A deep cavitand catalyzes the Diels-Alder reaction of bound maleimides

Article abstract of DOI:10.1039/b713104f

A deep cavitand catalyzes Diels-Alder reactions of bound maleimides via activation of the dienophile by interaction with the organized hydrogen bonding network at the cavitand rim. Rapid in-out exchange of reactant and product allows efficient turnover. The increase in steric bulk of the reaction product lessens its binding affinity, reducing (and in some cases completely eliminating) product inhibition. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713104f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A deep cavitand catalyzes the Diels–Alder reaction of bound maleimides†
Richard J. Hooley and Julius Rebek Jr.*
Received 28th August 2007, Accepted 21st September 2007
First published as an Advance Article on the web 4th October 2007
DOI: 10.1039/b713104f
A deep cavitand catalyzes Diels–Alder reactions of bound maleimides via activation of the dienophile by
interaction with the organized hydrogen bonding network at the cavitand rim. Rapid in–out exchange
of reactant and product allows efficient turnover. The increase in steric bulk of the reaction product
lessens its binding affinity, reducing (and in some cases completely eliminating) product inhibition.
Fig. 1, molecular modeling indicates that medium-sized cyclic
Introduction
alkyl groups such as adamantanes position the reactive maleimide
Selective binding of a substrate, followed by activation of that
for its carbonyl groups to make good contacts with the organized
species for reaction and subsequent product release from the active
H-bonding network at the cavitand rim. The maleimides’ double
site are the core features of catalysis, enzymatic or otherwise.1
bonds remain exposed above the receptor for reaction. The in–
out exchange rate for species of this type is on the order of 2 s−1,
far faster than the cycloaddition rate.6b The rapid exchange of
product and reactant positions the receptor to act as a catalyst,
not just a promoter of the reaction. In addition, cycloaddition
to this olefin would increase the steric bulk of the product with
respect to reactant, lowering its binding affinity and reducing
product inhibition. The proposed reaction mechanism is shown
in Fig. 2.
Enzymes have exquisite selectivities for transition states, but
this property is difficult to attain in most synthetic mimics2
and product inhibition,3 particularly for condensation reactions,
thwarts catalysis. Building steric hindrance into products can
facilitate displacement by reactants and stimulate turnover. This
tactic has led to acceleration4 of cycloadditions in nonhydroxylic
media using capsules. Even catalysis was recently observed using
a bowl-shaped, metal–ligand receptor in water by Fujita et al.5
Here we report the application of this method of reducing product
inhibition to cavitands in organic solvents.
Cavitands such as 1 are vase-like structures capable of binding
neutral and cationic guests that fill the appropriate amount of its
space.6 The base of the cavitand presents an electron-rich p surface
to guests. At the rim, eight secondary amides stabilize the vase-like
conformation shown and also provide a polar environment and
organized H-bonding sites for guests. The amides can rotate to
present hydrogen bond donors and acceptors to guests held within.
For example, this region of organized solvation can stabilize the
buildup of positive charge during quaternization of bound amine
nucleophiles,7 or stabilize the negative charge in the formation of
Meisenheimer complexes.8 Earlier results with stoichiometric re-
actions led us to the possibility of catalyzing Diels–Alder reactions.
Many cycloadditions of electron deficient olefins and anthracenes
occur under mild conditions and are performed in the absence
of catalyst at room temperature or below. Simple hydrophobic
association can increase effective concentrations in water and has
produced accelerations and catalysis.5,9 Lewis acid catalysis is well-
known to accelerate the Diels–Alder reaction, but Brønsted acids
have also been used as catalysts especially in recent times.10 Suitably
reactive dienophiles include N-alkylmaleimides: a number of these
show strong binding affinity (102–104 M−1, see Table 1) for cavitand
1 in mesitylene-d12. This solvent fits awkwardly into the cavitand
and does not compete well with intended guests.11 As shown in
Fig. 1 The deep cavitand used as catalyst; minimized representation of
the complex of 1 and adamantyl maleimide 4, illustrating the proximity of
the maleimide to the organized solvation of the amide rim.
The Skaggs Institute for Chemical Biology and the Department of Chemistry,
The Scripps Research Institute, La Jolla, CA, 92037, USA. E-mail: jrebek@
scripps.edu; Fax: +1 858.784.2876; Tel: +1 858.784.2250
† Electronic supplementary information (ESI) available: Tabulated kinetic
data. See DOI: 10.1039/b713104f
Fig. 2 Reaction mechanism.
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Table 1 Kinetic analysis of the Diels–Alder cycloaddition catalyzed by cavitand 1
Substrate
K/M−1
k
uncat/10−3 M−1 min−1
k
cat/10−3 M−1 min−1
kacc/kuncat
4
80
7.6
260
34
5
6
120
27
775
980
29
57
>104
17
7
8
>104
>104
3.3
140
100
43
4
22
accelerations in the range of >20-fold. The N-cyclooctylmaleimide
6 proved to be both the best guest for the cavitand, with a binding
constant >104 M−1 (the detection limit of the NMR spectrometer)
and the best reactant, showing a 57-fold acceleration upon
binding. In addition, no product inhibition was observed: product
11 showed no affinity for the cavitand. The tert-octylmaleimide 7
showed similar characteristics to 6, with no product inhibition.
The adamantyl derivatives 4 and 5 were poorer guests, with
binding constants of 80 and 120 M−1 respectively, most likely
due to steric clashes with the maleimide and the octamide rim.
In the case of 5, the cycloadduct also showed millimolar binding
efficiency, and so product inhibition was observed.
Results and discussion
A suitable diene for this system is 9-anthracenemethanol 2; it
shows reactivity at room temperature with the chosen maleimides
in hydrocarbon solvents. More appropriately, 2 shows no affinity
for the cavitand. We examined the reaction of 2 with maleimides
4–8 in the presence and absence of catalytic amounts of cavitand
1 (Table 1). The reactions were monitored by 1H NMR to
determine the kinetic data; products 9–13 were also independently
synthesized and compared to the species formed during the
reaction. Experimental data were fitted to kinetics simulations of
the activated reaction using KinTekSim.12 In order to determine
the rate enhancement gained upon binding, regression analysis
was used to determine kacc, the rate constant for the cycloaddition
of the maleimide with diene while bound inside the cavitand,
independent of Ka (see Supplementary Information for tabulated
kinetics data†). The ratio of kacc with kuncat (rate constant for the
cycloaddition in the absence of cavitand) provides a measure of
the activation provided by the fixation of the dienophile in an
environment of organized H-bond donors.
Figs. 3 and 4 show the most instructive regions of the 1H NMR
spectra. Fig. 3 shows the buildup of cycloadduct 9 from reaction
ꢀ
of adamantylmaleimide 4 (Hg/Hg d 4.7, 4.9) with no replacement
of the bound maleimide (d −1.0–−2.0). Two triplets for cavitand
methine Ha are seen as maleimide 4 does not completely occupy
the cavitand at 20 mM—the second triplet corresponds to free
cavitand (presumably solvated by mesitylene-d12). Fig. 4 shows
the analogous spectra for the reaction of 5 over time. Here, a
new set of bound product peaks slowly grow in (denoted by * in
Fig. 4), indicating that the effect of moving the reactive site further
away from the cavitand is to lessen the steric hindrance between
Table 1 reveals the effects of imide positioning. Maleimides
4–7 have binding “handles” of the correct size to position
the maleimide at the cavitand rim. Kinetic analysis shows rate
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Reaction of
8
was performed as
a
control—the 4-
cyclohexylphenyl binding handle is so large that it positions the
maleimide away from the amide network, minimizing H-bond
contacts. As expected, the cavitand had only a small effect on
the reaction, and the product displayed similar binding efficiency
towards 1 to that of reactant, resulting in significant product
inhibition and poor turnover. Product 13 is, from the point of
view of the cavitand, sterically identical to reactant 8, as they have
the same binding handle and the bulky cycloadduct is distant. The
binding affinity of 13 for the cavitand was essentially the same as
that of 8.
To determine that the acceleration is provided by the
supramolecular association of maleimide and 1 rather than
random intermolecular H-bond contacts, the cycloaddition of 2
and 3 was performed in the presence of 8 equivalents of acetanilide
as an intermolecular cavitand mimic. In this case the rate of
reaction was slower (2.7 × 10−3 M−1 min−1) than the control
reaction in the absence of cavitand, showing that the catalysis
is indeed a supramolecular effect. In addition, the reaction of
4 with 2 was performed in benzene solvent in the presence of
catalytic amounts of cavitand. Benzene is a competitive guest
for the cavitand and 4 shows no binding affinity for cavitand 1
in benzene solvent. In this case, the second order rate constant
of cycloaddition k = 8.0 × 10−3 M−1 min−1, essentially identical
to that of the control reaction in the absence of cavitand. The
intermolecular H-bonding provided to the system by cavitand in
the absence of binding has no effect on reaction, as one might
expect at the low concentrations used. Other dienes were also
tested for reaction. Anthracenes lacking a hydroxyl group did not
show reactivity for 4 with or without 1, whereas cyclopentadiene
and 1,3-cyclohexadiene were competitive guests for 1. For reaction
of diene 3 with maleimide 4, kacc/kuncat = 7. Unfortunately, the
smaller diene was not able to confer significant extra steric bulk to
the product and inhibition was extensive.
Fig. 3 1H NMR spectra of cycloaddition of maleimide 4 and diene 2
(mesitylene-d12, 20 mM, 4 mM cavitand 1) at time intervals a) 20 min,
b) 1400 min, c) 2800 min, d) 8500 min, e) 13400 min showing the buildup
of product, and illustrating the lack of product inhibition. Red label =
bound species; black label = unbound species.
An explanation for the lack of reactivity in the presence of
acetanilide can be postulated, based on these results and the
inactivity of non-hydroxylic anthracenes (Fig. 5). It has been pre-
viously shown for the Diels–Alder reaction of N-methylmaleimide
and anthracenemethanol in water and other polar solvents that an
H-bonding interaction occurs between the two reactants.13 This in-
teraction gathers the two reactants, accelerating the cycloaddition.
In a non-polar solvent such as mesitylene, the affinity of the two
polar groups for each other is high, resulting in a measurable effect.
When a protic molecule such as acetanilide is added in excess,
solvation of the H-bonding groups occurs, causing a disruption
of the desired interaction and a slowing of the cycloaddition rate.
The hydrogen bonding to the cavitand is sufficiently strong to
overcome this disruption and activate the dienophile for reaction.
Fig. 4 1H NMR spectra of cycloaddition of maleimide 5 and diene 2
(mesitylene-d12, 20 mM, 4 mM cavitand 1) at time intervals a) 70 min,
b) 1400 min, c) 1800 min, d) 3000 min and e) 4 mM cavitand 1 + 10 mM
cycloadduct 10. The binding of product in this case is labelled with *. Red
label = bound species; black label = unbound species.
cavitand and product. Fig. 4e shows the spectrum of cavitand 1
with cycloadduct 10 alone, for comparison.
Fig. 5 Effect of non-supramolecular intermolecular hydrogen bonding
on the cycloaddition process.
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1
(232 mg, 91%) as a yellow powder. H NMR (600 MHz, C6D6)
d 1.05–1.15 (m, 1H); 1.17–1.30 (m, 5H); 1.55–1.76 (m, 4H); 2.31
(tt, J = 11.4, 3.0 Hz, 1H); 5.73 (s, 2H); 7.08 (d, J = 8.4 Hz,
2H); 7.34 (d, J = 8.4 Hz, 2H); 13C NMR (150 MHz, C6D6) d
26.3; 27.1; 34.6; 44.4; 126.0; 128.3; 130.0; 133.1; 147.4; 169.2;
ESI-HRMS m/z: calcd for C16H17NO2 (M + H+) 256.1332; found
256.1337.
Conclusions
Cavitand 1 is capable of binding species bearing aliphatic binding
handles and reactive maleimide groups, then activating them to-
wards Diels–Alder reaction with suitable dienes through hydrogen
bonding. The region of secondary amides is permanently located
at the cavitand rim, and only simple rotations are needed to bring
these hydrogen bonds to bear on the reactants held temporarily
inside. These amides are not the conventional complements
to imides but they are there in number and cannot diffuse
away.14 On cycloaddition the increase in steric bulk lowers the
binding affinity of product with respect to reactant and reduces
product inhibition, in some cases completely. Further studies on
supramolecular effects on reaction promotion and catalysis are
currently underway.
Decyl (1E,3E)-penta-1,3-dienylcarbamate 3
A 250 mL three-necked flask equipped with a thermometer,
magnetic stirrer and dropping funnel was placed under an
argon atmosphere and charged with trans-2,4-hexadienoic acid
(5.00 g, 44.6 mmol), N,Nꢀ-diisopropylethylamine (7.15 g, 9.63 mL,
55.3 mmol), and acetone (50 mL), then cooled to 0 ◦C. A solution
of methyl chloroformate (4.21 g, 3.43 mL, 44.6 mmol) in acetone
(30 mL) was added over 30 min, keeping the temperature at
Experimental
0
◦C. The solution was stirred for 30 min at 0 ◦C, followed by
addition of sodium azide (89.2 mmol, 5.80 g) in water (30 mL).
After 15 min additional stirring, the mixture was poured into
ice water (200 mL). The product was extracted with toluene
(5 × 50 mL), dried (MgSO4) and the solvent removed by rotary
evaporation until ∼30 mL solvent remains. This solution of acyl
azide was added over 30 min to a stirred solution of 1-decanol
(35.7 mmol, 5.65 g, 6.80 mL) and tert-butyl catechol (25 mg) in
dry toluene (1◦00 mL) at reflux. After 30 min reflux, the solution was
cooled to 23 C and the solvent removed by rotary evaporation.
The product was rapidly recrystallized from ethyl acetate to give
carbamate 3 as a white solid (7.2 g, 60%), which was immediately
placed under an argon atmosphere and stored in the dark at −5 ◦C.
1H NMR (600 MHz, C6D5CD3) d 0.91 (t, J = 7.2 Hz, 3H); 1.14–
1.30 (m, 15H); 1.41–1.48 (m, 2H); 1.61 (d, J = 6.6 Hz, 3H); 3.96
(t, J = 6.6 Hz, 2H); 5.01 (dd, J = 7.2, 5.4 Hz, 1H); 5.29 (dq, J =
7.2, 6.6 Hz, 1H); 5.45 (d, J = 7.2 Hz, 1H); 5.66 (dd, J = 7.2 Hz,
5.4 Hz, 1H); 13C NMR (150 MHz, CD2Cl2) d 14.5; 18.4; 23.3; 26.4;
29.5 (two overlapping peaks); 29.8; 29.9; 30.1; 32.5; 66.2; 111.9;
125.2; 125.8; 129.2; 154.2; ESI-HRMS m/z: calcd for C16H29NO2
(M + H+) 268.2271; found 268.2275.
1H and 13C NMR spectra were recorded on an Avance Bruker
DRX-600 spectrometer with a 5 mm QNP probe. Proton (1H)
chemical shifts are reported in parts per million (d) with respect
to tetramethylsilane (TMS, d = 0), and referenced internally with
respect to the monoprotio solvent impurity. Deuterated NMR
solvents were obtained from Cambridge Isotope Laboratories,
Inc., Andover, MA, and used without further purification. ESI-
HRMS data were recorded on an Agilent Electrospray TOF
Mass Spectrometer. Melting points were recorded on a Thomas-
Hoover capillary melting point apparatus. Maleimides 4–7,2f
cavitand 16b and trans-2,4-hexadienoic acid15 were synthesized
according to published procedures. 9-Anthracenemethanol 2,
acetanilide and synthesis precursors were obtained from Sigma-
Aldrich Chemical Company, St. Louis, MO and used as received.
4-Cyclohexylaniline was obtained from Alfa Aesar, Ward Hill,
MA. Molecular modeling (molecular mechanics calculations) was
carried out using the AMBER force field16 with the solvation
(dielectric) setting for water as implemented by Macromodel
(Schro¨dinger, Inc.) on a Silicon Graphics Octane workstation.
N-(4-Cyclohexylphenyl)-maleimide 8
Representative procedure for independent synthesis of products
9–13
Maleic anhydride (150 mg, 1.25 mmol) was added to a 50 mL
round-bottomed flask equipped with a magnetic stirbar followed
by anhydrous ether (10 mL). 4-Cyclohexylaniline (200 mg,
1.14 mmol) was added dropwise via syringe and the mixture stirred
for 3 h, yielding a yellow precipitate of N-(4-cyclohexyl)-maleamic
acid, which was isolated by suction filtration and used in the next
step without further purification. N-(4-Cyclohexyl)-maleamic acid
(250 mg, 0.91 mmol) was added to a 10 mL round-bottomed
flask equipped with a magnetic stirbar and condenser. Acetic
anhydride (2.5 mL) and sodium acetate (2.22 mmol, 224 mg, 449
lL) were added and the mixture was heated at 100 ◦C for 6 h,
then cooled to room temperature. Ether (50 mL) and saturated
aqueous ammonium chloride (20 mL) were added, and the mixture
transferred to a separatory funnel. The layers were separated,
and the aqueous layer extracted with ether (3 × 10 mL). The
organic fractions were combined and washed with saturated brine
(20 mL) and water (20 mL), dried (MgSO4), filtered and the solvent
removed by rotary evaporation. Column chromatography (SiO2;
hexanes–ether 9 : 1) gave N-(4-cyclohexylphenyl)-maleamide 8
Maleimide (0.2 mmol), 9-anthracenemethanol (0.2 mmol) and
anhydrous toluene (5 mL) were added to a 25 mL round-bottomed
flask equipped with magnetic stirrer and reflux condenser. The
mixture was heated at 100 ◦C for 6 h, then cooled to room
temperature and the solvent removed by rotary evaporation. The
crude product was purified by column chromatography (SiO2;
CH2Cl2–MeOH).
Adduct 9
Synthesized using the above proce◦dure from adamantyl-
1
maleimide 4 in 89% yield, mp 283–284 C. H NMR (600 MHz,
C6D6) d 1.38 (d, J = 12.0 Hz, 3H); 1.49 (d, J = 12.0 Hz, 3H);
1.83 (s, 3H); 2.09 (s, 6H); 2.61 (m, 1H); 2.63 (dd, J = 8.4, 3.6 Hz,
1H); 2.74 (d, J = 8.4 Hz, 1H); 4.59 (d, J = 3.6 Hz, 1H); 4.75
(dd, J = 12.0, 6.0 Hz, 1H); 5.01 (dd, J = 12.0, 6.0 Hz, 1H); 6.89–
6.94 (m, 3H); 6.97–7.03 (m, 2H); 7.07–7.16 (m, 2H); 7.57 (d, J =
7.8 Hz, 1H); 13C NMR (150 MHz, CD2Cl2) d 30.1; 36.4; 39.2;
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46.0; 47.6; 50.0; 60.8; 61.2; 122.9; 123.4; 124.4; 125.7; 126.7 (two
overlapping peaks); 127.0 (two overlapping peaks); 139.7; 140.2;
142.9; 143.0; 178.6; 179.8 ESI-HRMS m/z: calcd for C29H30NO3
(M + H+) 440.2220; found 440.2222.
J = 3.6 Hz, 1H); 5.00 (dd, J = 12.6, 5.4 Hz, 1H); 5.13 (dd, J = 12.6,
5.4 Hz, 1H); 6.39 (d, J = 8.4 Hz, 2H); 7.14 (d, J = 8.4 Hz, 2H);
7.19–7.30 (m, 5H); 7.36 (d, J = 7.2 Hz, 1H); 7.44 (d, J = 7.2 Hz,
1H); 7.65 (d, J = 7.2 Hz, 1H); 13C NMR (150 MHz, CD2Cl2)
d 26.6; 27.3; 34.9; 44.8; 46.5; 46.8; 48.6; 50.3; 60.7; 123.0; 124.0;
124.7; 125.9; 126.9; 127.1; 127.5; 128.0; 129.7; 139.8; 140.2; 142.6;
142.7; 149.6; 176.5; 176.6; ESI-HRMS m/z: calcd for C31H30NO3
(M + H+) 464.2220; found 464.2220.
Adduct 10
Synthesized using the above procedure◦ from adamantylmethyl-
1
maleimide 5 in 95% yield, mp 239–240 C. H NMR (600 MHz,
C6D6) d 1.04 (s, 6H); 1.44 (d, J = 6.0 Hz, 3H); 1.53 (d, J = 6.0 Hz,
3H); 1.76 (s, 3H); 2.71 (dd, J = 9.0, 3.0 Hz, 1H); 2.82 (m, 1H);
2.85 (s, 2H); 2.86 (d, J = 9.0 Hz, 1H); 4.58 (d, J = 3.6 Hz, 1H);
4.72 (dd, J = 11.4, 5.4 Hz, 1H); 4.97 (dd, J = 11.4, 4.8 Hz, 1H);
6.84–6.90 (m, 3H); 6.94–7.00 (m, 2H); 7.09–7.18 (m, 2H); 7.49
(d, J = 7.8 Hz, 1H); 13C NMR (150 MHz, CD2Cl2) d 28.8; 35.0;
36.9; 40.6; 46.1; 47.3; 48.5; 49.7; 61.5; 123.4; 123.5; 124.5; 125.8;
126.9 (two overlapping peaks); 127.5; 127.6; 140.3; 140.7; 143.3;
143.4; 177.8; 178.4; ESI-HRMS m/z: calcd for C30H32NO3 (M +
H+) 454.2377; found 454.2387.
Kinetic measurements
In a typical experiment, maleimide (20.0 mM), diene (20.0 mM)
and cavitand 1 (4.0 mM) were dissolved in 600 lL mesitylene-d12
in an NMR tube. The sample (at room temperature, 23 C) was
periodically placed in the NMR spectrometer and a spectrum
was recorded. Concentrations were monitored by reference to
the methine peak of 1 (4H) at d 6.24 ppm, which was at nearly
◦
1
constant chemical shift in an open window of the H spectrum
irrespective of the molecule occupying 1. The concentrations
of free maleimide, bound maleimide, and cycloadduct (free and
bound) were monitored by integration of their peaks at d 5.73,
5.39 and 4.87 ppm respectively. Concentrations were tabulated
with respect to time. Control experiments were carried out under
the same conditions but in the absence of 1. KinTekSim12 was used
to simulate the Diels–Alder reactions in the presence and absence
of 1. Simulations were based on the mechanism described by the
simultaneous operation of eqn (1)–(4) (Fig. 6). In the equations, M,
C, D, P, M·C and C·P correspond to free maleimide, cavitand
1, diene (either 9-anthracenemethanol or carbamate 3), product,
bound maleimide and bound product respectively. The parameters
Ka and Kd were determined by independent NMR experiments.
The control (i.e. background) reaction was studied in separate
experiments, allowing for the independent determination of kuncat
by plotting 1/[M] − 1/[M]0 against time, in accordance with the
integrated rate law for a second order process. It was assumed that
both equilibria Ka and Kd were fast compared to the rate-limiting
alkylation step; this is in agreement with NMR observations. The
only remaining parameter, kacc, describing the reaction of bound
maleimide, was varied to fit simulated kinetics to experimental
data (the concentrations of free maleimide, bound maleimide, and
bound product with respect to time).
Adduct 11
Synthesized using the above procedure from cyclooctyl-maleimide
◦
1
6 in 93% yield, mp 172–174 C. H NMR (600 MHz, CD2Cl2) d
0.75–0.85 (m, 2H); 1.22–1.28 (m, 2H); 1.32–1.60 (m, 8H); 1.65–
1.73 (m, 2H); 2.85 (br s, 1H); 3.17 (dd, J = 8.4, 3.6 Hz, 1H);
3.23 (d, J = 8.4 Hz, 1H); 3.73 (tt, J = 10.8, 3.6 Hz, 1H); 4.70
(d, J = 3.6 Hz, 1H); 4.93 (dd, J = 11.4, 5.4 Hz, 1H); 5.09 (dd,
J = 12.0, 5.4 Hz, 1H); 7.11–7.27 (m, 6H); 7.37 (d, J = 7.8 Hz,
1H); 7.57 (d, J = 8.4 Hz, 1H); 13C NMR (150 MHz, CD2Cl2) d
15.7; 25.6 (two overlapping peaks); 26.7 (two overlapping peaks);
30.8 (two overlapping peaks); 46.3; 48.0; 50.0; 52.5; 61.0; 64.3;
123.0; 123.8; 124.5; 125.8; 126.9 (two overlapping peaks); 127.2
(two overlapping peaks); 139.8; 140.1; 142.9; 143.0; 176.9; 177.2;
ESI-HRMS m/z: calcd for C27H30NO3 (M + H+) 416.2220; found
416.2225.
Adduct 12
Synthesized using the above procedure from tert-octyl-maleimide
◦
7 in 94% yield, mp 206–208 C.1H NMR (600 MHz, CD2Cl2) d
0.82 (s, 9H); 1.11 (s, 3H); 1.12 (s, 3H); 1.57 (d, 2H); 2.78 (t, J =
6.6 Hz, 1H); 3.09 (dd, J = 8.4, 3.0 Hz, 1H); 3.13 (d, J = 8.4 Hz,
1H); 4.70 (d, J = 3.0 Hz, 1H); 4.92 (dd, J = 11.4, 6.6 Hz, 1H);
5.07 (dd, J = 12.0, 6.6 Hz, 1H); 7.14–7.21 (m, 4H); 7.26 (dd, J =
7.2, 1.8 Hz, 1H); 7.30 (dd, J = 7.2, 2.4 Hz, 1H); 7.38 (dd, J =
7.2, 1.2 Hz, 1H); 7.56 (d, J = 7.2 Hz, 1H); 13C NMR (150 MHz,
CD2Cl2) d 29.0; 31.3; 31.9; 46.1; 46.6; 47.8; 50.1; 50.4; 61.0; 62.6;
123.0; 123.6; 124.5; 125.8; 126.9 (two overlapping peaks); 127.3
(two overlapping peaks); 139.9; 140.4; 143.0; 143.1; 178.6; 179.0;
ESI-HRMS m/z: calcd for C27H32NO3 (M + H+) 418.2377; found
418.2384.
Fig. 6
Adduct 13
Acknowledgements
Synthesized using the above procedure from 4-cyclohexylphenyl-
◦
1
maleimide 8 in 86% yield, mp 233–235 C. H NMR (600 MHz,
CD2Cl2) d 1.20–1.30 (m, 2H); 1.32–1.42 (m, 4H); 1.32–1.60 (m,
4H); 1.75–1.88 (m, 4H); 2.48 (m, 1H); 2.62 (t, J = 5.4 Hz, 1H);
3.45 (dd, J = 8.4, 3.6 Hz, 1H); 3.51 (d, J = 8.4 Hz, 1H); 4.83 (d,
We are grateful to the Skaggs Institute and the National Institutes
of Health (GM 27932) for financial support and to Dr Laura
B. Pasternak and Dr Dee-Hua Huang for NMR assistance. R.J.H.
is a Skaggs Postdoctoral fellow.
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