N′-Alkylated Guanidiniocarbonyl Pyrroles: New Receptors for Amino Acid Recognition in Water

Article abstract of DOI:10.1021/ol0356340

(Matrix presented) N′-Substituted guanidiniocarbonyl pyrroles 7 were synthesized for the first time by activation of a Boc-protected guanidlnlocarbonyl pyrrole 3 with triflic anhydride and subsequent reaction with a primary amine. These guanidinium cation

Full text of DOI:10.1021/ol0356340

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4579-4581
N′-Alkylated Guanidiniocarbonyl
Pyrroles: New Receptors for Amino
Acid Recognition in Water
Carsten Schmuck* and Volker Bickert
Institute of Organic Chemistry, UniVersity of Wu¨rzburg,
Am Hubland, D-97074 Wu¨rzburg, Germany
schmuck@chemie.uni-wuerzburg.de
Received August 27, 2003
ABSTRACT
N′-Substituted guanidiniocarbonyl pyrroles 7 were synthesized for the first time by activation of a Boc-protected guanidiniocarbonyl pyrrole
3 with triflic anhydride and subsequent reaction with a primary amine. These guanidinium cations are efficient receptors for the complexation
of amino acid carboxylates even in water (Kassoc > 103 M-1) as could be shown by UV titration studies.
We have recently introduced a new de novo designed binding
motif for carboxylates, the guanidiniocarbonyl pyrroles 1,
which strongly bind carboxylates even in aqueous solvents
through a combination of ion pairing and multiple hydrogen
bonds (Figure 1).1 Due to the increased acidity of the acyl
guanidinium moiety and the additional H-bonds, these
complexes are much stronger than those of simple guani-
dinium cations, which only form stable ion pairs in organic
solvents of low polarity such as chloroform or acetonitrile.2
This recognition motif has already found versatile use in
various fields of supramolecular3 and bioorganic chemistry.4
However, in complexes with such guanidiniocarbonyl pyr-
roles, so far only one side of the carboxylate substrate is
used for binding interactions with the receptor. The other
side of the substrate is still completely free and only exposed
to the solvent. Additional binding interactions to this backside
of the substrate by a side chain attached to the N′ of the
guanidiniocarbonyl pyrrole could therefore help to further
increase the complex stability and also to increase the
selectivity of the recognition event with respect to the bound
carboxylate. We were therefore interested in the synthesis
of N′-substituted guanidiniocarbonyl pyrroles of type 2 and
the study of their binding properties (Figure 1).
(1) Schmuck, C. Chem. Eur. J. 2000, 6, 709-718.
(2) For recent reviews on carboxylate binding by artificial receptors
including guanidinium-based systems, see: (a) Best, M. D.; Tobey, S. L.;
Anslyn, E. V. Coord. Chem. ReV. 2003, 240, 3-15. (b) Gale, P. A. Coord.
Chem. ReV. 2003, 240, 191-221. (c) Fitzmaurice, R. J.; Kyne, G. M.;
Douheret, D.; Kilburn, J. D. J. Chem. Soc., Perkin Trans. 1 2002, 841-
864. (d) Schmidtchen, F. P.; Berger, M. Chem. ReV. 1997, 97, 1609-1646.
(3) (a) Schmuck, C.; Wienand, W. J. Am. Chem. Soc. 2003, 125, 452-
459. (b) Schmuck, C. Tetrahedron 2001, 57, 3063-3067. (c) Schmuck, C.
J. Org. Chem. 2000, 65, 2432-2437.
Figure 1. Additional binding interactions in complexes between
N′-substituted guanidiniocarbonyl pyrroles 2 and carboxylates
should alter their stability and selectivity compared to the unsub-
stituted guanidiniocarbonyl pyrrole 1.
(4) (a) Schmuck, C. Chem. Commun. 1999, 843-844. (b) Schmuck, C.;
Heil, M. Org. Biomol. Chem. 2003, 1, 633-636. (c) Schmuck, C.; Heil,
M. ChemBioChem 2003, in press.
10.1021/ol0356340 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003

Due to the low reactivity of pyrrole carboxylic acid
derivatives, most of the standard procedures reported in the
literature for the preparation of N′-alkylated guanidines,5 such
as the use of 1H-pyrazole-1-Boc-carboxamidine6 or Boc-
activated thioureas,5e do not work for pyrroles as it was not
possible to obtain the corresponding N-acylated pyrrole
derivatives in decent yields.
According to work by Kozikowski, di-Boc- or di-Cbz-
guanidine can be alkylated with alcohols using a Mitsunobu
protocol.7 However, the mono-Boc-protected acyl guanidine
3, also a diacylated guanidine, only reacted with reactive
alcohols such as benzyl but no aliphatic alcohols. The
reaction of 3 with benzyl alcohol and DIAD/PPH3 in THF
provided a single substitution product 4 in 83% yield
(Scheme 1), whereas aliphatic alcohols such as propanol or
Figure 2. Part of the 1H NMR of 4 indicating the N,N′ substitution
pattern of the guandinium moiety.
We finally succeeded to prepare the desired N′-alkyl-
substituted derivatives by using a N′-Boc-N′′-triflyl guani-
diniocarbonyl pyrrole 5 as the guanidinylation reagent.8
Reaction of mono-Boc-guanidiniocarbonyl pyrrole 3 with
triflic anhydride in the presence of NEt3 in CH2Cl2 gave the
corresponding triflyl guanidiniocarbonyl pyrrole 5, which can
be further reacted without isolation with a primary amine to
give the desired N′-substituted guanidiniocarbonyl pyrroles
6 in good overall yields (Scheme 2).9 Even deactivated
Scheme 1. Synthesis of N′-Substituted Guanidiniocarbonyl
Pyrroles via a Mitsunobu Protocol
Scheme 2. Synthesis of N′-Substituted Guanidiniocarbonyl
Pyrroles via Triflyl Activated Derivatives
3-hydroxy propanoic acid did not react at all even at elevated
temperatures. Obviously, the reactivity of the guanidinio-
carbonyl pyrrole 3 is greatly reduced compared to the di-
Boc-guanidine used by Kozikowski.
That the alkylation with benzyl alcohol indeed gave the
desired N′-substituted isomer 4 as the only product and not
the N-substituted isomer, with the benzyl group attached to
the amide NH, could be shown by NMR after removal of
the tBoc protecting group with TFA in CH2Cl2. The 1H NMR
spectrum clearly shows a signal for the guanidinium amide
NHa at δ ) 11.1, and two separate signals with a relative
intensity of 1:2 for the guanidinium NHb and NHc protons
at δ ) 9.5 and δ ) 8.9, respectively (Figure 2). For the
N-substituted isomer, the spectrum would not show the
guanidinium amide NHa at δ ) 11.1 any more butsdue to
fast exchange processessonly one broad signal for the four
guanidinium NH2 protons at δ ≈ 8-9 with an intensity of
4. In principle, the Mitsunobu reaction is hence a useful way
to prepare N′-alkyl-substituted guanidiniocarbonyl pyrroles
but only for reactive alcohols.
amines, such as aniline, do react but only with modest yields.
This reaction is, however, limited to unhindered primary
amines. Secondary amines or highly sterically hindered
primary amines such as tert-butylamine do not react under
these conditions.
To find out whether the corresponding N′-substituted
guandiniocarbonyl pyrrole cations 7, obtained as their
chloride salts after removal of the Boc-protecting group in
6 with HCl, are indeed efficient receptors for the complex-
ation of amino acid carboxylates in aqueous solvents, we
(5) (a) Li, J.; Zhang, G.; Zhang, Z.; Fan, E. J. Org. Chem. 2003, 65,
1611-1614. (b) Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron 2002,
58, 1739-1743. (c) Wu, Y.-Q.; Hamilton, S. K.; Wilkinson, D. E.; Hamilton,
G. S. J. Org. Chem. 2002, 67, 7553-7556. (d) Katritzky, A. R.; Rogovoy,
B. V.; Chassaing, C.; Vvedensky, V. J. Org. Chem. 2000, 65, 8080-8082.
(e) Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org. Chem.
2000, 65, 1566-1568. (f) Ghosh, A. K.; Hol, W. G. J.; Fan, E. J. Org.
Chem. 2001, 66, 2161-2164.
(6) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992,
57, 2497-2502.
(7) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977-
980.
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Org. Lett., Vol. 5, No. 24, 2003

investigated the complexation properties of a first example,
the valine-derived receptor 8, using UV-titration studies
(Figure 3). Aliquots of the substrate were added to a solution
sidearm attached to N′ are probably responsible for the
different complex stabilities.
According to molecular mechanic calculations (Macro-
model V 8.0, Amber* force field, GB/SA water solvation
treatment)11 the stronger binding of valine could reflect
favorable hydrophobic interactions between the two isopropyl
side chains in the aqueous solvent (Figure 4): The carbox-
Figure 3. UV titration data for the binding of valine to 8 in water.
of the receptor in water (bis-tris-buffer, 3 mM at pH ) 6.1,
[receptor]o ) 8 × 10-5 M, [substrate]o ) 2 × 10-3 M).
Changes in the UV spectrum of the receptor were recorded
and used to determine the binding constants as the absorbance
of the pyrrole moiety at λ ) 290 nm decreases upon complex
formation. Analysis of the data was performed using the
Specfit/32 software program from Spectrum Software As-
sociates using nonlinear least-squares fitting with a 1:1
association model.10
Figure 4. Proposed structure for the complex between 8 (gray)
and valine (yellow) based on molecular mechanics calculations (A,
top view; B, side view).
These preliminary binding studies show that the N′-
substituted guanidiniocarbonyl pyrrole 8 indeed strongly
binds amino acid carboxylates even in aqueous buffer
solution with association constants of Kassoc g 103 M-1.
Furthermore, the complex stability seems to depend on the
nature of the amino acid side chain. Valine is bound nearly
two times better than alanine (Kassoc ) 1750 and 1000 M-1,
respectively). As the unsubstituted guanidiniocarbonyl pyr-
role cation 1 does not discriminate between these two amino
acids, this indicates that interactions with the additional
ylate of the amino acid forms an ion pair with the guandinium
moiety with additional H-bonds from the pyrrole NH and
the side chain amides to the carboxylate. This places the two
alkyl side chains opposite to each other allowing for
hydrophobic and/or steric interactions. A detailed study of
the complexation properties of this new receptor class
concerning the complex structure and the substrate selectivity
is currently under investigation.
In conclusion, we have presented here for the first time
the successful synthesis of N′-substituted guanidiniocarbonyl
pyrroles 7. As preliminary binding data show, this new
receptor class efficiently binds amino acid carboxylates even
in water. Through a further variation of the side chain the
development of highly selective receptors for the recognition
of amino acids in water should be possible. Furthermore, a
second side chain attached at position 5 of the pyrrole, as in
our previous guanidiniocarbonyl pyrroles of type 1, should
lead to tweezer receptors with even more advanced com-
plexation properties.
(8) (a) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J. Org.
Chem. 1998, 63, 3804-3805. (b) Feichtinger, K.; Sings, H. L.; Baker, T.
J.; Matthews, K.; Goodman, M. J. Org. Chem. 1998, 63, 8432-8439.
(9) Typical Reaction Protocol. A solution of 3 (252 mg, 1 mmol, 1
equiv) and NEt3 (208 µl, 1.5 mmol, 1.5 equiv) in dry CH2Cl2 (5 mL) was
cooled to -78 °C under nitrogen atmosphere. Triflic anhydride (200 µl,
1.2 mmol, 1.2 equiv) was added dropwise within 10 min. After complete
addition, the mixture was stirred for 0.5 h and was then allowed to warm
to room temperature over 2 h. Five drops of water and a solution of â-alanine
methyl carboxylate hydrochloride (168 mg, 1.2 mmol, 1.2 equiv) with NEt3
(208 µl, 1.5 mmol, 1.5 equiv) in CH2Cl2 (2 mL) was added. The reaction
mixture was stirred overnight and then washed with saturated sodium
carbonate and brine. After removal of the solvent, the crude product was
purified by flash chromatography on silica gel using ethyl acetate/hexane
(1/1.6 with 1% NEt3) to yield 6 as pale yellow crystals (270 mg, 80% yield).
(10) Connors, K. A. Binding Constants; Wiley: New York, 1987.
(11) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufiled, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440-467.
Acknowledgment. This work was supported by the
Deutschen Forschungsgemeinschaft (SCHM 1501/2-2) and
the Fonds der Chemischen Industrie.
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