higher selectivity for AP-1-dependent activity
than other transcription factors.
Reaction Partner Screening. In a microwave reaction vessel (4
× 48 well SiC block) were charged dimer 2 (3.0 mg, 0.009 mmol),
dienophiles/dienes (10 equiv), and 100 μL of mesitylene.13 The
resulting mixtures were heated in a microwave reactor with a 48-well
SiC block (stir off) at 180 °C (IR temperature) for 1 h. After the
reaction, the crude mixture was passed through a short silica gel plug,
flushed using hexanes to remove mesitylene, and finally flushed with
EtOAc to elute both the product and excess dienophiles/dienes. The
organic fraction was finally concentrated and analyzed by UPLC-MS.
General Procedure for Microwave Reaction of o-Quinol
Dimers (20−30 mg Scale). A 10 mL microwave tube with a silicon
carbide chip was charged with o-quinol dimer (0.060 mmol) and
dienophile (equivalents, cf. Tables 2−4). A 0.5 mL portion of
mesitylene was added under an argon atmosphere, and the reaction
mixture was irradiated in a microwave reactor at 170 or 180 °C (IR
temperature) for 15 min (stir off). Reactions were stopped after the
indicated reaction time, and the crude mixture was passed through a
short silica gel plug, flushed using hexanes to remove mesitylene (and
in a few cases excess nonpolar dienophiles), and finally flushed with
EtOAc to elute the crude products. The organic fraction was
concentrated and dried in vacuo, and the residue was purified by
CONCLUSION
■
We have utilized microwave-assisted parallel screening for
evaluation of Diels−Alder reactions of o-quinol dimers in an
effort to identify reactive reaction partners among a broad panel
of compounds. Elucidation of products, analysis of the results,
and computational studies allowed us to not only confirm the
diastereoselectivity of [4 + 2] cycloadditions of o-quinols but
also determine that sterics and proper secondary orbital
alignment are the major governing factors for dienophile
reactivity. The high concordance between experimental and
calculated results suggest that theoretical calculations of
energetics may be used to prescreen reaction partners for [4
+ 2] cycloadditions of o-quinols.37 Furthermore, biological
evaluation of a set of compounds generated in the study
showed that bicyclo[2.2.2]octenones may be worthwhile
scaffolds for development of screening libraries, as novel AP-
1 inhibitory activity was observed for one member of the small
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silica gel column chromatography to afford the corresponding Diels−
Alder adducts.
(1R,3S,4S,7R)-3-Hydroxy-3-methyl-7-[(E)-2-phenylethenyl]-
6-(propan-2-yl)bicyclo[2.2.2]oct-5-en-2-one (12aα). Dimer 2
(20.0 mg, 0.120 mmol) and 1-phenyl-1,3-butadiene38 (11a; 76.1 mg,
1.20 mmol) were thermolyzed by following the general procedure.
The crude mixture was purified by preparative TLC (hexanes/EtOAc
4/1) to afford product 12aα (28.8 mg, 81%) as a white solid: Rf = 0.22
(hexanes/EtOAc 5/1); mp 68−70 °C; IR (thin film) νmax 3439, 2962,
(1R,3S,4S,7S)-3-Hydroxy-7-(4-methyoxy)phenyl-3-methyl-6-
(propan-2-yl)bicyclo[2.2.2]oct-5-en-2-one (10c). Dimer 2 (20.0
mg, 0.060 mmol) and 4-vinylanisole (9c; 81.0 μL, 0.60 mmol) were
thermolyzed by following the general procedure. The crude mixture
was purified by silica gel chromatography (hexanes/EtOAc 10/1 to 8/
1) followed by preparative TLC (CH2Cl2/EtOAc 10/1) to afford
product 10c (35.5 mg, 98%) as a yellow oil: Rf = 0.41 (hexanes/EtOAc
2/1); IR (thin film) νmax 3434, 2959, 1721, 1511, 1248, 1178 cm−1; 1H
NMR (CDCl3, 400 MHz) δ 7.07 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0
Hz, 2H), 6.18 (d, J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.38 (dd, J = 8.4, 5.6
Hz, 1H), 3.06 (d, J = 0.8 Hz, 1H), 2.94 (ddd, J = 6.0, 3.2, 2.4 Hz, 1H),
2.68 (ddd, J = 12.8, 9.6, 2.4 Hz, 1H), 2.53 (s, 1H), 1.90 (sept, J = 6.8
Hz, 1H), 1.61 (ddd, J = 12.8, 6.0, 2.8 Hz, 1H), 1.28 (s, 3H), 0.89 (d, J
= 6.8 Hz, 3H), 0.73 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100
MHz) δ 213.0, 158.4, 144.7, 135.9, 128.7 (two carbons overlapping),
125.7, 113.6 (two carbons overlapping), 72.1, 59.0, 55.2, 43.1, 39.9,
33.1, 27.6, 25.9, 20.5, 19.7; HRMS-ESI (m/z) [M − H2O + H]+ calcd
1
2932, 1725, 1449, 1126 cm−1; H NMR (CDCl3, 500 MHz) δ 7.27−
7.26 (m, 4H), 7.20−7.17 (m, 1H), 6.37 (dd, J = 16.0, 1.0 Hz, 1H),
6.11 (ddd, J = 7.0, 1.5, 1.5 Hz, 1H), 5.86 (dd, J = 16.0, 8.5 Hz, 1H),
3.09 (dd, J = 2.0, 2.0 Hz, 1H), 3.00−2.94 (m, 1H), 2.83 (ddd, J = 7.0,
3.0, 2.5 Hz, 1H), 2.53 (ddd, J = 12.5, 8.5, 3.0 Hz, 1H), 2.50 (bs, 1H),
2.30 (doublet of sept, J = 7.0, 1.0 Hz, 1H), 1.26 (s, 3H), 1.21 (ddd, J =
13.0, 5.0, 2.5 Hz, 1H), 1.02 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 212.9, 144.4, 137.1, 132.6,
129.7, 128.5 (two carbons overlapping), 127.2, 126.2, 126.0 (two
carbons overlapping), 72.3, 56.6, 42.9, 39.2, 33.1, 27.3, 25.9, 20.9, 20.5;
HRMS-ESI (m/z) [M − H2O + H]+ calcd for C20H23O 279.1749,
found 279.1748; [α]22 = +119.5° (c = 0.91, CHCl3).
D
for C19H23O2 283.1698, found 283.1713; [α]22 = +36.4° (c = 0.67,
(1R,3S,4S,7S)-3-Hydroxy-3-methyl-7-[(E)-2-phenylethenyl]-
6-(propan-2-yl)bicyclo[2.2.2]oct-5-en-2-one (12aβ). Utilizing
the same protocol as for compound 12aα, product 12aβ (19.8 mg,
97%) was isolated as a white solid: Rf = 0.32 (hexanes/EtOAc 5/1);
mp 104−106 °C; IR (thin film) νmax 3440, 2962, 2871, 1726, 1449,
1142, 1081 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.33−7.26 (m, 4H),
7.21−7.17 (m, 1H), 6.40 (d, J = 15.6 Hz, 1H), 6.10 (ddd, J = 15.6, 8.8,
1.6 Hz, 1H), 6.04 (dd, J = 6.8, 1.2 Hz, 1H), 3.03 (dd, J = 1.6, 1.6 Hz,
1H), 2.85−2.82 (m, 1H), 2.65−2.58 (m, 1H), 2.40 (sept, J = 6.8 Hz,
1H), 2.30 (s, 1H), 2.12 (ddd, J = 12.8, 5.2, 2.0 Hz, 1H), 1.77−1.70 (m,
1H), 1.28 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 213.4, 147.8, 137.1, 132.1, 130.3,
D
CHCl3).
(1R,2S,6R,7S,9S)-9-Hydroxy-9-methyl-11-(propan-2-yl)-3,5-
dioxatricyclo[5.2.2.02,6]undec-10-ene-4,8-dione (10e). Dimer 2
(20.0 mg, 0.060 mmol) and vinylene carbonate (9e; 77.3 μL, 1.20
mmol) were thermolyzed by following the general procedure. The
crude mixture was purified by silica gel chromatography (hexanes/
EtOAc 3/1) to afford product 10e (23.1 mg, 76%) as a white solid: Rf
= 0.11 (hexanes/EtOAc 3/1); mp 135−137 °C; IR (thin film) νmax
1
3426, 2964, 1795, 1731, 1164, 1057 cm−1; H NMR (CDCl3, 400
MHz) δ 5.97 (d, J = 6.4 Hz, 1H), 5.36 (dd, J = 8.0, 3.6 Hz, 1H), 5.04
(dd, J = 8.0, 3.6 Hz, 1H), 3.64 (dd, J = 3.6, 2.0 Hz, 1H), 3.38 (dd, J =
6.4, 3.6 Hz, 1H), 2.43 (s, 1H), 2.39 (sept, J = 6.8 Hz, 1H), 1.32 (s,
3H), 1.022 (d, J = 6.8 Hz, 3H), 1.016 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 205.5, 154.4, 145.5, 122.2, 74.6, 74.3, 71.9, 54.4,
45.8, 33.1, 25.2, 20.23, 20.18; HRMS-ESI (m/z) [2M + Na]+ calcd for
128.5 (two carbons overlapping), 127.2, 126.3 (two carbons
overlapping), 125.5, 73.5, 56.6, 43.1, 42.5, 32.6, 26.4, 26.3, 20.54,
20.50; HRMS-ESI (m/z) [M + H]+ calcd for C20H25O2 297.1855,
found 297.1867; [α]22 = +137.8° (c = 0.57, CHCl3).
D
C26H32NaO10 527.1893, found 527.1880; [α]22 = +125.6° (c = 0.52,
D
(1S,4aR,8aS)-1-Hydroxy-1-methyl-6-(4-methylpent-3-en-1-
yl)-4-(propan-2-yl)-4a,5,8,8a-tetrahydronaphthalen-2(1H)-one
(13b). Dimer 2 (20.0 mg, 0.060 mmol) and β-myrcene 11c (103.3
μL, 0.60 mmol) were thermolyzed by following the general procedure.
The crude mixture was purified, and 13b was isolated as a colorless oil
CHCl3).
(1R,4S,7S)-Dimethyl-7-hydroxy-7-methyl-8-oxo-5-(propan-
2-yl)bicyclo[2.2.2]octa-2,5-diene-2,3-dicarboxylate (10f).
Dimer 2 (20.0 mg, 0.060 mmol) and dimethyl acetylenedicarboxylate
(9f; 74.0 μL, 0.60 mmol) in 300 μL of mesitylene were thermolyzed
by following the general procedure. The crude mixture was purified by
silica gel chromatography (CH2Cl2/EtOAc 15/1 to 10/1) to afford
product 10f (33.3 mg, 90%) as a yellow oil: Rf = 0.30 (CH2Cl2/EtOAc
1
(20.8 mg, 57%). H NMR, 13C NMR, and IR spectra for compound
13b were found to be identical with those reported in the literature:17
Rf = 0.38 (hexanes/EtOAc 5/1); [α]22D = +217.9° (c = 1.01, CHCl3).
(1S,4aR,8aS)-1-Hydroxy-1,6,7-trimethyl-4-(propan-2-yl)-
4a,5,8,8a-tetrahydronaphthalen-2(1H)-one (13c). Dimer 2 (20.0
mg, 0.060 mmol) and 2,3-dimethyl-1,3-butadiene (11c; 67.9 μL, 0.60
mmol) were thermolyzed by following the general procedure. The
crude mixture was purified by silica gel chromatography (hexanes/
EtOAc 20/1 to 15/1) to afford product 13c (27.3 mg, 92%) as an oil:
Rf = 0.38 (hexanes/EtOAc 8/1); IR (thin film) νmax 3491, 2968, 2926,
1722, 1671, 1242, 1152 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.85 (d,
J = 2.8 Hz, 1H), 3.55 (s, 1H), 2.94−2.91 (m, 1H), 2.38 (sept, J = 6.8
Hz, 1H), 2.35−2.30 (m, 3H), 2.07 (dd, J = 17.6, 6.8 Hz, 1H), 1.59 (s,
3H), 1.48 (s, 3H), 1.32 (s, 3H), 1.06 (d, J = 6.8 Hz, 3H), 1.01 (d, J =
6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 203.1, 172.8, 126.1,
123.3, 120.0, 76.6, 44.4, 36.8, 33.3, 30.8, 29.4, 24.4, 22.4, 20.6, 19.0,
18.7; HRMS-ESI (m/z) [M + H]+ calcd for C16H24O2 249.1855,
1
5/1); IR (thin film) νmax 3485, 2959, 1726, 1265 cm−1; H NMR
(CDCl3, 400 MHz) δ 6.03 (d, J = 6.4 Hz, 1H), 4.35 (d, J = 2.0 Hz,
1H), 4.04 (d, J = 6.0 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 2.54 (s, 1H),
2.48 (doublet of sept, J = 6.8, 1.2 Hz, 1H), 1.32 (s, 3H), 1.02 (d, J =
6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 201.9, 166.4, 164.2,
149.8, 143.2, 134.4, 123.7, 67.4, 58.1, 52.7, 52.6, 50.8, 31.9, 26.3, 20.3
(two carbons overlapping); HRMS-ESI (m/z) [M + Na]+ calcd for
C16H20NaO6 331.1158, found 331.1158; [α]22 = +58.7° (c = 0.51,
D
CHCl3).
(1S,3S,4R)-3-Hydroxy-3-methyl-6-phenyl-7-(propan-2-yl)-
bicyclo[2.2.2]octa-5,7-dien-2-one (10g). Dimer 2 (20.0 mg, 0.060
mmol) and vinylene carbonate (9g; 65.9 μL, 1.20 mmol) were
thermolyzed by following the general procedure. The crude mixture
was purified by silica gel chromatography (hexanes/EtOAc 8/1) to
afford product 14 (25.8 mg, 80%) as a yellow oil: Rf = 0.27 (hexanes/
found 249.1876; [α]22 = +133.6° (c = 0.46, CHCl3).
D
(1S,2R,7S,8R,10S)-10-Hydroxy-10-methyl-12-(propan-2-yl)-
tricyclo[6.2.2.02,7]dodeca-5,11-dien-9-one (12e). Dimer 2 (60.0
mg, 0.180 mmol) and 1,3-cyclohexadiene (11e; 343.0 μL, 3.60 mmol)
were thermolyzed by following the general procedure. The crude
mixture was purified by silica gel chromatography (hexanes/EtOAc
20/1 to 15/1) to afford 12e (51.8 mg, 57%) as a white solid: Rf = 0.32
(hexanes/EtOAc 5/1); mp 46−48 °C; IR (thin film) νmax 3443, 2960,
2928, 1725, 1366, 1137 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.89 (d,
J = 7.6 Hz, 1H), 5.87−5.82 (m, 1H), 5.42 (ddd, J = 9.6, 2.4, 2.4 Hz,
1H), 3.00 (dd, J = 2.0, 2.0 Hz, 1H), 2.79−2.72 (m, 2H), 2.64−2.62
(m, 1H), 2.52 (s, 1H), 2.22 (doublet of sept, J = 7.2, 0.8 Hz, 1H),
1.93−1.86 (m, 1H), 1.84−1.75 (m, 1H), 1.61 (dddd, J = 12.4, 10.0,
EtOAc 3/1); IR (thin film) νmax 3434, 2963, 1724, 1445, 1068 cm−1
;
1H NMR (CDCl3, 400 MHz) δ 7.46−7.44 (m, 2H), 7.36−7.32 (m,
2H), 7.29−7.26 (m, 1H), 6.73 (dd, J = 6.0, 2.0 Hz, 1H), 6.08 (dd, J =
6.4, 2.0 Hz, 1H), 4.43 (dd, J = 2.0, 2.0 Hz, 1H), 3.79 (ddd, J = 6.4, 6.4,
2.0 Hz, 1H), 2.53 (sept, J = 6.8 Hz, 1H), 2.30 (s, 1H), 1.35 (s, 3H),
1.07 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 205.3, 149.2, 141.1, 136.0, 129.2, 128.6 (two carbons
overlapping), 127.8, 125.3 (two carbons overlapping), 125.1, 69.5,
60.3, 48.5, 32.1, 26.4, 20.7 (two carbons overlapping); HRMS-ESI (m/
z) [M + Na]+ calcd for C18H20NaO2 291.1361, found 291.1363;
[α]22 = +27.6° (c = 0.81, CHCl3).
D
8951
dx.doi.org/10.1021/jo201658y|J. Org. Chem. 2011, 76, 8944−8954

The Journal of Organic Chemistry
Article
4.8, 4.8 Hz, 1H), 1.23 (s, 3H), 1.21−1.16 (m, 1H), 0.94 (d, J = 6.8 Hz,
3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 213.6,
144.8, 130.2, 128.4, 125.3, 72.9, 56.3, 49.2, 35.5, 32.9, 31.8, 26.3, 25.9,
23.5, 20.8, 20.5; HRMS-ESI (m/z) [M + H]+ calcd for C16H23O2
C16H21O 229.1592, found 229.1604; [α]22 = −90.0° (c = 0.65,
D
CHCl3).
(1R,2S,6R,7S,9S)-11-tert -Butyl-9-hydroxy-9-methyl-3,5-
dioxatricyclo[5.2.2.02,6]undec-10-ene-4,8-dione (20). Dimer
(+)-15 (30.0 mg, 0.083 mmol) and methyl vinyl ketone (9; 105.4
μL, 1.66 mmol) were thermolyzed by following the general procedure.
The crude mixture was purified by silica gel chromatography
(hexanes/EtOAc 5/1 to 3/1) to afford product 20 (34.8 mg, 78%)
as a colorless oil: Rf = 0.13 (hexanes/EtOAc 3/1); IR (thin film) νmax
247.1698, found 247.1721; [α]22 = +160.4° (c = 1.17, CHCl3).
D
(1R,2S,3S,7R,8S )-3-Hydroxy-3-methyl-6-(propan-2-yl)-
tricyclo[6.2.2.02,7]dodeca-5,9-dien-4-one (13e). Utilizing the
same protocol for compound 12e, product 13e (22.5 mg, 25%) was
isolated as a white solid: Rf = 0.39 (hexanes/EtOAc 5/1); mp 52−53
1
3423, 2965, 1786, 1731, 1367, 1162, 1058 cm−1; H NMR (CDCl3,
1
°C; IR (thin film) νmax 3463, 2963, 2867, 1673, 1376, 1170 cm−1; H
400 MHz) δ 5.99 (d, J = 6.8, 1.2 Hz, 1H), 5.36 (dd, J = 8.0, 3.6 Hz,
1H), 5.03 (dd, J = 8.0, 3.2 Hz, 1H), 3.81 (dd, J = 3.6, 2.0 Hz, 1H), 3.39
(dd, J = 6.8, 3.2 Hz, 1H), 2.56 (bs, 1H), 1.31 (s, 3H), 1.04 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 205.8, 154.4, 147.9, 121.2, 74.5, 74.2,
71.8, 52.9, 45.6, 34.9, 27.8 (three carbons overlapping), 25.3; HRMS-
ESI (m/z) [2M + H]+ calcd for C28H37O10 533.2387, found 533.2399;
NMR (CDCl3, 400 MHz) δ 6.04 (dd, J = 3.2, 3.2 Hz, 1H), 5.84 (s,
1H), 5.77 (dd, J = 3.2, 3.2 Hz, 1H), 3.99 (s, 1H), 2.96 (dddd, J = 4.4,
3.2, 2.0, 2.0 Hz, 1H), 2.83 (dd, J = 8.0, 2.8 Hz, 1H), 2.78 (ddd, J = 4.0,
2.0, 2.0 Hz, 1H), 2.44 (sept, J = 6.8 Hz, 1H), 2.26 (dd, J = 8.4, 1.6 Hz,
1H), 1.64−1.59 (m, 1H), 1.52 (dddd, J = 12.4, 9.2, 2.8, 2.8 Hz, 1H),
1.40 (dddd, J = 12.4, 12.4, 3.2, 3.2 Hz, 1H), 1.27−1.20 (m, 1H), 1.19
(s, 3H), 1.08 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 202.5, 170.8, 133.8, 132.7, 119.2, 73.9, 47.9,
45.7, 35.4, 32.8, 32.0, 29.9, 26.1, 24.5, 23.2, 20.9; HRMS-ESI (m/z )
[α]22 = −176.9° (c = 1.09, CHCl3).
D
(12-Hydroxy-13-oxotetracyclo[9.2.2.02,10.03,8]pentadeca-
3,5,7,14-tetraen-12-yl)methyl Benzoate (21). Gradifloracin (16;
10.0 mg, 0.020 mmol) and indene (9b; 23.3 μL, 0.20 mmol) in
mesitylene were irradiated in a microwave reactor at 170 °C for 15
min. Following the general procedure, the obtained crude mixture was
purified by silica gel chromatography (hexanes/EtOAc 10/1 to 8/1) to
afford product 21 (11.8 mg, 80%) as a light yellow oil: Rf = 0.38
(hexanes/EtOAc 3/1). IR (thin film) νmax 3443, 2917, 2849, 1726,
1692, 1272 cm−1; 1H NMR (CDCl3, 400 MHz) δ 8.08 (dd, J = 8.4, 1.2
Hz, 2H), 7.60−7.56 (m, 1H), 7.45 (dd, J = 8.4, 8.4 Hz, 2H), 7.19−
7.13 (m, 3H), 7.12−7.09 (m, 1H), 6.35 (dd, J = 7.2, 7.2 Hz, 1H), 5.94
(dd, J = 7.2, 7.2 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.28 (d, J = 12.0
Hz, 1H), 3.83 (dd, J = 9.2, 2.0 Hz, 1H), 3.57 (ddd, J = 6.4, 2.8, 1.2 Hz,
1H), 3.50−3.43 (m, 1H), 3.29 (ddd, J = 6.4, 2.8, 1.2 Hz, 1H), 3.23
(dd, J = 16.8, 10.4 Hz, 1H), 3.13 (s, 1H), 2.69 (dd, J = 16.8, 4.4 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 209.9, 166.6, 144.3, 142.4,
133.3, 133.2, 129.8 (two carbons overlapping), 129.6, 128.6, 128.5
(two carbons overlapping), 127.3, 126.7, 124.4, 124.0, 74.3, 68.4, 53.1,
50.1, 45.4, 37.7, 33.9; HRMS-ESI (m/z) [M + Na]+ calcd for
[M + H]+ calcd for C16H23O2 247.1698, found 247.1707; [α]22
−128.1° (c = 0.52, CHCl3).
=
D
1-[(1R,2S,3S,6R ,7S)-3-Hydroxy-5-(propan-2-yl)tricyclo-
[5.2.2.02,6]undeca-4,8-dien-3-yl]ethanone (14). Utilizing the
same protocol for compound 12g, product 14 (8.2 mg, 9%) was
isolated as a white solid: Rf = 0.46 (hexanes/EtOAc 5/1); mp 98−100
°C; IR (thin film) νmax 3450, 2952, 2936, 2915, 1698, 1367, 1102
1
cm−1; H NMR (CDCl3, 500 MHz) δ 6.27 (dd, J = 7.2, 7.2 Hz, 1H),
5.89 (dd, J = 7.2, 7.2 Hz, 1H), 5.03 (dd, J = 1.5, 1.5 Hz, 1H), 3.92 (s,
1H), 2.98 (ddd, J = 8.5, 2.2, 2.2 Hz, 1H), 2.77−2.75 (m, 1H), 2.58−
2.55 (dd, J = 2.0 Hz, 1H), 2.34 (dd, J = 8.2, 2.2 Hz, 1H), 2.29 (sept, J
= 7.0 Hz, 1H), 2.09 (2, 3H), 1.49 (dddd, J = 12.0, 9.5, 4.5, 2.2 Hz,
1H), 1.41 (dddd, J = 12.0, 9.0, 3.0, 3.0 Hz, 1H), 1.33 (dddd, J = 11.5,
11.5, 3.5, 3.5 Hz, 1H), 1.26−1.20 (m, 1H), 1.06 (d, J = 7.0 Hz, 3H),
1.04 (d, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.5,
159.5, 134.0, 129.2, 124.8, 90.8, 53.5, 48.7, 32.7, 30.9, 27.7, 25.1, 24.2,
23.6, 21.7, 20.8; HRMS-ESI (m/z) [M − H2O + H]+ calcd for
C23H20NaO4 383.1259, found 383.1252; [α]22 = −22.3° (c = 0.24,
C16H21O 229.1592, found 229.1597; [α]22 = +210.4° (c = 0.30,
D
D
CHCl3). The ee for 21 (24%) was determined by using a Waters
Breeze HPLC System (ChiralPak AD-H, 150 × 4.6 mm, 10%
isopropyl alcohol in hexane, 1.0 mL/min, retention time 12.3 min
(minor enantiomer) and 14.6 min (major enantiomer)) using UV
detection at 254 nm.
CHCl3).
Gradifloracin (16). Oxidation of salicyl alcohol benzoate (50.0
mg, 0.17 mmol) according to the reported procedure12 (1.2 equiv of
DIEA, 1.5 equiv of [(−)-sparteine]2Cu2O2(PF6)2, 3 Å MS, O2,
CH2Cl2, −78 °C, 40 h) generated dimer 16 as a gray solid (15.0 mg,
9-Hydroxy-7,9-dimethyl-4-phenyl-4-azatricyclo[5.2.2.02,6]-
undec-10-ene-3,5,8-trione (22). Dimer 17 (20.0 mg, 0.072 mmol)
and N-phenylmaleimide (6; 37.4 mg, 0.216 mmol) were thermolyzed
by following the general procedure. The crude mixture was purified by
silica gel chromatography (hexanes/EtOAc 2/1) to afford product 2
(44.6 mg, 99%) as a light yellow solid: Rf = 0.08 (hexanes/EtOAc 3/
1); mp 161−163 °C; IR (thin film) νmax 3444, 2977, 1703, 1698, 1385,
1186 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.45−7.40 (m, 2H), 7.39−
7.34 (m, 1H), 7.17 (dd, J = 7.6, 1.6 Hz, 2H), 6.42 (dd, J = 8.4, 6.4 Hz,
1H), 5.95 (dd, J = 8.4, 1.2 Hz, 1H), 3.85 (dd, J = 8.4, 3.6 Hz, 1H), 3.54
(ddd, J = 6.4, 3.2, 1.6 Hz, 1H), 2.96 (d, J = 8.0 Hz, 1H), 2.95 (s, 1H),
1.57 (s, 3H), 1.32 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.3,
177.1, 174.4, 133.9, 132.9, 131.6, 129.1 (two carbons overlapping),
128.7, 126.4 (two carbons overlapping), 70.8, 50.5, 45.4, 44.9, 40.9,
25.6, 14.8; HRMS-ESI (m/z) [M + H]+ calcd for C18H18NO4
312.1236, found 312.1249.
1
28%, 61% brsm) after silica gel chromatography. The H, 13C NMR,
IR, and HRMS data for 16 were identical with those reported in the
literature:24,25 [α]22D = −5.1° (c = 0.57, CHCl3; lit. [α]22D = −13.6°, c
= 0.728, CHCl3). The ee for 16 (24%) was determined on the basis of
chiral HPLC analysis of its derivative 21.
Dimer (±)-17. Oxidation of 2,6-dimethylphenol (20.0 mg, 0.164
mmol) according to the reported procedure12 (1.0 equiv of
LiOH·H2O, 1.2 equiv of (N,N′-di-tert-butylethylenediami-
ne)2Cu2O2(PF6)2, 3 Å MS, O2, CH2Cl2, −78 °C, 16 h) generated
dimer 17 as a light yellow solid (16.2 mg, 72%) after silica gel
chromatography. 1H, 13C NMR, IR, and HRMS data for 17 were
identical with those reported in the literature.25
(1R,2S,6R,7S,9R)-11-tert-Butyl-9-hydroxy-9-methyltricyclo-
[5.2.2.02,6]undeca-4,10-dien-8-one (19). Dimer (+)-15 (30.0 mg,
0.083 mmol) and dicyclopentadiene (18; 54.9 mg, 0.415 mmol) were
thermolyzed according to the general procedure. The crude mixture
was purified by silica gel chromatography (hexanes/EtOAc 15/1) to
afford product 19 (38.0 mg, 93%) as a white solid: Rf = 0.26 (hexanes/
EtOAc 7/1); mp 92−93 °C; IR (thin film) νmax 3425, 2963, 2928,
1721, 1364 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.85 (dd, J = 6.8, 2.0
Hz, 1H), 5.62−5.59 (m, 1H), 5.34−5.32 (m, 1H), 3.25 (dd, J = 2.0,
2.0 Hz, 1H), 3.20−3.10 (m, 2H), 2.83 (dddd, J = 9.2, 4.8, 2.4, 2.4 Hz,
1H), 2.63 (bs, 1H), 2.46 (ddddd, J = 16.8, 9.2, 2.0, 2.0, 2.0 Hz, 1H),
1.94 (ddddd, J = 16.8, 6.0, 2.0, 2.0, 2.0 Hz, 1H), 1.21 (s, 3H), 0.92 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 214.9, 148.7, 132.8, 130.4,
122.2, 73.2, 52.6, 50.0, 47.5, 38.2, 34.2, 33.2, 28.2 (three carbons
overlapping), 26.3; HRMS-ESI (m/z) [M − H2O + H]+ calcd for
12-Hydroxy-12-methyl-14-(propan-2-yl)tetracyclo-
[9.2.2.02,10.03,8]pentadeca-3,5,7,14-tetraen-13-one (23). Dimer
17 (20.0 mg, 0.072 mmol) and indene (11; 83.9 μL, 0.72 mmol)
were thermolyzed by following the general procedure. The crude
mixture was purified by preparative TLC (hexanes/EtOAc 3/1) to
1
afford product 23 (28.7 mg, 78%) as a light yellow solid. The H, 13
C
NMR, IR, and HRMS dataf or 16 were identical with those reported in
the literature.1a
8-Hydroxy-1,8-dimethyl-3-oxatricyclo[5.2.2.02,6]undec-10-
en-9-one (24). Dimer 17 (20.0 mg, 0.072 mmol) and 2,3-
dihydrofuran 9d (111.9 μL, 1.48 mmol) were thermolyzed following
the general procedure. The concentrated mixture was dissolved in 2
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Article
mL of CH2Cl2 followed by addition of MP-TsOH resin (100 mg), and
the reaction mixture was shaken for 30 min. The MP-TsOH resin was
filtered away, and the filtrate was concentrated. The crude mixture was
purified by silica gel chromatography (hexanes/EtOAc 8/1 to 7/1) to
afford product 24 (25.6 mg, 85%) as a white solid: Rf = 0.27 (hexanes/
EtOAc 2/1); mp 117−119 °C; IR (thin film) νmax 3429, 2973, 2933,
ment by the U.S. Government. We thank Dr. Emil Lobkovsky
(Cornell University) for X-ray crystal structure analysis and
Anton Paar Corp., CEM Corp., and Waters Corp. for assistance
with instrumentation.
1
1726, 1451, 1366, 1080 cm−1; H NMR (CDCl3, 400 MHz) δ 6.33
REFERENCES
■
(dd, J = 7.2, 7.2 Hz, 1H), 5.75 (dd, J = 8.4, 1.6 Hz, 1H), 3.89−3.82 (m,
2H), 3.53 (ddd, J = 8.4, 8.4, 8.4 Hz, 1H), 3.18 (ddd, J = 8.4, 8.4, 8.4
Hz, 1H), 2.92−2.90 (m, 1H), 2.50 (s, 1H), 2.10−2.00 (m, 1H), 1.64−
1.55 (m, 1H), 1.32 (s, 3H), 1.24 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 213.4, 134.1, 132.6, 84.5, 71.9, 69.1, 55.1, 46.4, 39.0, 30.9,
26.5, 14.5; LRMS m/z (% relative intensity): 231.1 [(M + Na)+, 31],
191.1 (100), 163.1 (70), 141.1 (34) .
(1) For use of o-quinol dimers in retro-[4 + 2]/[4 + 2] cascades, see:
(a) Singh, V. K.; Deota, P. T.; Bedekar, A. V. J. Chem. Soc., Perkin
Trans. 1 1992, 903. (b) Singh, V.; Samanta, B. Tetrahedron Lett. 1999,
40, 1807.
(2) Dong, S.; Hamel, E.; Bai, R.; Covell, D. G.; Beutler, J. A.; Porco,
J. A. Jr. Angew. Chem.; Int. Ed. 2009, 48, 1494.
(3) For use of MOB-derived dimers, see: (a) Liao, C. C.; Peddinti,
R. K. Acc. Chem. Res. 2002, 35, 856. (b) Chittimalla, S. K.; Shiao, H. Y.;
Liao, C. C. Org. Biomol. Chem. 2006, 4, 2267. (c) Snyder, S. A.;
Kontes, F. J. Am. Chem. Soc. 2009, 131, 1745.
(4) For reviews on o-quinol and MOB-derived [4 + 2] cyclodimers,
see: (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004,
104, 1383. (b) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008,
467.
9-Hydroxy-11-methyl-4-phenyl-9-(propan-2-yl)-4-
azatricyclo[5.2.2.02,6]undec-10-ene-3,5,8-trione (25). Dimer 18
(30.0 mg, 0.090 mmol) and N-phenylmaleimide (6; 46.9 mg, 0.271
mmol) in mesitylene were thermolyzed by following the general
procedure. The crude mixture was purified by silica gel chromatog-
raphy (hexanes/EtOAc 6/1 to 5/1) to afford product 25 (49.1 mg,
80%) as a white solid: Rf = 0.31 (hexanes/EtOAc 2/1); mp 169−170
°C; IR (thin film) νmax 3480, 2966, 2924, 1708, 1500, 1383, 1187
cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.45−7.41 (m, 2H), 7.38−7.35
(m, 1H), 7.14 (dd, J = 7.2, 1.2 Hz, 2H), 6.03 (ddd, J = 6.4, 1.6, 1.6 Hz,
1H), 3.68 (dd, J = 8.0, 3.2 Hz, 1H), 3.59 (dd, J = 3.2, 1.6 Hz, 1H), 3.56
(dd, J = 6.4, 3.2 Hz, 1H), 3.36 (dd, J = 8.0, 3.2 Hz, 1H), 2.46 (s, 1H),
1.87 (sept, J = 6.8 Hz, 1H), 1.84 (d, J = 1.6 Hz, 3H), 0.98 (d, J = 6.8
Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
209.4, 177.5, 175.1, 136.0, 131.6, 129.1(two carbons overlapping),
128.8, 126.3 (two carbons overlapping), 125.0, 75.9, 53.5, 42.9, 42.2,
39.8, 33.2, 20.7, 17.8, 16.2; HRMS-ESI (m/z) [M + H]+ calcd for
C20H22NO4 340.1549, found 340.1553.
Computational Methods. All calculations were carried out with
Gaussian 03 revision E.01,39 Spartan 06, or Spartan 08.40 Structures
were optimized and characterized by frequency analysis at the B3LYP/
6-31G(d) level of theory with all transition states showing a single
imaginary vibrational mode corresponding to the expected reaction.41
Unscaled zero point vibrational energy (ZPVE) corrections have been
applied to total energies. Energies and geometries for stationary points
are summarized in the Supporting Information. Solvation was not
included in these calculations, because it is expected that our nonpolar
solvents would not significantly affect reaction energetics.
(5) Kappe, C. O. Chem. Soc. Rev. 2008, 37, 1127.
(6) For a recent review on use of graphite in microwave reactions,
see: (a) Besson, T.; Thiery, V.; Dubac, J. Microwaves in Organic
Synthesis, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2006; Vol. 1, p
416. For a recent example employing graphite, see: (b) Cho, H. Y.;
Ajaz, A.; Himali, D.; Waske, P. A.; Johnson, R. P. J. Org. Chem. 2009,
74, 4137.
(7) (a) Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2006, 71, 4651.
(b) Razzaq, T.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73,
6321. For silicon carbide, see: (c) Properties of Silicon Carbide; Harris,
G. L., Ed.; Institute of Electrical Engineers: London, 1995. (d) Silicon
Carbide: Recent Major Advances; Choyke, W. J., Matsunami, H., Pensl,
G., Eds.; Springer: Berlin, 2004. (e) Advances in Silicon Carbide
Processing and Applications; Saddow, S. E., Agarwal, A, Eds.; Artech
House: Norwood, MA, 2004.
(8) Damm, M.; Kappe, C. O. Mol. Diversity 2009, 13, 529.
(9) Kremsner, J. M.; Stadler, A; Kappe, C. O. J. Comb. Chem. 2007, 9,
285. (b) Damm, M.; Kappe, C. O. J. Comb. Chem. 2009, 11, 460.
(10) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A. Jr. J. Am.
Chem. Soc. 2007, 129, 1413.
(11) (a) Li, C.; Johnson, R. P.; Porco, J. A. Jr. J. Am. Chem. Soc. 2003,
125, 5095−5106. (b) Lei, X.; Johnson, R. P.; Porco, J. A. Jr. Angew.
Chem., Int. Ed. 2003, 42, 3913.
(12) Dong, S.; Zhu, J.; Porco, J. A. Jr. J. Am. Chem. Soc. 2008, 130,
2738.
(13) See the Supporting Information for complete instrumentation
and experimental details.
(14) For UPLC, see: (a) Mazzeo, J. R.; Neue, U. D.; Kele, M.;
ASSOCIATED CONTENT
* Supporting Information
Text, figures, and a CIF file giving experimental procedures and
characterization data for all new compounds, including X-ray
structure analysis of compound 10e, X-ray crystallographic data,
and detailed computational methods and results. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
Plumb, R. S. Anal. Chem. 2005, 77, 460A. (b) Novak
́ ́ ́
ova, L.; Matysova,
L.; Solich, P. Talanta 2006, 68, 908.
AUTHOR INFORMATION
Corresponding Author
*E-mail: porco@bu.edu; richard.johnson@unh.edu.
■
(15) For a recent review on the dienone−phenol rearrangement, see:
Whiting, D. A. In Comprehensive Organic Syntheses; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 3, pp
803−821.
(16) Carman, R. M.; Van Dongen, J. M. A. M. Aust. J. Chem. 1984,
37, 2607.
(17) Wannere, C. S.; Paul, A.; Herges, R.; Houk, K. N.; Schaefer, H.
F. III; Schleyer, P. v. R. J. Comput. Chem. 2007, 28, 344.
(18) Snider, B. B.; Chen, Z. Org. Prep. Proced. Int. 1999, 31, 537.
(19) Kuo, Y. H.; Chen, C. H.; Huang, S. L. Chem. Pharm. Bull. 1999,
46, 181.
(20) Competition between Cope rearrangements and retro-Diels−
Alder reactions in similar bicyclic structures has been reported: (a) Su,
K.-J.; Mieusset, J.-L.; Arion, V. B.; Brecker, L.; Brinker, U. H. Org. Lett.
2007, 9, 113. (b) Jeong, J.-P.; Lee, O.-S.; Yang, K. Bull. Korean Chem.
Soc. 2002, 23, 829. (c) Singh, V.; Sharma, U.; Prasanna, V.; Porinchu,
M. Tetrahedron 1995, 51, 6015.
ACKNOWLEDGMENTS
■
This work was generously supported by the NIGMS CMLD
Initiative (P50 GM067041, J.A.P.), the National Science
Foundation (CHE-0910826, R.P.J.), and the Intramural
Research Program of the NIH, National Cancer Institute,
Center for Cancer Research. This project has been funded in
part with federal funds from the National Cancer Institute,
National Institutes of Health, under contract
HHSN261200800001E. The content of this publication does
not necessarily reflect the views or policies of the Department
of Health and Human Services, nor does mention of trade
names, commercial products or organizations imply endorse-
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Article
(21) For [3,3]-sigmatropic rearrangement of bridged 1,5-dienes, see:
Bultman, M. S.; Ma, J.; Gin, D. Y. Angew. Chem., Int. Ed. 2008, 47,
6821 and references cited therein.
(22) Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477.
(23) (a) Nagahama, S.; Tazaki, M. Bull. Chem. Soc. Jpn. 1987, 60,
4175. (b) Shimizu, T.; Hiranuma, S.; Qian, Z.-H.; Yoshioka, H. Synlett
1991, 725.
(24) Liao, Y. H.; Xu, L. Z.; Yang, S. L.; Dai, J.; Zhen, Y. S.; Zhu, M.;
Sun, N. J. Phytochemistry 1997, 45, 729.
(25) Gagnepain, J.; Castet, F.; Quideau, S. Angew. Chem., Int. Ed.
2007, 46, 1533.
(26) Dory, Y. L.; Roy, A.-L.; Soucy, P.; Deslongchamps, P. Org. Lett.
2009, 11, 1197.
(27) Gagnepain, J.; Mereau, R.; Dejugnac, D.; Leger, J.-M.; Castet,
F.; Deffieux, D.; Pouysegu, L.; Quideau, S. Tetrahedron 2007, 63, 6493.
(28) Details of computational methods and results are presented in
the Supporting Information.
(29) (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.
(b) Macaulay, J. B.; Fallis, A. G. J. Am. Chem. Soc. 1990, 112, 1136.
(30) Hou, H.-F.; Peddinti, R. K.; Liao, C.-C. Org. Lett. 2002, 4, 2477.
(31) In each case, we find that the transition state DFT wavefunction
is stable relative to becoming an open shell. Thus, these reactions may
be described as asynchronous but concerted. Further examples of
transition-state structures are shown in the Supporting Information.
(32) Miller, B. Acc. Chem. Res. 1975, 8, 245 and references therein.
(33) Ruocco, K. M.; Goncharova, E. I.; Young, M. R.; Colburn, N.
H.; McMahon, J. B.; Henrich, C. J. J. Biomol. Screen. 2007, 12, 133.
(34) Booth, N. L.; Sayers, T. J.; Brooks, A. D.; Thomas, C. F.;
Jacobsen, K.; Goncharova, E. I.; McMahon, J. B.; Henrich, C. J. Cancer
Immunol. Immunother. 2009, 58, 1229.
(35) Woldemichael, G. M.; Vasselli, J. R.; Gardella, R. S.; McKee, T.
C.; Linehan, W. M.; McMahon, J. B. J. Biomol. Screen. 2006, 11, 678.
(36) Young, M. R.; Li, J.; Rincon, M.; Flavell, R. A.; Sathyanarayana,
B. K.; Hunziker, R. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9827.
́
(37) Rodriguez, A. M.; Prieto, P.; de la Hoz, A.; Diaz-Ortiz, A. Org.
Biomol. Chem. 2011, 9, 2371.
(38) Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 320.
(39) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.;
Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J.
B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J.
J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A. Gaussian 03, Revision
E.01; Gaussian Inc., Wallingford, CT, 2004.
(40) Spartan 06 and Spartan 08; Wavefunction Inc., Irvine, CA.
(41) (a) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100,
12974. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (c) Lee, C.;
Yang, Y.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
8954
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