Enzyme mimics for Michael additions with novel proton transport groups

Article abstract of DOI:10.1002/ejoc.200701207

Molecular receptors with an enzyme-like behavior in the Michael addition of pyrrolidine to an α,β-unsaturated lactam have been designed. Catalytic activities are discussed and related to the substrate association constants. Chiral assistance of enantiomerically pure receptors was also investigated. One of the receptors shows a 4:1 enantiomeric ratio (60% ee) for the addition of pyrrolidine and 3-pyrroline. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701207

FULL PAPER
DOI: 10.1002/ejoc.200701207
Enzyme Mimics for Michael Additions with Novel Proton Transport Groups
Luis Simón,[a][‡] Francisco M. Muñiz,[a] Silvia Sáez,[a] César Raposo,[b] and
Joaquín R. Morán*[a]
Dedicated to Prof. Miguel Yus on the occasion of his 60th birthday
Keywords: Homogeneous catalysis / Supramolecular chemistry / Hydrogen bonds / Enzyme mimics / Proton slide
Molecular receptors with an enzyme-like behavior in the
Michael addition of pyrrolidine to an α,β-unsaturated lactam
have been designed. Catalytic activities are discussed and
related to the substrate association constants. Chiral assist-
ance of enantiomerically pure receptors was also investi-
gated. One of the receptors shows a 4:1 enantiomeric ratio
(60% ee) for the addition of pyrrolidine and 3-pyrroline.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
In the course of searching for catalysts that are as effec-
tive as natural enzymes, H-bond catalysis has recently re-
ceived much attention due to the resemblance of many of
them to natural enzymes.[1–23] The design of these artificial
enzymes could be inspired in knowledge about enzyme
catalytic mechanisms. In this regard, enoyl CoA hydratase
is an attractive model.[24,25] Its active site shows an oxy-
anion hole (Figure 1), a well-established feature for many
other enzymes, which allows stabilization of the negative
charge developed in the Michael acceptor carbonyl
group.[26–31] The active site also contains two glutamate res-
idues (Figure 1), which hold the nucleophile in the right po-
sition. One of them provides assistance for the proton trans-
fer of the nucleophile to the unsaturated carbonyl α-carbon.
Figure 1. Structure of the oxyanion hole in enoyl-CoA hydratase.
Despite their important role in natural enzymes, gluta-
In a recent paper,[23] we have designed and synthesized mates were ruled out because the carboxylate probably
molecular receptors with excellent catalytic activities in the blocks the receptor cleft. Instead, basic amino groups were
Michael addition of pyrrolidine to α,β-unsaturated valero- included in the structure (receptors 4 to 6, Scheme 1), yield-
lactam 1. These receptors, and the ones prepared in this ing receptors with up to 10000-fold kcat/kuncat values. Mo-
work, combine an oxyanion-like structure (a xanthonedi- lecular-modelling studies showed that amino-group activity
amide skeleton) with groups capable of assisting the proton in the receptors corresponded to a Bruice proton slide-like
transfer from the nucleophile to the lactam (Figure 2).
mechanism, in which the non-bonding electrons of the good
H-bond acceptor (amino group) facilitate proton trans-
fer.[32–35]
[a] Organic Chemistry Department, University of Salamanca,
37008 Salamanca, Spain
Nevertheless, the basic amino group is also able to estab-
lish intramolecular H bonds with the xanthoneamide
groups, reducing the substrate association constant. As a
consequence, the measured half-life time of the reaction
does not reflect the actual catalytic activity. As pointed out
by Bruice[32,33] it is the ability as an H-bond acceptor and
not the basicity that is important for an auxiliary group to
carry out the proton transport in a proton-slide mechanism.
Therefore, in this paper the catalytic effect of non-basic oxy-
Fax: +34-923-294574
E-mail: romoran@usal.es
[b] Mass Spectrometry Service, University of Salamanca,
37008 Salamanca, Spain
E-mail: raposo@usal.es
[‡] Present address: Unilever Centre for Molecular Science In-
formatics, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge CB2 1EW, UK
E-mail: ls428@cam.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2397–2403
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Simón, F. M. Muñiz, S. Sáez, C. Raposo, J. R. Morán
FULL PAPER
Results and Discussion
Kinetic experiments were carried out in benzene at
298 K. The lactam concentration was 0.8 . A high concen-
tration of pyrrolidine (3.0 ) was used to prevent catalytic
activity by the reaction product, which could have compli-
cated the interpretation of the process under study. Under
these conditions, the half-life time of the reaction (referred
to lactam) was 2385 min in the absence of a catalyst.[23] Re-
ceptors were added at 0.04  concentration and the lactam
1
concentration was deduced from the H NMR spectra at
different times.
Despite the formation of diastereomeric complexes with
the amino lactam 2, the chiral receptors (8, 10, 11 or 12)
did not split the signals of the reaction product. To assess
asymmetric induction, we prepared a chiral shift reagent
13 derived from the xanthone-diamine skeleton (Figure 3).
Although this receptor shows no improved catalytic ac-
tivity, it associates the Michael adduct 2, leading to dia-
stereomeric complexes with different 1H NMR spectra. The
aromatic rings in the diphenylethylenediamine moiety sup-
ply strong anisotropic fields, while the sulfonamide NH pro-
vides an additional H bond with the amine nitrogen of lac-
tam 2, fixing the geometry of the complex and improving
the association constant. Addition of 25% of this receptor
completely split the signals of the pyrrolidine α-hydrogen
atoms (Figure 3). These signals were used in the analysis
owing to their large size and because irradiation of the β
pyrrolidine protons affords reasonably narrow signals,
which after Gaussian deconvolution using the Mestre-C[39]
program afforded the enantiomeric ratio. The absolute ste-
reochemistry was determined using the circular dichroism
of the product (see Supporting Information).
Figure 2. Proposed mechanism for the catalytic effect of the recep-
tors with sulfonamide active groups in the addition of amines to
the lactam 1.
Figure 3. Structure of the complex between the chiral shift reagent
13 and the aminolactam 2 and the induced chemical shifts in the
pyrrolidine signals.
The results are summarized in Table 1. The previously
reported receptors included here (4, 5, and 6) showed only
small chiral assistances (ratio below 3:1).
The CPK models suggested that the receptors 7 and 8
can place the carbonyl oxygen atoms of the phthalimide
group close to the valerolactam α carbon in the complex.
Scheme 1. Structure of the catalysts studied in this work. The group
responsible for catalysis by the proton slide is highlighted.
gen atoms, which are good H-bond acceptors,[36–38] is re- Therefore, they could be active in transporting the pyrroli-
ported. Additionally, the asymmetric induction of the chiral dine proton. Both phthalimide derivative receptors showed
receptors was investigated (including the previously re- improved half-life times, in agreement with a proton-slide
ported receptors 4–6[23]).
mechanism. The alanine derivative 8 had a smaller half-life
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Eur. J. Org. Chem. 2008, 2397–2403

Enzyme Mimics for Michael Additions
Table 1. Relative association constants and kinetic activities of re- receptors 8, 9, and 12, we performed a similar analysis to
ceptors.[a]
that described already for these receptors.[23]
We first noticed that the equation that describes
Michael–Menten kinetics in the presence of a competing
product, can be further simplified if one assumes that the
association constant of the product and the substrate is sim-
ilar; see Equation (1).
Receptor t1/2
Krel
Enantiomeric
ratio S/R
(pyrrolidine)
Enantiomeric
ratio S/R
(3-pyrroline)
[min]
85
3
1.00
4
48
85
33
68
42
24
96
102
51
0.064
0.007
0.071
0.588
0.053
0.280
0.599
1.6:1 (23% ee)
2.6:1 (44% ee)
0.4:1 (42% ee)
1.2:1 (9% ee)
1.4:1 (16% ee)
0.4:1 (42% ee)
5
6
7
8
3.8:1(58% ee)
1.9:1 (31% ee)
9
10
11
12
1:1
1:1
0.240
4.0:1 (60% ee)
4.3:1 (62% ee)
(1)
[a] Kinetic experiments in benzene at 298 K. [pyrrolidine] = 3.0 ;
[lactam] = 0.8 ; [receptor] = 0.04 . For chiral assistance experi-
ments, [nucleophile] = 0.80 . The enantiomeric ratio was mea-
sured in the reaction half-life. Krel relative to receptor 3, measured
in benzene solution.
Numerical integration of the kinetic equations was per-
formed using the fourth-order Runge–Kutta method.[40] In
this analysis it is assumed that the mechanism is first order
in pyrrolidine (n = 1) and that the contribution from a bi-
molecular mechanism is negligible. Although it would be
time than the glycine derivative 7, even though the associa- desirable to confirm this point, determination of this order
tion constant was 10 times smaller. The methyl group in the is difficult in the presence of the catalyst: it will require
alanine fragment probably favours a suitable conformation kinetic experiments at different pyrrolidine concentrations,
for catalysis. This receptor also shows a noticeable chiral but pyrrolidine concentration may also affect the associa-
assistance (3.8 ratio, 58% ee). Asymmetric induction was tion constant with the catalyst, making interpretation of the
also checked using 3-pyrroline as the nucleophile. In this results difficult. Therefore, we simply used n = 1 in the inte-
case, integration of the 1H NMR signals was easier, but the gration and checked that the kcat/kuncat ratio obtained was
enantiomeric excess was smaller, showing only a ratio of 2.0 at least 10 times larger than the same value obtained for
(33% ee) between the integrals of the enantiomeric lactams. the receptor 3. Because the receptor 3 lacks any group that
Sulfonamides have been shown to be hydrogen-bond ac- might assist the proton-transport step, this 10-fold in-
ceptors similar to amines.[36] Therefore, the receptors 9 to crement in catalytic activity is probably a consequence of
12 were prepared. The best catalytic activity was obtained the auxiliary group replacing the second pyrrolidine mole-
for the tosylglycine derivative 9 (half-life time 24 min). The cule (kinetic order in pyrrolidine has been found to be 2 in
presence of the methyl group in the tosylalanine receptor the absence of catalyst).[23] If there is a contribution of a
10 strongly reduced the catalytic activity despite a stronger possible second-order mechanism, it will be small for the
association constant. Unlike in the phthalimide derivative accuracy that is sought in these experiments. A similar esti-
receptors, the methyl group handicaps the productive con- mation of kcat for the receptors 7, 10 and 11 shown in this
formation in the receptor. Since the half-lives and associa- work was not valid because, from the values obtained for
tion constants were similar to those of the decanoyl recep- kcat for these receptors, it was not possible to rule out a
tor 3, the sulfonamide is probably not active in the proton- relevant contribution for the bimolecular mechanism.
transport step. This can also explain the lack of asymmetric
In order to calculate kcat it is necessary to measure KM.
induction. The same features were observed for the receptor The measurement of small association constants with recep-
11, with long half-life times (102 min) and no asymmetric tors using 3.0  pyrrolidine is problematic, so indirect mea-
induction.
surement of KM was employed. Relative association con-
The most interesting results were obtained with the tosyl stants with respect to the receptor 3 have been found by
norephedrine derivative 12. The complex of this receptor means of competitive titration in deuterated chloroform.
and lactam 1 was four times weaker than for the decanoyl These relative constants were used to approximate real as-
receptor 3, probably due to intramolecular H-bond forma- sociation constants, assuming that the same ratio would be
tion. Although the catalytic activity was slightly smaller obtained under the reaction conditions. With these values,
than for the receptors 8 and 9 (t1/2 = 51 min), analysis of the and the association constant for receptor 3 measured in the
chiral assistance afforded a 4.0:1 ratio (60% ee). A different reaction conditions (between 11 –1 and 40 –1),[23] KM val-
experiment with 3-pyrroline revealed a similar result, with ues were estimated.
a 4.3:1 ratio (62% ee).
The results are shown in Table 2. In this Table, values for
Although half-life times of the catalyzed reaction might the receptors 3, 4, 5 and 6 are also included to facilitate
be useful in characterizing the catalytic activity of the recep- comparison. As can be seen, carbonyl and sulfonamide oxy-
tors, this magnitude might conceal other phenomena as as- gen lone pairs are almost as effective as amine lone pairs in
sociation of the substrate or inhibition. For the receptors 4, assisting the proton transfer for the reaction. Besides, these
5 and 6 these effects have been shown to be very relevant receptors do not show the association problems of the
in determining the real catalytic activity. Therefore, for the amine receptors.
Eur. J. Org. Chem. 2008, 2397–2403
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2399

L. Simón, F. M. Muñiz, S. Sáez, C. Raposo, J. R. Morán
FULL PAPER
Table 2. Catalytic activities of receptors.
Due to the flexibility of the receptor, two diastereomeric
transition states have been found, each driving to different
enantiomers. Although the calculations were able to predict
correctly the major enantiomer of the reaction, the energy
difference between both transition states (4.0 kcal/mol) is
too high for the enentioselectivity obtained. Single-point
calculations on structures derived from these transition
states revealed that in the one leading to S product the
phthalimide amino acid adopts a 1.8 kcal/mol more stable
conformation (see details in the Supporting Information).
Additionally, the pyrrolidine-lactam reacting complex
shows a 0.9 kcal/mol more stable arrangement in this tran-
sition state. In conclusion, despite the energy difference cal-
culated for both transition states, it is clear that both
enantiomers are generated in a catalytic reaction, explaining
the low enantioselectivity of the receptor.
Receptor
kcat/kuncat
Receptor
kcat/kuncat
3
4
5
6
102.7Ϯ0.1 [a]
103.4Ϯ0.1 [b]
104.2Ϯ0.2 [b]
103.9Ϯ0.2 [b]
8
103.8Ϯ0.2 [b]
103.8Ϯ0.1 [b]
103.5Ϯ0.1 [b]
9
12
[a] Calculated considering second-order kinetics in pyrrolidine (ad-
imensional). [b] molL–1.
The low enantioselectivity of these receptors (compared
with the high catalytic activity) cannot be ascribed to a
competing no enantioselective process in which auxiliary
groups acts only as spectators. It is reasonable to think that
these receptors will be as effective as receptor 3 in catalyzing
this non selective process, but comparison of the catalytic
activities allows us to deduce that product generated by this
process will not exceed 10% of the total product, so enan-
tiomeric ratios around 20:1 will be expected. Instead, it is
very likely that, due to their structure flexibility, receptors
can adopt different conformations to catalyze the formation
of both enantiomers.
Modelling studies were performed for the receptor 9
using the GAUSSIAN 98W[41] program. Transition-state
structures were optimized using ONIOM[42–44] method.
Those atoms directly involved in the reaction were treated
with a B3LYP[45]/3-21G**[46–49] level of theory. The rest of
atoms were studied using the semiempirical AM1[50]
method. The resulting structures are shown in Figure 4,
where atoms included in the high-level layer are drawn as a
“ball and stick” model, whereas those in the low-level layer
are drawn as wires. Single-point energies were calculated
on optimized structures using B3LYP/6-31G**[51–53] level of
theory, and PCM[54–57] solvation model was employed to
account for the benzene solvent. This energy was added to
the thermal corrections to Gibbs free energy calculated with
the same level of theory used in the optimization.
Conclusions
The catalytic activities and chiral assistances of some re-
ceptors included in this study support the notion that no
basic, good H-bond acceptor groups (such as neutral imide
and sulfonamide oxygen atoms) can assist the proton-trans-
fer mechanism. To the best of our knowledge, this is the
only example in the literature in which these groups have
been proposed to play this role. These unprecedented results
broaden the possibilities in the design of new artificial en-
zymes. Nevertheless, the catalytic and stereochemical results
obtained with these xanthone receptors are still far from
those obtained with natural enzymes. A more careful design
of the receptor auxiliary groups, and the employment of
more rigid receptors, should in the future lead to enzyme
mimics with enhanced synthetic possibilities.
Experimental Section
Synthesis of the receptors 3, 4, 5, and 6 has been described pre-
viously.[21,23]
Synthesis of the Receptors 7 to 11: See Figure 5. An excess (3 to
5 equiv.) of acyl chlorides obtained from phthaloyl amino acid de-
rivatives and tosyl amino acid derivatives was added to a solution
of xanthoneamine derivative (1 g, 2.1 mmol) in THF (10 mL). Af-
ter 20 min at room temperature, water (1 mL) was added dropwise
and the reaction mixture was heated to 50 °C for 10 min. The sol-
vent was evaporated off at reduced pressure and the solid residue
was dissolved in ethyl acetate. This solution was washed several
times with a Na2CO3 solution (4%) and the organic layer was dried
with anhydrous NasSO4. Recrystallization of receptors was per-
formed in methanol/water mixtures. Yields of receptors, 7: 89%
(1.24 g), 8: 92% (1.31 g), 9: 92% (1.58 g), 10: 90% (1.33 g), 11: 87%
(1.33 g).
Synthesis of Receptor 12: See Figure 6. Xanthoneamine derivative
(1 g, 2.1 mmol) was dissolved in CH2Cl2 (10 mL) and an excess of
0.6  phosgene solution in toluene was added (2 mL). The mixture
was refluxed for 30 min. The solvent and reagent excess were evap-
orated off at reduced pressure and the solid residue was dissolved
in toluene (40 mL). This solvent was again evaporated off under
Figure 4. Structure of the transition states obtained from modelling
studies for receptor 8.
The found transition-state structures show a hydrogen
bond between the pyrrolidine nucleophile and the phthal-
imide oxygen, in agreement with a proton-slide mechanism. vacuum, and chlorobenzene (10 mL) was used to dissolve the solid
2400 Eur. J. Org. Chem. 2008, 2397–2403
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Enzyme Mimics for Michael Additions
Figure 5. Synthesis of the receptors 7 to 11.
Figure 6. Synthesis of the receptor 12.
Figure 7. Synthesis of the receptor 13.
Eur. J. Org. Chem. 2008, 2397–2403
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Simón, F. M. Muñiz, S. Sáez, C. Raposo, J. R. Morán
FULL PAPER
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residue. To this solution, an excess (3.2 g, 10.5 mmol) of N-tosylno-
rephedrine was added and the mixture was heated to 130 °C for
one week. The solvent was evaporated and receptor 12 was purified
by column chromatography on silica gel. Yield 43% (0.73 g).
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Synthesis of Receptor 13: See Figure 7. The isocyanate of the xan-
thone amine derivative 2, obtained as described for receptor 12
(1 g, 2.0 mmol), was dissolved in toluene (40 mL). A solution of
diphenylethylenediamine (2 g, 9.4 mmol) in toluene (40 mL) was
added dropwise for 15 min. The reaction mixture was washed first
with a dilute solution of HCl and then with a 4% Na2CO3 solution.
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93% (1.32 g). The amino intermediate (1 g, 1.4 mmol) was dis-
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Supporting Information (see also the footnote on the first page of
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dichroism of product. Cartesian coordinates of transition state
structures.
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Received: December 20, 2007
Published Online: March 27, 2008
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