New guanidinium-based carboxylate receptors derived from 5-amino-pyrrole-2-carboxylate: Synthesis and first binding studies

Article abstract of DOI:10.1016/j.tetlet.2005.08.115

The syntheses of two new guanidinium-based carboxylate receptors 2a,b derived from 5-amino pyrrole-2-carboxylate 4 are described. These receptors bind N-acetyl alanine carboxylate and O-acetyl lactate efficiently in aqueous DMSO as could be shown by NMR studies. However, compared to previously reported guanidiniocarbonyl pyrrole receptors 1, the reversal in the direction of the amide group in 2a,b changes both the substrate selectivity (amides are now preferred over esters) and their relative binding affinities. Both effects can be explained based on the calculated complex structure.

Full text of DOI:10.1016/j.tetlet.2005.08.115

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7101–7105
New guanidinium-based carboxylate receptors derived from
5-amino-pyrrole-2-carboxylate: synthesis and first binding studies
Carsten Schmuck* and Jurgen Dudaczek
¨
Universita¨t Wu¨rzburg, Institut fu¨r Organische Chemie, Am Hubland, 97074 Wu¨rzburg, Germany
Received 2 August 2005; accepted 23 August 2005
Abstract—The syntheses of two new guanidinium-based carboxylate receptors 2a,b derived from 5-amino pyrrole-2-carboxylate 4
are described. These receptors bind N-acetyl alanine carboxylate and O-acetyl lactate efficiently in aqueous DMSO as could be
shown by NMR studies. However, compared to previously reported guanidiniocarbonyl pyrrole receptors 1, the reversal in the
direction of the amide group in 2a,b changes both the substrate selectivity(amides are now preferred over esters) and their relative
binding affinities. Both effects can be explained based on the calculated complex structure.
Ó 2005 Elsevier Ltd. All rights reserved.
The binding of anions in polar solutions is an important
aspect of todayÕs supramolecular chemistry.1 Artificial
anion receptors can function as sensors for the detection
of environmentally critical analytes or as model systems
to studythe binding of small anionic biomolecules by
natural anion receptors such as proteins or enzymes.
The latter aspect is especiallyappealing as a varietyof
interesting biomolecules can be anionic such as DNA,
amino acids,2 peptides3 and proteins or carbohydrates.
In these cases, ionic interactions, for example, the for-
mation of ion pairs is veryoften crucial for the selective
complexation of anions in polar solvents.4 However, this
primaryinteraction is normallyfine-tuned byadditional
attractive or repulsive interactions to increase substrate
selectivity.
1.2a–c,5,6 Due to the increased aciditycaused bythe acyl-
ation and the additional H-bonds, the binding is much
more efficient compared to simple guanidinium cations.5
But, so far, we have onlyinvestigated receptors derived
from pyrrole-2,5-dicarboxylic acid. We have now pre-
pared a new class of amino acid receptors 2 based on
5-amino-pyrrole-2-carboxylate 4 in which the direction
of the amide group in position 5 at the pyrrole is re-
versed. This exchange of H-bond donor and acceptor
could have interesting effects on either the stabilityor
the selectivityof such receptors. We want to present here
the syntheses of two prototypes 2a,b and preliminary
binding studies using both N-acetyl alanine 18 and O-
acetyl-lactate 19 as substrates.
The synthesis of these two new compounds proved to be
more difficult than initiallyexpected. Our first attempt
was based on our previous strategyfor the synthesis of
the pyrrole dicarboxylic acid based receptors 1 (Scheme
1).5 Nitration of pyrrole carboxylic acid should provide
after reduction the 5-amino-pyrrole-2-carboxylic acid
ester 4. The free amino group in 4 could then be reacted
with any acyl chloride, for example, to give the acylated
esters 3. The pyrrole carboxylic acid obtained after
hydrolysis thereof could then be coupled with t-Boc-
guanidine 13 to give the desired receptors 2 after
deprotection.
O
R
O
N
H
N
1
N
H
N
N
H
H
H
H
O
H
R
'
O
We are currentlystudying the complexation of amino
acid carboxylates by guanidiniocarbonyl pyrrole cations
Keywords: Supramolecular chemistry; Amino acid receptors; Guanid-
inium cations; Pyrroles.
However, the direct nitration of pyrrole-2-carboxylic
acid ester 6 in position 5 was rather low yielding
(Scheme 2). Besides only10% of the desired 5-amino
*
Corresponding author. Tel.: +49 931 8885326; fax: +49 931
8884625; e-mail: schmuck@chemie.uni-wuerzburg.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.115

7102
C. Schmuck, J. Dudaczek / Tetrahedron Letters 46 (2005) 7101–7105
O
O
O
H
N
H
N
NH2
NH2
NH2
NH2
OMe
N
H
H2N
N
H
N
H
N
H
O2N
CO2Me
N
H
N
H
O
O
O
O
nitric acid : < 10 %
clayclop: 4 %
2a
2b
8
7
pentylnitrite: 40 % yield
2
H2N
CO2Me
R
N
H
CO2Me
N
H
N
H
Scheme 3. Direct nitration of 7 using various reagents and conditions.
4
3
ii
i
OMe
CCl3
CCl3
O2N
O2N
CO2Me
N
H
N
H
N
H
N
H
97 %
61 %
O
O
O
5a
6
9
10
Scheme 1. Retrosynthesis for the new amino acid receptors of type 2.
iii
O2N
CO2Me
H2N
CO2Me
N
H
N
H
quant.
5
4
O2N
Scheme 4. Synthesis of 5-amino pyrrol-2-carboxylate 4. Reagents and
conditions: (i) HNO3, Ac2O, À40 °C; (ii) MeONa, MeOH, reflux; (iii)
H2, Pd/C, MeOH.
HNO3
+
OMe
O2N
CO2Me
(10 %)
CO2Me
(7 %)
N
H
N
H
N
H
Ac2O
-15°C
O
5a
5b
6
gave 5a in only10% yield ( Scheme 2). After basic hydro-
lysis of the trichloroacetyl group the nitro group in 5
was then successfullyreduced with hydrogen (Pd/C) to
give the desired 5-amino-pyrrole-2-carboxylic acid
methyl ester 4.
Scheme 2. Direct nitration of 6 gives a mixture of the two regioisomers
5a and 5b in low overall yields.
derivative 5a also 7% of the unwanted 4-amino pyrrole
5b were isolated. The general problem of the synthesis
of nitro pyrroles is their decomposition most likely due
to oxidation under the reaction conditions.7 In accord-
ance with this, only modest yields varying from 10%
to 30% are reported in the literature for such reactions.8
And the more efficient reactions are normallyonlyob-
served in the case of N-alkylated or acylated pyrroles.
Another problem besides the low yields in general is
the regioselectivity, which favours substitution in posi-
tion 5 of a 2-acceptor substituted pyrrole only under
kinetic conditions whereas under thermodynamic con-
trol substitution in 4 position is preferred.9 Due to the
electron withdrawing carboxyl group in the starting
material, the reaction is unfortunatelyveryslow under
kinetic conditions (e.g. low temperature).
Amino pyrrole 4 was then used to prepare two proto-
types of our new receptor class, the acyl derivative 2a
and the valine derivative 2b. For the acyl derivative
2a, amino pyrrole 4 obtained after the reduction of nitro
pyrrole 5 was directlyreacted without further purifica-
tion with Ac2O in chloroform at 60 °C to give the acet-
amido pyrrole 11 in good yields of 88% (Scheme 5).
After hydrolysis of the methyl ester with lithium hydr-
oxide in methanol at 60–80 °C, pyrrole carboxylic acid
12 was coupled with t-Boc-guanidine 13 using PyBOP
as the coupling reagent. After cleavage of the t-Boc-pro-
tecting group in 14 with TFA in dichloromethane the
acetyl receptor 2a was isolated as the picrate salt.
For the valine derivative 2b, the amino pyrrole 4 was
reacted with N-Ac-Val-OH 20 using DCC, HOBT and
We tried to circumvent both problems byusing 3,4-di-
methyl-pyrrole-2-carboxylic acid 7 as the starting mate-
rial (Scheme 3). In 7, the methyl groups not only block
the 3 and 4 positions but also increase the electron den-
sityin the pyrrole making it in principle more suscepti-
ble for nitration, but obviouslyunfortunatelyalso for
oxidation and decomposition. When we tested different
nitrating reagents such as nitric acid,8 ÔclaycopÕ10 and
n-pentylnitrite11 under different reaction conditions by
varying the temperature and concentrations, the yields
of the desired nitro pyrrole 8 were 40% at best besides
significant amount of decomposition.
O
i
ii
5
CO2Me
NHBoc
N
H
N
H
88 %
60 %
11
O
iii
H2N
CO2H
+
N
H
N
H
12
30 %
NH
13
O
H
N
iv
NHBoc
NH
2a
N
H
N
H
14
We finallysucceeded in preparing the desired 5-nitro-
pyrrole-2-carboxylate 5 bydirect nitration of the trichlo-
roacetylated pyrrole 9 (Scheme 4).9 Reaction of 9 with
nitric acid and Ac2O at À40 °C provided the 5-nitro regio-
isomer 10 as the major product with 61% yield. Under
similar reaction conditions pyrrole carboxylic ester 6
quant.
O
Scheme 5. Synthesis of the acetyl receptor 2a. Reagents and condi-
tions: (i) 1. H2, Pd/C, MeOH, rt, 2. Ac2O, CHCl3, 18 h, 60 °C; (ii)
LiOH, MeOH, 80 °C; (iii) PyBOP, NMM, DMF, rt; (iv) TFA.

C. Schmuck, J. Dudaczek / Tetrahedron Letters 46 (2005) 7101–7105
7103
DMAP in a mixture of DMF and dichloromethane (1:1)
to obtain 15 in good yields of 67%. Similar to the syn-
thesis of 2a, the methyl ester was hydrolyzed (NaOH)
and the free acid coupled with t-Boc-guanidine (13).
Deprotection (TFA) provided the valine receptor 2b
(isolated as the picrate salt) (see Scheme 6).
We then performed quantitative NMR titration studies.
Aliquots of the amino acid carboxylate 18 (NMe4+-salt)
were added to a solution of receptor 2a (picrate salt,
[2a] = 1.5 mM) in 40% water in DMSO-d6. The NMR
spectrum was recorded after each addition and from
the observed shift changes the binding constant can be
calculated using a nonlinear curve fitting procedure for
a 1:1-complexation model (Fig. 2).12 The complex stoi-
chiometrywas independentlyconfirmed bya Job-plot
(Fig. 3).13 In the same way, the binding of 18 to the
valine receptor 2b (1.5 mM) was studied. Furthermore,
O-acetyl lactate 19 was studied as a substrate for both
receptors. The corresponding association constants as
obtained from these NMR titration experiments are
summarized in Table 1.
After successful synthesis of these two prototypes 2a and
2b, their complexation properties were first probed qual-
itativelybyNMR studies in 40% H 2O in DMSO. Upon
the addition of N-Ac-L-Ala-OÀ (NMe4+-salt) 18 to a
solution of 2a significant complexation induced shift
changes for protons of both substrate and receptor are
observed (Fig. 1) indicating a molecular interaction be-
tween anionic guest and cationic receptor in this solvent
mixture.12
With association constants ranging from K = 220 to
460 MÀ1 both receptors bind the two carboxylates quite
efficientlyin aqueous DMSO. Interestingly, compared
to our previous receptors of type 1,5 which bind lactate
better than alanine carboxylate, the substrate selectivity
is now reversed. Especially, the acetyl receptor 2a binds
alanine significantlybetter than lactate. Hence, the new
O
i
H
4
15
16
N
R = Me
CO2R
N
H
N
H
67 %
ii
R = H
O
65 %
O
O
iii
H
H
N
N
NHBoc
NH
N
H
N
H
35 %
7.05
O
O
O
O
H
N
NH2
NH2
7.00
6.95
6.90
6.85
6.80
6.75
6.70
N
H
N
H
17
O
iv
H
H
N
N
NH2
NH2
N
O
quant.
N
H
H
δ
O
O
O
2b
O
Scheme 6. Synthesis of the valine receptor 2b. Reagents and condi-
tions: (i) 1. H2, Pd/C, MeOH, rt, 2. 20, DCC, HOBT, DMAP, CH2Cl2,
DMF; (ii) NaOH, MeOH, rt; (iii) 13, PyBOP, NMM, DMF, rt; (iv)
TFA.
0
5
10
15
20
25
equiv. guest
Figure 2. Binding isotherm for the complexation of O-acetyl lactate 19
bythe acetyl receptor 2a in 40% water in DMSO-d6 (shift change of the
pyrrole CH).
0.06
0.05
0.04
0.03
0.02
0.01
0.00
1:1 complex
0.0
0.2
0.4
0.6
0.81.0
mole ratio x
Figure 3. NMR based Job plot for the complexation of N-acetyl
alanine carboxylate 18 bythe valine receptor 2b in 40% water in
DMSO-d6 proving the 1:1-complex stoichiometry.
Figure 1. Parts of 1H NMR spectrum of 2a and N-Ac-L-Ala-OÀ
(NMe4+-salt) in 40% water in DMSO-d6.

7104
C. Schmuck, J. Dudaczek / Tetrahedron Letters 46 (2005) 7101–7105
Table 1. Association constants for 2a and 2b
Conclusion: We have shown here how the reversal of the
direction of an amide group in 5-amino substituted
guanidiniocarbonyl pyrrole receptors 2 changes both
substrate selectivityand relative binding affinities. We
are now exploring the scope of this new receptor class
for the selective binding of dipeptides over depsipetides.
N-Ac-L-Ala-OÀ
(NMe4+-salt) 18
O-Ac-L-Lac-OÀ
(NMe4+-salt) 19
2a
2b
460 MÀ1
320 MÀ1
220 MÀ1
270 MÀ1
Acknowledgements
amino pyrrole based receptors 2 prefer amides over
esters. Another noteworthyobservation is that the
acetyl receptor 2a binds alanine more efficientlythan
the valine receptor 2b, which is also in contrast to our
previous receptors 1 where the association constants
for the analogous valine derivative were close to three
times larger than those of simple alkyl amide receptors.
Hence, the change of the direction of the amide group
going from 1 to 2 significantlyaffects both the substrate
selectivity(amide vs ester) and the relative binding affin-
ities of these receptors (2a vs 2b).
This work was supported bythe Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie.
Supplementary data
Details of the synthesis of receptor 2a and 2b. Supple-
mentarydata associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2005.08.115.
The energyminimized structure (Macromodel 8.0, Am-
ber*, GB/SA water solvation, Monte Carlo search with
50.000 steps)14 of the complex between the acetyl recep-
tor 2a and alanine carboxylate 18 shown in Figure 4 of-
fers a possible explanation for these two effects, the
changes both in substrate selectivityand relative recep-
tor affinities: As in complexes with receptors of type 1,
the carboxylate forms a H-bond enforced ion pair with
the guanidiniocarbonyl pyrrole moiety of 2. Further-
more, the CO of the reversed amide can now form an
additional H-bond to the amide NH of the substrate
as also supported bythe observed complexation induced
shift changes in the NMR (Fig. 1). This explains the
preference for amides over esters. This interaction, how-
ever, brings the two acetyl groups of the substrate and
the receptor into close proximity. Any larger group at
this position of the receptor such as the valine substitu-
ent in 2b probablyleads to destabilizing steric interac-
tions with the substrate. Hence, the binding affinityof
2b is smaller than that of 2a.
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