Reversible Diels-Alder reactions for the generation of dynamic combinatorial libraries

Article abstract of DOI:10.1021/ol048065k

(Chemical Equation Presented) Condensation reactions between various dienes and dienophiles have been screened for reversibility. Functionalized fulvenes, bearing in particular biological groups, and cyanolefins have been found to react rapidly and reversibly, in the temperature range from -10 to +50°C. These results pave the way for the development of dynamic combinatorial libraries based on reversible Diels-Alder chemistry.

Full text of DOI:10.1021/ol048065k

ORGANIC
LETTERS
2005
Vol. 7, No. 1
15-18
Reversible Diels−Alder Reactions for the
Generation of Dynamic Combinatorial
Libraries
Peter J. Boul, Philippe Reutenauer, and Jean-Marie Lehn*
Laboratoire de Chimie Supramole´culaire, ISIS, UniVersite´ Louis Pasteur,
8, alle´e Gaspard Monge, BP70028, F67083 Strasbourg, Cedex, France
lehn@isis.u-strasbg.fr
Received September 23, 2004
ABSTRACT
Condensation reactions between various dienes and dienophiles have been screened for reversibility. Functionalized fulvenes, bearing in
particular biological groups, and cyanolefins have been found to react rapidly and reversibly, in the temperature range from 10 to 50 C.
These results pave the way for the development of dynamic combinatorial libraries based on reversible Diels Alder chemistry.
−
+
°
−
Constitutional dynamic chemistry (CDC) introduces adaptive
behavior in both molecular and supramolecular chemistry
by giving access to dynamic diversity through reversible
covalent reactions and noncovalent interactions, respectively.1
On the molecular (covalent) level2 it is embodied in the
burgeoning field of dynamic combinatorial chemistry (DCC)
and opens new perspectives for both drug discovery and
materials science.3-5 DCC relies on target-driven selection
of a given (optimal) species from a dynamic combinatorial
library (DCL) whose covalent constituents are generated by
exchange of their components. DCLs have been realized
using a variety of reversible reactions including different
types of amine/carbonyl condensations,6 transesterifications,7
disulfide exchange,8 peptide exchange,9 boronic ester forma-
tion,10 and olefin metathesis.11 The search for other reversible
reactions is of paramount importance for unlocking the
potential of the conceptual framework of covalent CDC.
The Diels-Alder (DA) reaction is of special interest, as
it possesses the particularly attractive features of (1) yielding
a three-dimensional structure upon reaction of two planar
reactants; (2) belonging to the class of self-contained
(1) (a) Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4763. (b)
Lehn, J.-M. Science 2002, 295, 2400.
(2) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898.
(3) (a) Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455. (b) Eliseev, A. V.; Lehn,
J.-M. Science 2001, 291, 2331. (c) Ramstro¨m, O.; Lehn, J.-M. Nat. ReV.
Drug DiscoVery 2001, 1, 26.
(4) (a) Cousins, G. R. L.; Poulsen, S.-A.; Sanders, J. K. M. Curr. Opin.
Chem. Biol. 2000, 4, 270. (b) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M.
Curr. Opin. Chem. Biol. 2002, 6, 321. (c) Klekota, B.; Miller, B. L.
TIBTECH 1999, 17, 205. (d) Wittmann, V. Nachr. Chem. 2002, 50, 1364.
(5) For dynamic materials, see: (a) Lehn, J.-M. in Supramolecular
Science: Where It Is and Where It Is Going; Ungaro, R., Dalcanale, E.,
Eds.; Kluwer: Dordrecht, The Netherlands, 1999; p 287. (b) Lehn, J.-M.
Polym. Int. 2002, 51, 825. (c) Polyacylhydrazones: Skene, W. G.; Lehn,
J.-M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8270.
(6) (a) Huc, I.; Lehn, J.-M Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2106.
(b) Nitschke, J. R.; Lehn J.-M. Proc. Natl. Acad. Sci. U.S.A. 2003, 100,
11970. (c) Nguyen, R.; Huc, I. Chem. Commun. 2003, 8, 942.
(7) Brady, P. A.; Bonar-Law, R. P., Rowan, S. J.; Suckling, C. J.; Sanders,
J. K. M. Chem. Commun. 1996, 319.
(8) (a) Ramstro¨m, O.; Lehn, J.-M. ChemBioChem 2000, 1, 41. (b) Otto,
S.; Furlan R. L. E.; Sanders, J. K. M. J. Am. Chem. Soc. 2000, 122, 12063.
(c) Hioki, H.; Still, W. C. J. Org. Chem. 1998, 63, 904.
(9) Swann, P. G.; Casanova, R. A.; Desai, A.; Frauenhoff, M. M.;
Urbancic, M.; Slomczynska, U.; Hopfinger, A. J.; Le Breton, G. C.; Venton,
D. L. Biopolymers 1996, 40, 617.
(10) Nakazawa, I.; Suda, S.; Masuda, M.; Asai, M.; Shimizu, T. Chem.
Commun. 2000, 10, 881.
(11) (a) Bra¨ndli, C.; Ward, T. R. HelV. Chim. Acta 1998, 81, 1616. (b)
Nicolaou, K. C.; Hughes, R.; Cho, S. Y.; Winssinger, N.; Smethurst, C.;
Labischinski, H.; Enderman, R. Angew. Chem., Int. Ed. 2000, 39, 3832.
10.1021/ol048065k CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/07/2004

reversible reactions,12 where all atoms present in the starting
materials are also present in the products; and (3) being
amenable to easy generation of structural and functional
diversity. There has been no demonstration of its use in DCC
at this time, and our focus has been to engineer reversible
DA reactions that would be dynamic at room and moderate
temperatures. The retro DA reaction has been known since
the discovery of the forward DA itself.13 Such retro reactions,
however, usually require elevated temperatures.14 Furans and
maleimides react at room temperature and undergo a retro
DA reaction at about 110 °C,15,16 the equilibrium being
reached only slowly in organic solvents, although it is faster
in water, as is known for other DA processes.17 In the case
of 3-furfuryl alcohol and N-methyl maleimide, the half-life
of the reaction was found to be about 1 h at 33 mM in
aqueous solution, whereas it was on the order of days in
chloroform.
We have uncovered a series of DA reactions that are
dynamic between 25 and 50 °C and present efficient kinetics,
reaching equilibrium in a matter of 1 min or less at 25 °C
and 100 mM concentration. In the course of our search for
reversible DA reactions involving in particular fulvenes, it
was reported that 2,2-bis(trifluoromethyl)-1,1-dicyanoethyl-
ene and 6,6-dimethylfulvene, 1, reacted in toluene at 20 °C,
with an equilibrium constant (Keq) of 11.2 M-1.18 This
example of a DA reaction equilibrating at room temperature
led us to explore the condensation between fulvenes and
cyanoolefins presenting functionalities with potential for
expanded chemistry. It was found that 6,6′-disubstituted
fulvenes, such as 1-9, engage in reversible DA reactions
with two types of cyanoolefincarboxyesters, the dicyano 10-
1319 and the tricyano 14-1620 compounds, in organic
medium.
following the procedure described in the literature,21 giving
9 in 87% yield. This procedure provides a general access to
fulvenes decorated with various biological fragments or other
functional groups, which may be engaged in reversible (or
nonreversible) DA reactions. The compounds 4, 7, and 8
have been obtained by the same procedure. Compound 5
resulted from acetylation of 4 and compound 6 from
condensation of 4 with N(1)-thymineacetic acid also using
diisopropylcarbodiimide. The full synthetic details will be
given in a full paper.
The addition of an equimolar amount of the fulvenes 1-9
to diethyldicyanofumarate 10 in chloroform yields an equi-
librium mixture of product (1-9,10) and starting materials
(Scheme 1). Thermodynamic equilibrium was reached within
Scheme 1. Reversible Diels-Alder Reactions between
Fulvenes 1-9 and Diethyldicyanofumarate 10
The introduction of functional groups, as in the fulvene
derivatives 4-9, offers the possibility for expanded chemistry
in this dynamic system. Thus, the fulvenes bearing thymine
6 and amino acid (L-phenylalanine) 9 groups have been
synthesized and reacted with the cyanolefins to establish a
room-temperature reversible DA process. The synthesis of
9 involved the condensation of 5-ketohexanoic acid with (L)-
phenylalaninemethylester using diisopropylcarbodiimide as
coupling reagent (57% yield). The resulting amide was
reacted with cyclopentadiene in the presence of pyrrolidine,
seconds after mixing. Two isomeric compounds are obtained
in different proportions with the unsymmetrically substituted
fulvenes 2 and 4-9 (for instance, about 44% and 56% at 25
°C in the case of 4 and 10, respectively). Removal of the
solvent for the 1 + 10 mixture gave a solid adduct, which
regenerated the equilibrium mixture on redissolution.
The equilibrium constants for the reaction of 1 and 10
were determined to be 63 M-1 [33% of 1 and 10; 67% of
(12) Other reactions of this type are cycloadditions in general, the Michael
addition, aldol formation, etc., and their retro processes. Conversely,
reactions such as imine formation, liberating an ancillary water molecule,
are not self-contained. The latter may be manipulated or affected by acting
upon the ancillary compound, whereas the former respond to physicochem-
ical parameters (temperature, medium).
Table 1. Equilibrium for Diels-Alder Reactions in
Chloroform
equilibrium constants (M-1
)
a
(13) Diels, O.; Alder, K. Ber. Dtsch. Chem. Ges. 1929, 64, 554.
(14) Kwart, H.; King., K. Chem. ReV. 1968, 68, 415.
diene
dienophile
25 °C
50 °C
(15) McElhanon, J. R.; Wheeler, D. R. Org. Lett. 2001, 3, 2681.
(16) Chen, X. M.; A. Dam, A.; Ono, K., Mal, A.; Shen, H.; Nutt, S. R.;
Sheran, K.; Wudl, F. Science 2002, 295, 1698.
1
3
1
1
1
1
3
1
10
10
11
12
13
14
14
15
63 ( 3
72 ( 2
99 ( 6
11 ( 1
13 ( 2
17 ( 1
10 ( 1
16 ( 1
140 ( 6
39 ( 3
44 ( 4
(17) (a) Rideout, D. C., Breslow, R. J. Am. Chem. Soc. 1980, 102, 7817.
(b) Breslow, R. Acc. Chem. Res. 1991, 23, 4340. (c) Grieco, P. A. Organic
Synthesis in Water; Blackie Academic & Professional: London, 1998;
Chapter 1.
(18) Howard, M. H.; Alexander, V.; Marshall, W. J.; Roe, D. C.; Zheng,
Y.-J. J. Org. Chem. 2003, 68. 120.
(19) (a) For 10, 11 see: Ireland, C. J.; Jones K.; Pizey, J. S.; Johnson S.
Synth. Commun. 1976, 6, 185. (b) 12, 13 prepared following ref 19a.
(20) Preparation adapted from Hall, H. K., Jr.; Padias, A. B.; Way,
T.-F.; Bergmani, B. J. Org. Chem. 1987, 52, 5528.
43 ( 2
158 ( 3
2345 ( 40
1616 ( 30
581 ( 13
a Determined by H NMR signal integration in CDCl3.
1
16
Org. Lett., Vol. 7, No. 1, 2005

(1,10) at 100 mM] at 25 °C and 11 M-1 [61% of 1 and 10;
39% of (1,10) at 100 mM] at 50 °C. The equilibrium
constants for the cycloadditions of some fulvenes with
cyanoolefins were determined at 25 and 50 °C and are listed
in Table 1.
Comparing the reactions with 6,6-dimethylfulvene 1
(Scheme 2), it is seen that the tricyanoethylenecarboxylates
Scheme 2. Cyanoolefins as Dienophiles
Figure 1. Plots of the equilibrium constants -ln(Keq) as a function
of inverse temperature T-1 (K) for the DA reactions of 1 with 10
(O) and of 1 with 14 (b) in CDCl3 at 100 mM concentration.
adduct (3,10) and components 3 and 10, virtually all of (3,10)
was displaced in favor of the (1,10) adduct in approximately
a minute or less at 25 °C (Scheme 3).
Indeed the signal at 1.05 ppm, which corresponds to the
protons of the terminal methyl of the bridge ethyl group of
adduct (3,10), has almost completely disappeared after the
addition of 5 equiv of 1 (Figure 2).
14-16 display higher equilibrium constants, i.e., higher
reactivity, favoring the adducts more than the dicyanofuma-
rates 10-13. The equilibrium constant for the reaction of
methyl tricyanoethylenecarboxylate 14 with 1 was found to
be 2345 and 140 M-1 at 25 and 50 °C, respectively.
Lowering the temperature increases the value of the
equilibrium constant. Although there are no kinetic con-
straints to the reaction of diethyldicyanofumarate 10 at room
temperature (thermodynamic equilibrium is reached in a
matter of seconds), at temperatures in the -10 to 0 °C range
it is necessary to wait on the order of hours for the solution
to reach equilibrium. For example, the reaction between 1
and 10 at a concentration of 100 mM produces 94% DA
adduct after 6 h at -10 °C.
The equilibrium constants Keq for the reactions of fulvene
1 with the dicyanodiester 10 and tricyanomonoester 14
dienophiles have been determined as a function of temper-
ature. The results plotted in Figure 1 provide the correspond-
ing thermodynamic data. The slope of the graphs of -ln(Keq)
versus the inverse absolute temperature T-1 (in K-1 units)
gives ∆H/R and the intercept gives -∆S/R. The enthalpies
for the equilibria (1 + 10) and (1 + 14) are calculated to
be, respectively, -13 and -22 kcal‚mol-1, and the entropies
of reaction are, respectively, -36 and -57 cal‚gmol-1‚K-1.
The dynamics and reversibility of the present DA reactions
were studied by performing diene exchange experiments. The
process was followed by 1H NMR spectroscopy. For instance,
when 5 equiv of 1 was added to the equilibrating mixture of
Figure 2. 1H NMR observation of component exchange indicating
the dynamic nature of the Diels-Alder reaction between fulvenes
and dicyanofumarate esters: (a) 1/1 mixture of diethyl dicyano-
fumarate 10 (100 mM) and diethylfulvene 3 (100 mM) in
d-chloroform; (b) mixture obtained after addition of 1 equiv of
dimethylfulvene, 1, to solution (a); (c) mixture obtained after
addition of 5 equiv of dimethylfulvene, 1, to solution (a). The broad
signal around 1.6 ppm is due to residual water.
(21) Stone, K. J.; Little, R. D. J. Org. Chem. 1984, 49, 1849.
Org. Lett., Vol. 7, No. 1, 2005
17

thermodynamic equilibrium was reached at room tempera-
ture. The adduct (1,14) was favored over (1,10) in a 4/1 ratio,
and this preference increased with temperature (see also
Figure 1). On lowering back to room temperature, the ratio
of adducts returned to the same value as prior to heating.
Scheme 3. Fulvene Exchange Diels-Alder Reaction
In summary, we have found a series of reactive diene and
dienophile Diels-Alder building blocks that display both
variable reactivity and reversibility. It has further been
demonstrated that these building blocks, which are involved
in reversible chemistry, undergo exchange in adduct forma-
tion, generating dynamic DA diversity. These features
provide a basis for the implementation of the reversible
Diels-Alder reaction in DCC, toward the discovery of both
biologically active substances and mendable materials. In
particular, the expanded DA chemistry based on variously
functionalized substituted fulvenes and cyanoolefin esters
opens the door for the development of reversible dynamic
polymers (dynamers)5 and other dynamic materials. Such
extensions are being pursued.
Similarly, the reactions of the alkyl tricyanoethylenecar-
boxylates 14-16 with dimethylfulvene 1 also exhibit re-
versibility, as was shown both by the temperature-dependent
change in equilibrium concentrations and by competition
experiments (Scheme 4). Establishing the two equilibria
Scheme 4. Equilibria and Component Exchange, Starting
Either from (1,10) and 14 or from (1,14) and 10
Acknowledgment. P.J.B. and P.R. thank the French
Government respectively for a Chateaubriand postdoctoral
fellowship and for a Ph.D. fellowship.
Supporting Information Available: Protocol for study-
ing reversibility and component exchange in the Diels-Alder
reactions, as well as selected 1H NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
starting either from [(1,10) + 14] or from [(1,14) + 10]
(Scheme 4) led to the same final mixture, indicating that
OL048065K
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Org. Lett., Vol. 7, No. 1, 2005