Cyclic trimer of 5-(aminomethyl)-2-furancarboxylic acid as a novel synthetic receptor for carboxylate recognition

Article abstract of DOI:10.1016/S0040-4039(01)02367-X

A novel 18-membered cyclic oligopeptide 1 based on 5-(aminomethyl)-2-furancarboxylic acid (2), is developed as an excellent receptor for carboxylate binding having an association constant of 8.64×10³ M^-1 for tetrabutylammonium acetate in CD₃CN. The synthesis of 1 was achieved by a high-yielding cyclotrimerization reaction of the unfunctionalized furan amino acid 2.

Full text of DOI:10.1016/S0040-4039(01)02367-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1317–1320
Cyclic trimer of 5-(aminomethyl)-2-furancarboxylic acid as a
novel synthetic receptor for carboxylate recognition
Tushar K. Chakraborty,* Subhasish Tapadar and S. Kiran Kumar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 October 2001; revised 4 December 2001; accepted 13 December 2001
Abstract—A novel 18-membered cyclic oligopeptide 1 based on 5-(aminomethyl)-2-furancarboxylic acid (2), is developed as an
excellent receptor for carboxylate binding having an association constant of 8.64×103 M−1 for tetrabutylammonium acetate in
CD3CN. The synthesis of 1 was achieved by a high-yielding cyclotrimerization reaction of the unfunctionalized furan amino acid
2. © 2002 Elsevier Science Ltd. All rights reserved.
The creation of structurally rigid molecular frameworks
with predisposed cavities of precise dimensions provides
attractive tools for chemists to carry out in vitro studies
of molecular recognition processes of biological systems
with the ultimate aim of developing their therapeutic
applications.1–3 Cyclic peptides with restricted confor-
mational degrees of freedom, especially those based on
constrained molecular scaffolds or unnatural amino
acids represent a notable class of such compounds that
are being extensively studied as hosts for various
guests.4 The introduction of unnatural components in
these designs also leads to their improved pharmacoki-
netic properties. We report here the synthesis of a novel
18-membered cyclic oligopeptide 1 prepared from a new
monomeric building block based on the furan amino
acid, 5-(aminomethyl)-2-furancarboxylic acid (2, Faa)
and demonstrate that it is an excellent artificial receptor
for carboxylate binding.5 Studies on the binding of
amino acid carboxylates by multiple hydrogen bonding
receptors have gained increasing importance in recent
years,6 especially due to the alarming emergence of
vancomycin resistant strains.7 The presence of multi-
dentate H-bonding sites in 1 was expected to make it an
ideal receptor for various carboxylate ligands.
the corresponding methyl ester 5 in 85% yield.9 The
chloromethyl substituent was next transformed into a
Boc-protected aminomethyl moiety in three steps: dis-
placement by azide, selective azide reduction and
finally, in-situ protection using Boc2O giving the pro-
tected Faa 6 in 80% overall yield.9 Saponification of 6
was followed by Boc deprotection to give 7 that is the
TFA salt of 2. A solution of 7 in amine-free dry DMF
(10−2 M) was treated with benzotriazol-1-yloxytris-
(dimethylamino)phosphonium
hexafluorophosphate
(BOP reagent) at 0°C, followed by the slow addition of
Et3N.10 After the reaction was over, it was subjected to
aqueous work-up and finally, chromatographic purifi-
cation furnished the cyclic trimer 1 in 65% yield from
6.11
The 1H NMR spectra of 1 in different solvents, DMSO-
d6, CD3CN and CDCl3, showed a perfect C3 symmetric
structure12 with only four signals from the four differ-
ent types of protons attached to each unit. Energy
minimization of 1 was carried out using Sybyl 6.7
program on a Silicon Graphics O2 workstation. The
Tripos force field with default parameters was used and
minimizations were done first with steepest decent,
followed by conjugate gradient methods for a maxi-
mum of 2000 iterations each or RMS deviation of 0.001
kcal/mol, whichever was earlier. The energy-minimized
structure thus obtained (Fig. 1) displayed a near-planar
geometry with s-cis orientation of all the amide car-
bonyls. The average distance between any one of the
three ring oxygens and its adjacent amide protons is
Scheme 1 outlines the synthesis of 1 and 2. Acid
treatment of -fructose (3), following a reported proce-
D
dure,8 gave 5-(chloromethyl)-2-furancarboxaldehyde (4)
in 80% yield. Jones’ oxidation of 4 was followed by
esterification of the resulting acid using CH2N2 to give
,
ꢀ2.1 A indicating the possibilities of the existence of a
network of intramolecular NH“O(ring) H-bonds
where each amide proton is hydrogen bonded to two
adjacent furan oxygens and vice versa. This is sup-
Keywords: cyclic peptides; furan amino acid; synthetic receptors;
molecular recognition.
* Corresponding author. E-mail: chakraborty@iict.ap.nic.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02367-X

1318
T. K. Chakraborty et al. / Tetrahedron Letters 43 (2002) 1317–1320
O
O
N
O
N
O
O
H
O
O
H
H2N
O
H
N
OH
2
1
O
O
HN
O(O)C
NH
O
O
-
O
H
N
O
A
a
c
D-Fructose
Cl
b
R
O
3
4: R = CHO
5: R = CO2Me
d
BocHN
e
TFA.H2N
CO2Me
O
CO2H
O
Figure 1. Energy minimized (Tripos, Sybyl 6.7) structure of 1
viewed from top (a) and along the plane of the molecule (b).
6
7
1
Scheme 1. Synthesis of 1. Reagents and conditions: (a)
MgCl2·6H2O, HCl, toluene, 75°C, 1.5 h, 80% (Ref. 8); (b) (i)
Jones’ oxidation; (ii) CH2N2, Et2O, 85%; (c) (i) NaN3, DMF,
65°C, 1 h; (ii) Ph3P, MeOH, rt, 2 h; (iii) Boc2O, rt, 10 min,
80% (three steps); (d) (i) LiOH, THF–MeOH–H2O (3:1:1),
0°C, 2 h, quantitative; (ii) trifluoroacetic acid (TFA), CH2Cl2,
0°C to rt, 30 min, quantitative; (e) BOP reagent, Et3N, DMF,
rt, 12 h, 65%.
tained a dynamic equilibrium that did not disturb the
symmetry of the host. Although, the structure of the
carboxylate-bound complex A or the orientations of the
amide protons in it are not known, loss of extended
conjugation was expected to prevent any out of plane
bending of the amide moieties, unless it was getting
compensated by the binding energy.
Following the procedure reported by Kelly et al.,15
NMR titrations were carried out by adding increasing
amounts of TBAA to a solution of 1 in CD3CN at
21°C. While the initial chemical shift of the host amide
proton was 7.55 ppm, at the saturation point it shifted
to 10.01 ppm. A graph between chemical shift differ-
ences (Dlobs) and [guest]/[host] was plotted (Fig. 2(a)).
The stoichiometry of complexation of 1 with TBAA
was determined by using Job’s method of continuous
variations16 (Fig. 2(b)) that showed a maximum at 0.5
mole fraction, confirming the formation of a 1:1 com-
plex. The association constant (Ka) measured by NMR
titration method15,17 was 8.64×103 M−1 (< 14%) in
CD3CN.
ported by the observed low-field chemical shift of the
amide proton in nonpolar solvent, l 6.75 in CDCl3.
The planar structure of the molecule with extended
conjugation between the furan rings and their adjacent
amide moieties and the convergence of all three hydro-
gen bond donors inside the ring make compound 1 a
tailor-made receptor for carboxylate binding as shown
schematically in structure A.
The binding capability of 1 with a carboxylate anion
1
was measured by the H NMR titration method13 using
tetrabutylammonium acetate (TBAA) in CD3CN.
Addition of an excess of TBAA to a CD3CN solution
of 1 caused huge a downfield shift (2.46 ppm) of the
host amide proton resonance, suggesting the formation
of a very tightly-bound H-bonded complex.14 The sym-
metry of the molecule remained intact even after bind-
ing with the carboxylate that caused the downfield shift
only for the amide proton leaving other proton shifts
unchanged. This indicates that the binding of 1, having
three H-bond donors, with carboxylate anion main-
In conclusion, the novel oligopeptide-based macrocyclic
synthetic receptor 1,18 prepared from a new building
block-furan amino acid 2, demonstrates excellent bind-
ing capability with carboxylates that will find many
useful applications, especially, in the synthetic and
mechanistic studies on many structurally similar C3-
symmetric
and
pseudo
C3-symmetric
natural
products.10a,19

T. K. Chakraborty et al. / Tetrahedron Letters 43 (2002) 1317–1320
1319
man, I.; Pascard, C. J. Chem. Soc., Chem. Commun. 1991,
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9. Data for 5: Rf=0.55 (silica gel, 30% EtOAc in petroleum
ether); IR (neat): wmax 3137, 1728, 1600, 760 cm−1 1H
;
NMR (CDCl3, 200 MHz): l 7.11 (d, J=4.65 Hz, 1H);
6.49 (d, J=4.65 Hz, 1H); 4.58 (s, 2H); 3.92 (s, 3H); 13C
NMR (CDCl3, 100 MHz): l 158.58, 153.98, 144.63,
118.63, 111.25, 51.84, 36.50; MS (EI): m/z (%): 174 (12)
[M+]; HRMS (EI): calcd for C7H7ClO3 [M+]: 174.0084,
found: 174.0088.
Figure 2. 1H NMR titration curve (a) and Job plot (b) for the
complexation of 1 (host) with TBAA in CD3CN.
Data for 6: Rf=0.4 (silica gel, 30% EtOAc in petroleum
ether); IR (neat): wmax 3356, 1717 cm−1
;
1H NMR
Acknowledgements
(CDCl3, 200 MHz): l 7.04 (d, J=4.65 Hz, 1H), 6.31 (d,
J=4.65 Hz, 1H), 4.91 (bs, 1H), 4.31 (d, J=7.1 Hz, 2H),
3.85 (s, 3H), 1.44 (s, 9H); 13C (CDCl3, 50 MHz): l
158.89, 156.81, 155.40, 143.74, 118.82, 108.84, 79.87,
51.61, 37.93, 28.23; MS (LSIMS): m/z (%): 279 (25)
[M++H+Na]; HRMS (LSIMS): calcd for C12H18NO5 [M+
+H]: 256.1185, found: 256.1186.
Authors wish to thank Drs. A. C. Kunwar and M.
Vairamani for NMR and mass spectrometric assistance,
respectively; CSIR, New Delhi for research fellowships
(S.T. and S.K.K.).
10. For earlier works on similar cyclization reactions, see: (a)
Somogyi, L.; Haberhauer, G. H.; Rebek, J., Jr. Tetra-
hedron 2001, 57, 1699−1708; (b) Singh, Y.; Sokolenko,
N.; Kelso, M. J.; Gahan, L. R.; Abbenante, G.; Fairlie,
D. P. J. Am. Chem. Soc. 2001, 123, 333−334; (c) Blake,
A. R.; Hannam, J. S.; Jolliffe, K. A.; Pattenden, G.
Synlett 2000, 1515−1518.
11. Synthesis of 1 from 6. To a stirred solution of 6 (1 g, 3.92
mmol) in THF–MeOH–H2O (3:1:1, 15 mL), LiOH·H2O
(493.9 mg, 11.76 mmol) was added. After being stirred at
room temperature for 1 h, the reaction mixture was
acidified with 1 M HCl (pH 2), extracted with ethyl
acetate, washed, dried (Na2SO4) and concentrated in
vacuo. The crude acid was dissolved in dry CH2Cl2 (6
mL), cooled to 0°C and TFA (4 mL) was added. After
being stirred at room temperature for 2 h, the solvent was
evaporated in vacuo and the residue was used directly in
the next step.
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The crude amino acid salt was dissolved in amine free dry
DMF (392 mL, 10−2 M) and cooled to 0°C. BOP reagent
(2.42 g, 5.49 mmol) was added to it and stirred for 15 min
at the same temperature. Next, Et3N (2.73 mL, 19.6
mmol) was slowly added to the reaction mixture over a
period of 15 min. After the addition was over, it was
stirred at room temperature for 12 h. DMF was removed
under reduced pressure, the residue extracted with 10%
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matography (SiO2, 4–8% Methanol in CHCl3) afforded 1
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Rf=0.4 (silica, 60% EtOAc in petroleum ether); IR

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T. K. Chakraborty et al. / Tetrahedron Letters 43 (2002) 1317–1320
1
(KBr): wmax 3402, 3269, 1651, 1561, 1502, 1292 cm−1; H
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3 H, furanH), 4.62 (d, J=5.6 Hz, 6H, furan-CH2NHCO);
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(8) [M++H]; MS (MALDI): m/z 370 (50) [M++H]; HRMS
(LSIMS): calcd for C18H16N3O6 [M++H]: 370.1039,
found: 370.1041.
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entirely bound (see Ref. 15). The titrations were usually
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possible. The average association constant was deter-
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error limit is specified.
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