Enzymelike catalysis of the nazarov cyclization by supramolecular encapsulation

Article abstract of DOI:10.1021/ja102633e

The water-soluble, self-assembled, tetrahedral assembly K ₁₂Ga₄L₆ (L = 1,5-biscatecholamidenaphthalene) catalyzes the Nazarov cyclization of 1,3-pentadienols with extremely high levels of efficiency. The catalyzed reaction proceeds over a million times faster than the background reaction, an increase comparable to those observed in some enzymatic systems. This catalysis operates under aqueous conditions at mild temperatures and pH, and the reaction is halted by the addition of an appropriate inhibitor. This unprecedented rate enhancement is attributed to both the stabilization of protonated reaction intermediates and the effect of constrictive binding on the bound guest.

Full text of DOI:10.1021/ja102633e

Published on Web 05/05/2010
Enzymelike Catalysis of the Nazarov Cyclization by Supramolecular
Encapsulation
Courtney J. Hastings, Michael D. Pluth, Robert G. Bergman,* and Kenneth N. Raymond*
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460, and DiVision of Chemical
Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720-1460
Received March 29, 2010; E-mail: rbergman@berkeley.edu; raymond@socrates.berkeley.edu
A primary goal in the design and synthesis of molecular hosts
is the selective recognition and binding of a variety of guests
1
using noncovalent interactions. Supramolecular catalysis, which
2
is the application of such hosts toward catalysis, has much in
2
b,3
common with many enzymatic reactions,
chiefly the use of
both spatially appropriate binding pockets and precisely oriented
functional groups to recognize and activate specific substrate
molecules. Although there are now many examples that dem-
onstrate how selective encapsulation in a host cavity can enhance
the reactivity of a bound guest, all have failed to reach the degree
4
of increased reactivity typical of enzymes. We now report the
Figure 1. (left) Schematic view of 1 in which the bisbidentate ligands are
represented by blue lines and the gallium atoms by red circles. (right) Space-
filling model of 1.
use of a self-assembled coordination cage to catalyze the Nazarov
cyclization, a carbon-carbon bond-forming reaction that pro-
ceeds under mild, aqueous conditions. The acceleration in this
system is over a million-fold, representing the first example of
supramolecular catalysis that achieves a level of rate enhance-
ment comparable to that observed in several enzymes. We
explain the unprecedented degree of rate increase as due to the
combination of (a) preorganization of the encapsulated substrate
molecule, (b) stabilization of the transition state of the cyclization
by constrictive binding, and (c) an increase in the basicity of
the complexed alcohol functionality.
Having demonstrated the ability of 1 to perform acid-catalyzed
hydrolysis reactions, we sought to apply this reactivity to more
synthetically useful acid-catalyzed reaction types. Acid-catalyzed
cyclizations are particularly interesting because 1 could accelerate
such a reaction both by enhancing the basicity of the bound substrate
1
0
and by preorganizing the substrate in a reactive conformation.
The Nazarov cyclization, an acid-catalyzed reaction in which a 1,4-
dien-3-ol forms a cyclopentadiene (e.g., the example shown in
Scheme 1a), is attractive from this perspective. This reaction
proceeds via the intermediacy of a diallylic carbocation that
undergoes conrotatory electrocyclic ring closure in accordance with
Raymond and co-workers have designed the supramolecular host
(
1) having Ga
4 6
L stoichiometry (L ) N,N′-bis(2,3-dihydroxyben-
zoyl)-1,5-diaminonaphthalene; Figure 1) that exploits reversible
5
,6
metal-ligand interactions to spontaneously self-assemble. In
these assemblies, the biscatecholate ligands span the edges of a
tetrahedron whose vertices are occupied by metal ions. Polyanion
1
1
the Woodward-Hoffmann rules. This reaction is widely utilized
in synthetic organic chemistry as well as in organometallic
chemistry, where it has provided a route to substituted polymeth-
1
is soluble in water and other polar solvents, while the host interior
1
2
ylcyclopentadienyl ligands.
is paneled by the naphthalene rings of the ligand, creating a
hydrophobic inner environment. A wide variety of cationic guests
can be encapsulated in 1, from quaternary ammonium and phos-
phonium cations to organometallic complexes. In aqueous solution,
neutral molecules such as hydrocarbons are bound by 1 because of
As a proof of principle, 10 equiv of 3,4,5-trimethylhepta-2,5-
dien-4-ol 2 (obtained as a mixture of the three possible olefin
stereoisomers; Scheme 1b) was added to a solution of 1 in H O
2
(
buffered at pH 11.0) and heated to 50 °C. Under these reaction
conditions, a set of peaks corresponding to host-guest complexes
of 2 was observed by H NMR spectroscopy. After 12 h, the organic
7
the hydrophobic effect.
1
Our approach toward supramolecular catalysis using 1 exploits
the preference of the polyanionic host for encapsulating mono-
cationic guests. Encapsulation in 1 can perturb acid-base
equilibria to favor the protonation of a wide range of amines
and phosphines, even at strongly basic pH. This behavior led
to the development of proton-catalyzed hydrolysis reactions
2 2
products were extracted into CH Cl , whereupon GC-MS analysis
showed the complete consumption of the starting material and the
quantitative formation of the Nazarov product, Cp*H. A control
+
reaction run using 1.1 equiv of a strongly binding guest (NEt
4
) to
8
block the host interior halted product formation through a mech-
1
3
anism analogous to enzyme inhibition.
inside 1, in which a protonated transition state is stabilized in
the host interior. The stabilization of even transient protonated
species produces a several thousand-fold rate acceleration of
orthoformate and acetal hydrolysis under basic conditions.
However, even this substantial acceleration does not reach that
typically seen in enzyme-catalyzed reactions.
Having obtained these preliminary results, we sought to quantify
the rate enhancement of the catalyzed reaction over the background
reaction. Because of the low solubility of substrate 2 in water,
9
further studies were carried out in D O with 50% added DMSO-
2
d6. The three possible stereoisomers of 2 (Scheme 1b) were
independently synthesized for these experiments. Under these
6
938 9 J. AM. CHEM. SOC. 2010, 132, 6938–6940
10.1021/ja102633e  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. (a) General Scheme for the Acid-Catalyzed Nazarov
Reaction of Pentadienols To Form Cyclopentadienes; (b)
Pentadienol Reactants for the Nazarov Cyclization Used in This
Study
The catalysis under these conditions was quite efficient, and
turnover numbers of up to 160 were achieved. The observed
rate constants for the catalyzed cyclization of Z,Z substrate 2b
and E,Z substrate 2c were an order of magnitude larger than
that for the cyclization of E,E substrate 2a (Table 1). We find it
remarkable that the reactivities of these three substrates are so
different when they differ only in stereochemistry at positions
remote from the forming carbocation. Since guest exchange is
fast relative to the reaction rate, the rate constants for the reaction
of host-bound substrate,
Michaelis-Menten equation using experimentally determined
values. Substrate 2a was too weakly bound under the mixed-
cat
k , were calculated from the
K
M
M
solvent conditions for the K value to be measured, so its kcat
value is not reported.
conditions, the disappearance of each of the three stereoisomers of
1
In order to quantify the rate acceleration attributable to catalysis,
the background reaction rate for each substrate was measured in
the absence of 1. The uncatalyzed reaction are extremely slow under
these reaction conditions and strongly depend on the substrate
stereochemistry, with methyl groups in the Z configuration giving
the slowest reaction. This suggests that the reacting molecule must
adopt a U-shaped conformation prior to or at the transition state of
the rate-determining step in order to react. This compact conforma-
tion necessary for reaction is sterically disfavored by Z methyl
groups in comparison with the linear conformation of the same
molecule (Scheme 3).
2
catalyzed by 7 mol % 1 was monitored by H NMR spectroscopy.
The product of these reactions, Cp*H, is not soluble under these
conditions and was not observed during the course of the reaction,
but it could be extracted into an organic solvent after the reaction
was complete. Again, no reaction was observed when a strongly
binding guest was added to exclude the substrate from the interior
of 1.
For all three stereoisomers of 2, the initial reactions were
rapid, but deviation from pseudo-first-order kinetic behavior was
observed as the reaction progressed. In each case, kobs for the
disappearance of starting material (calculated from the slope of
a plot of ln[2] vs time) was constant at the beginning of the
reaction and then decreased as the reaction proceeded. This effect
was especially severe for the reaction of substrate 2a, which
nearly halted after 25% conversion. This decrease in reaction
rate is consistent with product inhibition, a common occurrence
in both synthetic and enzymatic catalysis when the host does
not bind the reactant substantially more strongly than it binds
Scheme 3. Linear and U-Shaped Conformations of Substrate 2b
1
4
Table 1. Kinetic Data for Nazarov Substrates at 45 °C with
Maleimide Added as a Trapping Agent
the product. Competition experiments involving Cp*H and the
stereoisomers of 2 showed that Cp*H is a competitive guest.
Adding a full equivalent of Cp*H to the 1-catalyzed reaction
shut down the Nazarov cyclization. These experiments clearly
implicated product inhibition as the cause of the decrease in
rate
acceleration
(kcat/kuncat)
-1
-1
-1
uncat (s
substrate
kobs (s
)
K
M
(mM)
kcat (s
)
k
)
-
5
-8
-9
-8
1
5
2a
5.1(1) × 10
4.2(1) × 10
-
-
4.0(3) × 10
7.7(8) × 10
3.3(1) × 10
-
k
obs observed as the reaction progressed.
A solution to this problem was developed by chemically
converting the product Cp*H into a poor guest, a strategy that
-4
-2
-2
2
b
42(1) 1.6(1) × 10
2 100 000
1 700 000
-
3
2c
1.08(2) × 10
91(1) 5.7(1) × 10
1
0
has been utilized in other examples of supramolecular catalysis.
The addition of maleimide (3) to the 1-catalyzed Nazarov
cyclization completely alleviated product inhibition by converting
Cp*H into the Diels-Alder adduct 4, which is soluble under
the reaction conditions (Scheme 2). In the reaction using
maleimide as a trapping agent, the rate of Diels-Alder adduct
formation was equal to rate of starting material consumption,
implying that no Cp*H built up in solution. The concentration-
versus-time plots for reactions with added maleimide subse-
quently showed no deviation from pseudo-first-order behavior,
indicating that product inhibition was eliminated. Competitive
binding experiments involving Cp*H and 4 showed that 4 is a
weaker-binding guest, which explains why it did not noticeably
retard the reaction rate.
The rate accelerations of the catalyzed reaction over the
6
uncatalyzed reaction are on the order of 10 , which are the largest
1
6
measured for supramolecular catalysis by orders of magnitude.
This very high level of catalytic activity is reminiscent of
enzymatic catalysis. The observed rate acceleration is too large
to be explained only by an increase in the basicity of the bound
substrate. In previous studies, we observed a maximum of 4
orders of magnitude in the equilibrium shift of protonated amines
and a thousand-fold rate acceleration in the hydrolysis of
8,9
a
orthoformates.
We propose that the additional rate enhance-
ment in this system is due to constrictive binding in the pocket
of 1, which favors both the U-shaped conformation of the
substrate and the compact transition state of the electrocycliza-
tion. Constrictive binding is responsible for rate enhancements
of nearly 3 orders of magnitude in the 1-catalyzed aza-Cope
rearrangement of enammonium cations, where encapsulation
Scheme 2. Conversion of Cp*H into a Noncompetitive Guest (4)
To Alleviate Product Inhibition
1
0
preorganizes the substrate into a reactive conformation. We
conclude that the million-fold rate enhancement in this system
is due to the combination of an increase in the basicity of the
alcohol functionality upon encapsulation, preorganization of
the bound substrate, and stabilization of the transition state of
the electrocyclic reaction. We suggest that combining the effects
J. AM. CHEM. SOC. 9 VOL. 132, NO. 20, 2010 6939

C O M M U N I C A T I O N S
of constrictive binding with functional-group activation may
represent a general strategy for achieving enhanced reactivity
in supramolecular catalysis.
and through fellowships from the NSF (to M.D.P.) and Chevron
(to C.J.H.). The authors thank Lee Bishop, Casey Brown, Jeff
Mugridge, and Dr. Carmelo Sgarlatta for helpful discus-
sions.
To probe the mechanism of this reaction, we sought to identify
the encapsulated species observed during the reaction, which
1
3
Supporting Information Available: Experimental details, kinetic
data, and characterization of host-guest complexes. This material
is available free of charge via the Internet at http://pubs.acs.
org.
must be the resting state of the catalyst. The C-labeled
1
3
compound 2- C, prepared as a mixture of three stereoisomers,
was used for this purpose. If the encapsulated species is either
the dienyl cation 5 or the cyclized allyl cation 6 (Scheme 4),
1
3
there should be a dramatic shift in the C NMR resonance of
1
7
13
the labeled carbon. When 2- C was encapsulated in 1, the
enriched 13C resonances were shifted upfield by only a few parts
per million relative to those of the unencapsulated alcohol. This
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