Recognition-mediated facilitation of a disfavored Diels - Alder reaction

Article abstract of DOI:10.1021/ol9908880

(matrix presented) The rational design of a system which is capable of accelerating and facilitating a thermodynamically disfavored Diels-Alder cycloaddition between a furan and a maleimide is presented. The origins of the acceleration and facilitation of the cycloaddition reaction are traced by kinetic studies-allied to results from ¹H NMR spectroscopy and X-ray crystallography-to the formation of strong intramolecular hydrogen bonds in the cycloadduct.

Full text of DOI:10.1021/ol9908880

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1087-1090
Recognition-Mediated Facilitation of a
Disfavored Diels−Alder Reaction
Raphae1l Bennes, Douglas Philp,* Neil Spencer, Benson M. Kariuki, and
Kenneth D. M. Harris
School of Chemistry, UniVersity of Birmingham,
Edgbaston, Birmingham B15 2TT, United Kingdom
d.philp@bham.ac.uk
Received July 30, 1999
ABSTRACT
The rational design of a system which is capable of accelerating and facilitating a thermodynamically disfavored Diels−Alder cycloaddition
between a furan and a maleimide is presented. The origins of the acceleration and facilitation of the cycloaddition reaction are traced by
kinetic studiessallied to results from 1H NMR spectroscopy and X-ray crystallographysto the formation of strong intramolecular hydrogen
bonds in the cycloadduct.
Although enzymes are capable of effective and selective
catalysis of many simple chemical reactions, there have, to
date, been few reports of naturally occurring enzymes1 which
are capable of accelerating the Diels-Alder reaction2 in a
specific and selective manner. The design and synthesis of
enzyme mimics has been a major focus3 of supramolecular
chemistry and a few recognition-based systems have been
described4 which can accelerate the rate and/or control the
stereochemical outcome of Diels-Alder reactions. These
approaches rely on the selective stabilization of the transition
state leading to the desired product. Recently, we have
adopted a different approach5 to this problem. In principle,
the location of complementary recognition sites on two
reagents, A and B, in a chemical reaction permits the
association of A and B through their mutually compatible
recognition sites to form a complex, [A‚B]. Within the [A‚
B] complex, the chemical reaction between A and B is
effectively intramolecular as opposed to intermolecular and,
therefore, we would expect the formation of the [A‚B]
complex to accelerate6 the transformation involving A and
B significantly. Additionally, the molecular recognition,
(1) Ichihara, A.; Oikawa, H. Curr. Org. Chem. 1998, 2, 365. Katayama,
K.; Kobayashi, T.; Oikawa, H.; Honma, M.; Ichihara, A. Biochim. Biophys.
Acta 1998, 1384, 387. Catalytic antibodies have been described which are
capable of catalyzing cycloaddition reactions. Hilvert, D.; Hill, K. W.; Nared,
K. D.; Auditor, M.-T. M. J. Am. Chem. Soc. 1989, 111, 9261. Braisted, A.
C.; Schultz, P. G. J. Am. Chem. Soc. 1990, 112, 7430. Gouverneur, V. E.;
Houk, K. N.; de Pascual-Theresa, B.; Beno, B.; Janda, K. D.; Lerner, R. A.
Science 1993, 262, 204. Romesberg, F. E.; Spiller, B.; Schultz, P.; Stevens,
R. C. Science 1998, 279, 1929. Heine, A.; Stura, E. A.; Yli-Kauhaluoma,
J. T.; Gao, C.; Deng, Q.; Beno, B. R.; Houk, K. N.; Janda, K. D.; Wilson,
I. A. Science 1998, 279, 1935.
(2) For a review of the use of furan Diels-Alder chemistry in synthesis,
see: Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179. For reviews of intramolecular Diels-Alder reactions, see: Brieger,
G.; Bennett, J. N. Chem. ReV. 1980, 80, 63. Fallis, A. G. Can. J. Chem.
1984, 62, 183. Ciganek, E. Org. React. 1984, 32, 1. Craig, D. Chem. Soc.
ReV. 1987, 16, 187. Fallis, A. G. Acc. Chem. Res. 1999, 32, 464.
(3) Breslow, R. Acc. Chem. Res. 1995, 28, 146. Murakami, Y.; Kikuchi,
J.; Hisaeda, Y.; Hayashida, O. Chem. ReV. 1996, 96, 721. Kirby, A. J.
Angew. Chem., Int. Ed. Engl. 1996, 108, 707.
(4) Kang, J.; Hilmersson, G.; Santamaria, J.; Rebek, J., Jr. J. Am. Chem.
Soc. 1998, 120, 7389. Kang, J.; Hilmersson, G.; Santamaria, J.; Rebek, J.,
Jr. J. Am. Chem. Soc. 1998, 120, 3650. Marty, M.; Clyde-Watson, Z.;
Twyman, L. J.; Nakash, M.; Sanders, J. K. M. Chem. Commun. 1998, 2265.
Hamilton, A. D.; Hirst, S. C. J. Am. Chem. Soc. 1991, 113, 382. Tripathy,
R.; Carroll, P. J.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 7630. Kelly,
T. R.; Ekkundi, V. S.; Meghani, P. Tetrahedron Lett. 1990, 31, 3381.
(5) Philp, D.; Robertson, A. Chem. Commun. 1998, 879. Booth, C. A.;
Philp, D. Tetrahedron Lett. 1998, 39, 6987. Robertson, A., Philp, D.
Tetrahedron 1999, 55, 11365.
10.1021/ol9908880 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/04/1999

which is present in the [A‚B] complex, may also persist in
the final product and might therefore have a profound
influence on the stability of the products of the reaction. This
stabilizing effect on the product ground state will manifest
itself when the reaction in question is under thermodynamic
control and the selective stabilization of one product with
respect to another will serve to facilitate7 the formation of
the more stable product. Therefore, unlike enzymes or
enzyme mimics, our methodology is ideally suited for
reactions which have unfavorable equilibrium constants under
normal conditions, i.e. reactions which suffer from a
thermodynamic disadvantage as opposed to a kinetic disad-
vantage. Here, we report the recognition-mediated facilitation
of the reaction between a 2-phenylfuran derivative and a
maleimide and the characterization and analysis of the origins
of this facilitation by kinetic simulation, 1H NMR spectros-
copy, and X-ray crystallography.
2-Phenylfuran derivatives are notoriously poor dienes in
Diels-Alder cycloaddition reactions as a direct result of their
high level of π conjugation, which is destroyed by the
formation of a Diels-Alder cycloadduct. Thus, when a 100
mM solution of diene 1 and maleimide 2 in CDCl3 was
heated at 50 °C (Scheme 1), only very small amounts of the
Figure 1. Rate profiles for (a) the reaction between 1 and 2 in
CDCl3 at 50 °C and (b) the reaction between 4 and 5 in CDCl3 at
50 °C. In both cases, the starting concentrations of the reactants
were 100 mM. In both plots, the filled squares represent the
concentration of the appropriate exo cycloadduct. The solid lines
represent the best fit of the appropriate kinetic model to the
experimental data. For clarity, error bars are omitted from the
graphs; however, errors in concentration are estimated to be (4%.
Scheme 1
value of the equilibrium constant (Keq) for this reaction of
0.18 M-1. To investigate the recognition-mediated facilitation
of this cycloaddition reaction, diene 4, bearing an amidopy-
ridine recognition site, and maleimide 5, bearing a comple-
mentary carboxylic acid recognition site, were prepared10
from readily available starting materials. When a 100 mM
solution of diene 4 and maleimide 5 in CDCl3 was heated at
50 °C (Scheme 1), a significant quantity of the exo
1
cycloadduct 6 could be detected by 500 MHz H NMR
spectroscopy after 15 h. Kinetic simulation and fitting of
the reaction profile (Figure 1b) allowed the extraction of a
value of the equilibrium constant (Keq) for this reaction of
15.3 M-1.
From these results, it is clear that the introduction of the
recognition elements within the diene and dienophile has
increased the extent of reaction dramatically. To assess the
1
exo cycloadduct could be detected8 by 500 MHz H NMR
spectroscopy after 15 h. Kinetic simulation and fitting9 of
the reaction profile (Figure 1a) allowed the extraction of a
(8) In all cases, only the exo cycloadduct was detected in solution. This
is consistent with the fact that the exo adduct is normally the thermodynamic
product of furan cyclodaddition reactions.
(9) Kinetic simulation and fitting was carried out using Gepasi (version
3.21): Mendes, P. Comput. Appl. Biosci. 1993, 9, 563. Mendes, P. Trends
Biochem. Sci. 1997, 22, 361. Mendes P.; Kell, D. B. Bioinformatics 1998,
14, 869).
(6) Page, M. I.; Jencks, W. P. Proc. Natl. Acad. Sci. USA 1971, 68, 1678.
Page, M. I. Chem. Soc. ReV. 1973, 2, 295. Kirby, A. J. AdV. Phys. Org.
Chem. 1980, 17, 183. Page, M. I. In The Chemistry of Enzyme Action; Page,
M. I., Ed.; Elsevier: Amsterdam, 1984; p 1. Menger, F. M. Acc. Chem.
Res. 1985, 18, 128. Page, M. I. Philos. Trans. R. Soc. London B 1991, 332,
149. Kirby, A. J. Philos. Trans. R. Soc. London A 1993, 345, 67. Menger,
F. M. Acc. Chem. Res. 1993, 26, 206. Bruice, T. C.; Lightstone, F. C. Acc.
Chem. Res. 1999, 32, 127.
(7) To distinguish between transition state effects and ground-state effects,
we will use the description accelerated when the rate of a reaction is
enhanced by the lowering of the energy of the transition state by a
recognition event and the description facilitated when the extent of reaction
is enhanced by the lowering of the energy of the product by a recognition
event.
(10) Selected spectroscopic data for 4: 1H NMR (300 MHz, CDCl3) δH
3
8.71 (1H, s), 8.21 (1H, d, JHH ) 7.3 Hz), 8.19 (1H, s), 7.85-7.78 (2H,
m), 7.65 (1H, t, 3JHH ) 7.3 Hz), 7.49 (1H, d, 4JHH ) 0.7 Hz), 7.48 (1H, t,
3JHH ) 7.7 Hz), 6.92 (1H, d, 3JHH ) 7.3 Hz), 6.74 (1H, d, 3JHH ) 3.3 Hz,
4JHH ) 0.7 Hz), 6.49 (1H, dd, 3JHH ) 1.5, 3.3 Hz), 2.45 (3H, s); 13C NMR
(75 MHz, CDCl3) δC 165.7, 156.8, 152.7, 151.0, 142.6, 138.7, 135.0, 131.4,
129.1, 127.0, 126.0, 122.6, 119.5, 111.8, 111.3, 106.1, 23.8; m/z (EIMS)
[M]+ 278 (55), 249 (88), 171 (100). Selected spectroscopic data for 5: 1H
NMR (300 MHz, CDCl3) δH 6.7 (2H, s), 3.82 (2H, t, 3JHH ) 6.9 Hz), 2.69
(2H, t, 3JHH ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δC 176.6, 170.4, 134.3,
33.3, 32.6; m/z (EIMS) [M]+ 169 (9), 123 (51), 44 (100).
1088
Org. Lett., Vol. 1, No. 7, 1999

origin of this facilitation of the cycloaddition reaction, several
lines of investigation were employed.
protons are anisochronous in the 500 MHz 1H NMR
spectrum. Molecular mechanics calculations suggest that the
origin of the strong preference for the formation of 6 as its
exo stereoisomer arise from the ability of the cycloadduct
to form intramolecular hydrogen bonds. The 10 lowest
energy conformations calculated12 for exo-6 all contain two
intramolecular hydrogen bonds, whereas 7 of the 10 lowest
energy conformations calculated for endo-6 contain no
intramolecular hydrogen bonds and the remaining three
conformations contain only one intramolecular hydrogen
bond.
The role of the noncovalent interactions in stabilizing the
cycloadduct 6 could be demonstrated by the disruption of
the intramolecular hydrogen bonds by preparing a 50 mM
solution of 6 in d6-DMSO. Under these conditions, the retro
Diels-Alder reaction to afford the starting diene 4 and
maleimide 5 is rapid13 (Figure 3), as assessed by recording
Evidence for the presence of strong intramolecular hy-
drogen bonding in the product 6 was obtained from X-ray
1
crystallography and H NMR spectroscopy. Single crystals
of 6 suitable for X-ray diffraction were grown by slow
diffusion of hexane into a saturated solution of 6 in
chloroform. Compound 6 crystallizes in the P21/n space
group with four molecules of 6 occupying the unit cell. In
the solid state, individual molecules of 6 adopt a conforma-
tion (Figure 2) in which two intramolecular hydrogen bonds
are present.
Figure 2. X-ray crystal structure of cycloadduct 6. Hydrogen bonds
are marked by dashed lines. Double-headed arrows show nOes
1
which are observed in the 500 MHz H NMR spectrum recorded
in CDCl3 solution at 30 °C.
Evidence for the persistence of these intramolecular
hydrogen bonds in solution comes from 500 MHz 1H NMR
1
spectroscopy. In the H NMR spectrum of 6, recorded in
CDCl3 at 30 °C, the resonance arising from the amide NH
proton of the amidopyridine recognition unit is shifted
downfield by around 2.7 ppm11 and appears as a sharp singlet
at δ 11.45. This dramatic change in chemical shift is
indicative of the amide proton being involved in a strong
hydrogen bond. The intramolecular nature of this hydrogen
bond is confirmed by the absence of a concentration
dependence of the chemical shift of the amide NH resonance.
Further evidence for the persistence of the conformation
supporting two intramolecular hydrogen bonds in solution
comes from gradient nOe experiments performed in CDCl3
at 30 °C. Significant and diagnostic nOes are observed
(Figure 2) between a proton on the disubstituted benzene
ring and an alkene proton of the cycloadduct or a proton on
the disubstituted benzene ring and the amide NH proton.
Additionally, the intramolecular hydrogen bonding forces the
CH2CH2 chain, connecting the carboxylic acid to the
cycloadduct, to adopt a conformation in which all four
Figure 3. Rate profile for the retro Diels-Alder reaction of 6 in
d6-DMSO at 50 °C from a starting concentration of 6 of 50 mM.
The filled squares represent the concentration of 6. The solid lines
represent the best fit of the appropriate kinetic model to the
experimental data. For clarity, error bars are omitted from the
graph; however, errors in concentration are estimated to be (4%.
1
500 MHz H NMR spectra of the solution over a period of
15 h. Kinetic simulation and fitting of the reaction profile
(Figure 3) allowed the extraction of a value of the equilibrium
(12) All molecular mechanics calculations were carried out using the
AMBER* force field as implemented in Macromodel (version 5.0:
Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.;
Caufield, C.; Chang, G. Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440) together with the GB/SA solvation model for CHCl3. All
calculations were performed on a Silicon Graphics Power Indigo2 computer.
Conformational searching was carried out using 10 000-step Monte Carlo
simulations, and all conformations generated within 50 kJ of the global
minimum were minimized.
(13) The retro Diels-Alder reaction has also been observed and
characterized in CDCl3 solutions containing between 1 and 5% of CD3OD.
The equilibrium constants derived from all of these retro Diels-Alder
reactions are in close agreement.
(11) A suitable comparison compound is 4, in which no intramolecular
hydrogen bonding is possible. In compound 4, the amide NH resonance
appears at δ 8.67.
Org. Lett., Vol. 1, No. 7, 1999
1089

constant (Keq) for this reaction of 0.05 M-1, which is in
reasonable agreement with that determined from the Diels-
Alder reaction between 1 and 2.
cloaddition reaction leading to 6. Thus, we can conclude that
the introduction of recognition sites has both facilitated and
accelerated the Diels-Alder cycloaddition reaction between
4 and 5. In other words, the recognition sites change both
the position of the equilibrium in this cycloaddition reaction
and the rate at which that equilibrium position is reached.
Using the thermodynamic and kinetic studies described
above, it is possible to derive a value14 for the stabilization
of the ground state of 6 of 11.8 kJ mol-1, with respect to 3,
as a result of the presence of the two intramolecular hydrogen
bonds in cycloadduct 6. Additionally, the rate of recognition-
mediated reaction is enhanced9 7-fold over that for the control
reaction, indicating that there is significant recognition-
induced enhancement in the rate of the Diels-Alder cy-
Acknowledgment. This research was supported by the
University of Birmingham (Postgraduate studentship for
R.B.), the Engineering and Physical Sciences Research
Council (postdoctoral support for B.M.K.), and the Biotech-
nology and Biological Sciences Research Council (Grants
6/B03840 and 6/B04100).
(14) It is possible that the reaction between 1 and 2 is not a perfect control
reaction. In particular, the electronic properties of the tertiary amide in 1
are likely to be markedly different from those of the amidopyridine in 4.
The equilibrium constants derived from the retro Diels-Alder reactions
are all much smaller (0.03-0.06 M-1) than that derived for the reaction
between 1 and 2. The use of these values in the comparison between the
recognition-mediated reaction and that in the absence of recognition leads
to much higher values for the recognition-induced stabilization of 6saround
15.3 kJ mol-1. We therefore regard the value for the recognition-induced
stabilization of 6 stated in the text as a lower limit.
Supporting Information Available: Data, in CIF format,
for the X-ray crystal structure of 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 1, No. 7, 1999