Cyclic trimers of chiral furan amino acids

Article abstract of DOI:10.1055/s-2004-834807

Chiral furan amino acids were synthesized as novel peptide building blocks. Cyclooligomerization of these monomers by a single-step process led to the selective formation of chiral C₃-symmetric cyclic trimers, which were studied for their struc

Full text of DOI:10.1055/s-2004-834807

2484
LETTER
Cyclic Trimers of Chiral Furan Amino Acids
Cyclic
Trimers
u
F
ur
s
a
n
A
mino
h
A
cids ar K. Chakraborty,*a Subhasish Tapadar,a T. Venugopal Raju,a J. Annapurna,a Harjinder Singh*b
a
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193108; E-mail: chakraborty@iict.res.in
b
Department of Chemistry, Panjab University, Chandigarh 160014, India
Received 19 August 2004
bered heterocyclic ring containing amino acids using
various reagents have been carried out by many others
(Figure 1).12
Abstract: Chiral furan amino acids were synthesized as novel pep-
tide building blocks. Cyclooligomerization of these monomers by a
single-step process led to the selective formation of chiral C3-sym-
metric cyclic trimers, which were studied for their structures and
properties, like anion binding and antimicrobial activities.
O
R
H2N
OH
O
Key words: chiral furan amino acids, anion binding, synthetic re-
ceptors, cyclic trimers, antimicrobial
O
R
N
O
N
O
R
O
O
H
O
H
R
1
H
N
a: R = H
b: R = Me
c: R = CHMe2
d: R = CH2Ph
Cyclization of linear peptides or covalent bridging of their
constituent amino acids at appropriate places is a widely
used method to constrain their conformational degrees of
freedom, preorganize their ligand binding elements and
induce desirable structural biases essential for their bio-
logical activities, such as transporting ions or molecules
across membranes through tubular structures,1 anion
binding by directed hydrogen bonding interactions,2 and
acting as receptors to various other hosts.3 In this context,
many structurally rigid molecular scaffolds have been de-
signed to create varieties of amide-linked artificial cyclic
receptors containing predisposed cavities that could be
moulded to precise dimensions providing attractive tools
to chemists to carry out in vitro studies of molecular rec-
ognition processes of biological systems with the ultimate
aim of developing their therapeutic applications.4–6 Re-
cently, we developed a novel furan amino acid, 5-(ami-
nomethyl)-2-furancarboxylic acid (1a) and prepared its
trimer, an 18-membered cyclic oligopeptide 2a,7 which
was found to be an excellent receptor for carboxylate
binding.8 Studies on the binding of amino acid carboxyl-
ates by multiple hydrogen bonding receptors have gained
increasing importance in recent years,9 especially due to
the alarming emergence of vancomycin resistant strains.10
The presence of multidentate H-bonding sites in 2a made
it an ideal receptor for carboxylate anion. The synthesis of
2a was achieved by a high-yielding cyclotrimerization re-
action of the unfunctionalized furan amino acid 1a with
BOP reagent using DIPEA as base and DMF as solvent. It
avoids the lengthy step-wise assembling of linear precur-
sors, conventionally followed for making such cyclic
products. An extension of this work by us led to the syn-
thesis of cyclic homooligomers of furanoid sugar amino
acids that showed interesting structures and properties.11
Also, similar one-pot cyclooligomerizations of five-mem-
2
Figure 1
As part of our ongoing project on the development of
novel cyclic oligomers of various multi-functional mono-
meric building blocks, we were interested in developing
optically active furan amino acids 1b–d to prepare their
cyclooligomers 2b–d, respectively. It was felt by us that
introduction of a chiral center in the amino terminus of 1a
can give rise to an additional combinatorial site in this bi-
functional building block that will allow to mimic the
side-chains of natural amino acids influencing the hydro-
phobicity/hydrophilicity of the resulting peptidomimetic
molecules. In this paper, we describe the stereoselective
synthesis of chiral furan amino acids, 5-(1-aminoalkyl)-2-
furoic acids 1b–d, in enantiomerically pure forms starting
from their corresponding chiral amino aldehydes. Cyclo-
trimerization of these monomers by the above-mentioned
single-step process led to chiral C3-symmetric cyclic
products 2b–d, which were studied for their anion binding
properties. These molecules were also tested for their
antimicrobial properties and showed significant activities
against some Gram-positive and Gram-negative bacteria.
The details of the synthesis of compounds 2b–d are
shown in Scheme 1. The starting materials in this scheme
were chiral N-Boc-amino aldehyde 3 derived from the
corresponding amino acid13 and the 3,4-O-isopropyl-
idene-1,1-dibromobut-1-en-3,4-diol (4) that was prepared
from (R)-glyceraldehyde acetonide.14 Chiral purity of the
starting N-Boc-amino aldehyde 3 is very critical in this
scheme. This was ascertained in the beginning by measur-
ing its optical rotation and comparing with reported val-
ues. Treatment of 3 with the Li-acetylide prepared in situ
by reacting 4 with n-BuLi, gave the propargyl alcohol
adduct 5 as a mixture of isomers. Cis-hydrogenation of
5 using P2-Ni15 provided the cis-allylic alcohol inter-
SYNLETT 2004, No. 14, pp 2484–2488
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834807; Art ID: G32604ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cyclic Trimers of Chiral Furan Amino Acids
2485
OH
Br
O
BocHN
Ni(OAc)2-4H2O
H2, NaBH4,
O
BocHN
BocHN
CHO
OH
Br
4
O
R
O
R
(CH2NH2)2, EtOH
70–75%
n-BuLi, THF
75–80%
5
3
O
OH
OH
1. CSA, MeOH
1. PCC, CH2Cl2
O
OAc
BocHN
2. Ac2O, pyridine
70–8%
R
2. K2CO3, MeOH
60–65%
R
6
7
1. (COCl)2, DMSO, Et3N, CH2Cl2
or, SO3-pyridine, Et3N, DMSO, CH2Cl2
BocHN
BocHN
OH
OH
O
2. NaClO2, NaH2PO4,
H2O2, CH3CN
80–85%
O
O
R
R
9
8
FDPP, DIPEA,
DMF
TFA-CH2Cl2
quantitative
1
2
60-75%
TFA-salt
[b: R = Me; c: R = CHMe2; d: R = CH2Ph]
Scheme 1 Synthesis of chiral furan amino acids 1b–d and their cyclic trimers 2b–d.
mediate 6. Treatment of 6 with acid led to the deprotection for the trimer than the dimer. Solvation by DMF showed
of the acetonide and the primary hydroxyl was selectively enhancement of this preference further as seen in greater
protected as acetate to get the ‘cis-2-butene-1,4-diol’ in- difference in the free energy, and even in the electronic
termediate 7. The resulting ‘cis-2-butene-1,4-diol’ moiety energy, of the monomer and the trimer than that of the
of 7 was next transformed into a furan ring on oxidation monomer and the dimer. Interestingly, the formation of
with pyridinium chlorochromate (PCC),16 which was fol- the tetramer is also found favorable, indeed a little more
lowed by the treatment of the intermediate with anhydrous so than the trimer. That it is not formed experimentally
K2CO3 to deprotect the acetate to give the chiral furanyl implies that calculations on isolated systems are not suffi-
alcohol intermediate 8. Finally, a two-step oxidation pro- cient to understand the chemistry of such a large system.
cess, (i) Swern oxidation (8a) or oxidation by SO3–pyri- However, calculation for solvation by DMF for the forma-
dine complex (8b,c) to an aldehyde, and (ii) oxidation of tion of the tetramer is yet to be done to draw the final
the aldehyde to acid using NaClO2–H2O2, converted the conclusion.18
primary hydroxyl group of 8 into the acid functionality to
1
The H NMR spectra of 2b–d in different solvents,
furnish Boc-protected intermediate 9. Deprotection of the
DMSO-d6, CD3CN and CDCl3, showed perfect C3-sym-
Boc group using trifluoroacetic acid (TFA) in CH2Cl2
metric structures19 with signals from a single unit. The NH
gave the TFA salts of 1, which were directly subjected to
signal appeared at d = 8.36 ppm with a 3J of 8.9 Hz for 2b
cyclooligomerization reaction. Treatment of the TFA salt
and at d = 8.15 ppm with a 3J of 10.4 Hz for 2c in DMSO-
of 1 dissolved in amine-free DMF with pentafluorophenyl
d6. The NH signal of 2d appeared at d = 8.49 ppm with a
diphenylphosphinate (FDPP) followed by the slow addi-
coupling constant of J = 8.9 Hz in DMSO-d6 and at d =
tion of DIPEA provided the cyclic trimer 2 selectively.17
6.78 ppm with J = 9.4 Hz coupling in CDCl3. Energy
The choice of FDPP over BOP reagent was made as the
minimization of these compounds were carried out using
former was found to give slightly better yields of the
MOPAC in CS Chem3D (Pro, version 5.0). The energy-
minimized structures thus obtained (Figure 2) displayed
cyclized products.12l
Detailed theoretical studies were carried out to examine tripod bowl shaped structures for 2b–d with s-cis orienta-
the selective formation of the cyclic trimer in these tion of all the amide carbonyls and NH bonds pointing to
cyclooligomerization reactions using the unsubstituted 5- the same side of the side-chains. The H-N-Ca-H torsional
(aminomethyl)-2-furancarboxylic acid (1a). Ab initio cal- angle in both 2b and 2d is ca 175°, while the same in 2c
culations at HF 6-31G** levels revealed that while the is ca 180° (trans), which are in conformity with the ob-
formation of the higher order cyclized oligopeptides, served 3J values. The bulkier Cb substituents in 2c made
[HN-CH2-(furan)-CO]n with n = 3,4, is energetically fa- the approach of guests to its NH groups sterically more
vorable, that of the cyclic dimer is thermodynamically un- demanding than in 2b and 2d. It is to be noted here that the
favorable. The difference in the free energy between the H-N-Ca-H torsional angle in the energy-minimized struc-
monomer and the oligomer is significantly more favorable ture of 2a was ca 120° supported by a 3J of 5.6 Hz.7
Synlett 2004, No. 14, 2484–2488 © Thieme Stuttgart · New York

2486
T. K. Chakraborty et al.
LETTER
of TBA salts to a solution of 2d in CD3CN at 21 °C. A
graph between the chemical shift differences (Ddobs) and
[guest]/[host] was plotted (Figure 3). The stoichiometry
of complexation of 2d with various anions was deter-
mined by using Job’s method of continuous variations22
(Figure 3) that showed a maximum at ca 0.5 mole fraction
in each case, confirming the formation of a 1:1 complex.
Figure 2 Energy-minimized structures of 2b (top left), 2c (top
right) and 2d (bottom).
The average distance between any one of the three ring
oxygens and its adjacent amide protons in 2b–d is ca 2.4–
2.5 Å indicating the possibilities of the existence of a net-
work of intramolecular NH → O(ring) H-bonds where
each amide proton is hydrogen bonded to two adjacent fu-
ran oxygens and vice versa. This is supported by the ob-
served low-field chemical shifts of the amide protons, >8
ppm in DMSO-d6 and at ca 6.7 ppm in nonpolar CDCl3.
The binding capabilities of one of these cyclic peptides 2d
with various anions were measured by the 1H NMR titra-
tion method20 using their tetra-n-butylammonium (TBA)
salts in CD3CN and DMSO-d6. Addition of an excess of
TBA salt (ca. 10–12 equiv) to a solution of the host caused
downfield shifts of the amide proton resonance with
Ddmax = 2.74 ppm using tetra-n-butylammonium acetate
(TBAA) and 2.29 ppm with tetra-n-butylammonium chlo-
ride (TBACl) in CD3CN, suggesting the formation of very
tightly bound H-bonded complexes. With tetra-n-butyl-
ammonium iodide (TBAI), the amide proton shift was
moderate (1.05 ppm) suggesting weak binding. Binding
studies with another carboxylate anion, the tetra-n-butyl-
ammonium salt of Ac-D-Ala-D-Ala-O– (TBAX), were
carried out in DMSO-d6, a strong H-bonding solvent, due
to its poor solubility in CD3CN. The downfield shift of the
amide proton signal in this case was smaller than those
with TBAA and TBACl in CD3CN, with a Ddmax of 1.04
ppm suggestive of moderate binding.
Figure 3 1H NMR titration plots (top) and Job plots (bottom) for the
complexation of 2d (host) with tetra-n-butylammonium (TBA) salts
of acetate (A), chloride, iodide and Ac-D-Ala-D-Ala-O– (X), in
CD3CN solution for the first three and DMSO-d6 for the last one.
The association constant (Ka) measured by NMR titration
method21,23 are shown in Table 1. While the association
constants for tetra-n-butylammonium acetate (TBAA)
and tetra-n-butylammonium chloride (TBACl) were high,
binding with iodide (entry 3, Table 1) was weak, may be,
due to its bulkier size. In polar solvent DMSO-d6, moder-
ate association constant was observed with TBA[Ac-(D-
Ala)2] (entry 4, Table 1) in spite of the solvent molecules
also competing for the H-bonding sites.
3
The symmetries of the molecules as well as the J cou-
Table 1 Association Constants (Ka) (M-1) of 2d with Different TBA
Salts
plings of their amide signals remained intact even after
binding with the anions that caused downfield shifts only
for the amide protons leaving other proton shifts un-
changed. This indicates that the binding with various
anions did not disturb the symmetry of the host or its
structure. Furthermore, loss of extended conjugation was
expected to prevent any out of plane bending of the amide
moieties. Similar binding studies with 2c using various
anions did not show any shift of its amide proton reso-
nance indicating inaccessibility of its binding site due to
the presence of bulky isopropyl groups in the molecule.
Entry
Salts
Ka (M-1)·10–3 (stand. dev.)
5.50 ( 1.30)
1
2
3
4
TBAAa
TBACla
TBAIa
8.46 ( 1.18)
0.47 ( 0.06)
TBA[Ac-(D-Ala)2]b 1.78 ( 0.06)
a CD3CN.
b DMSO-d6.
Following the procedure reported by Kelly et al.,21 NMR
titrations were carried out by adding increasing amounts
Synlett 2004, No. 14, 2484–2488 © Thieme Stuttgart · New York

LETTER
Cyclic Trimers of Chiral Furan Amino Acids
2487
(2) For recent reviews see: (a) Choi, K.; Hamilton, A. D. Coord.
Chem. Rev. 2003, 240, 101. (b) Gale, P. A. Coord. Chem.
Rev. 2001, 213, 79. (c) Gale, P. A. Coord. Chem. Rev. 2000,
199, 181.
The strong binding of 2d with various anions, especially
with carboxylates, encouraged us to test these cyclic pep-
tides for their antimicrobial activities. The antimicrobial
activities of the cyclic peptides 2b–d were evaluated by
Agar diffusion assay using nutrient medium.24 Com-
pounds 2c and 2d were excellently active against Escher-
ichia coli. In case of Pseudomonas aeruginosa,
compound 2c showed relatively higher degree of activity
compared to 2b, whereas compound 2d was inactive
against the same microorganism in comparison with the
standard streptomycin.
(3) For some recent representative works see: (a) Choi, K.;
Hamilton, A. D. J. Am. Chem. Soc. 2003, 125, 10241.
(b) Choi, K.; Hamilton, A. D. J. Am. Chem. Soc. 2001, 123,
2456. (c) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y.-F.;
Redman, J. E.; Sanders, J. K. M. Angew. Chem. Int. Ed.
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Chem. 2001, 311. (e) Anzenbacher, P. Jr.; Jursíková, K.;
Lynch, V. M.; Gale, P. A.; Sessler, J. L. J. Am. Chem. Soc.
1999, 121, 11020. (f) Snowdown, T. S.; Bisson, A. P.;
Anslyn, E. V. J. Am. Chem. Soc. 1999, 121, 6324. (g) Cho,
C. Y.; Youngquist, R. S.; Paikoff, S. J.; Beresini, M. H.;
Hebert, A. R.; Berleau, L. T.; Liu, C. W.; Wemmer, D. E.;
Keough, T.; Schultz, P. G. J. Am. Chem. Soc. 1998, 120,
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(4) Molecular Recognition Tetrahedron Symposia-in-Print,
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(5) Molecular Recognition Chem. Rev. 1997, 97 (5), ; Gellman,
S. H., Guest Ed.; American Chemical Society: Washington,
DC, USA.
Compounds 2c and 2d have comparable activities against
Gram-positive bacteria like Bacillus cereus with the stan-
dard streptomycin. The cyclic peptides 2b–d were, other-
wise, inactive against most of the Gram-positive bacteria
for which they were tested.
Compound 2b displayed very mild activity against fungi
like Candida albicans with standard nistatin. The other
two cyclic peptides 2c and 2d did not have any antifungal
activity.25
(6) Perry, J. J. B.; Kilburn, J. D. Contemp. Org. Synth. 1997, 4,
61.
(7) Chakraborty, T. K.; Tapadar, S.; Kumar, S. K. Tetrahedron
Lett. 2002, 43, 1317.
In conclusion, the novel oligopeptide-based macrocyclic
synthetic receptors 2b–d, prepared from a new class of
chiral building blocks, chiral furan amino acids 1b–d,
demonstrate excellent binding capabilities with various
anions and show encouraging biological activities that
may find many useful applications.
(8) For some earlier works on the cyclic receptors for
carboxylate bindings see: (a) Moore, G.; Levacher, V.;
Bourguignon, J.; Dupas, G. Tetrahedron Lett. 2001, 42,
261. (b) Ranganathan, D.; Lakshmi, C.; Karle, I. L. J. Am.
Chem. Soc. 1999, 121, 6103. (c) Flack, S. S.; Chaumette, J.
L.; Kilburn, J. D.; Langley, G. J.; Webster, M. J. Chem. Soc.,
Chem. Commun. 1993, 399. (d) Lehn, J. M.; Méric, R.;
Vigneron, J. P.; Bkouche-Waksman, I.; Pascard, C. J. Chem.
Soc., Chem. Commun. 1991, 62. (e) Garcia-Tellado, F.;
Goswami, S.; Chang, S.-K.; Geib, S. J.; Hamilton, A. D. J.
Am. Chem. Soc. 1990, 112, 7393. (f) Hosseini, M. W.;
Lehn, J. M. J. Am. Chem. Soc. 1982, 104, 3525.
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M. J. Tetrahedron 2001, 57, 1139. (b) Beer, P. D.; Gale, P.
A. Angew. Chem. Int. Ed. 2001, 40, 486.
Acknowledgment
Authors wish to thank DST, New Delhi for financial support
(T.K.C. and H.S.) and CSIR, New Delhi for research fellowships
(S.T.).
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2488
T. K. Chakraborty et al.
LETTER
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ring proton), 6.15 (d, J = 2.97 Hz, 1 H, furan ring proton),
5.46 (ddd, J = 8.92, 8.18 Hz, 1 H, Ca-H), 3.19 (m, 2 H, Cb-
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(17) Selected physical data of 2b: Rf = 0.4 (silica, 8% MeOH in
CHCl3); [a]D29 –33.9 (c 0.115, MeOH). 1H NMR (200 MHz,
DMSO-d6): d = 8.37 (d, J = 9.52 Hz, 1 H, NH), 7.02 (d,
J = 2.93 Hz, 1 H, furan ring proton), 6.51 (d, J = 2.97 Hz, 1
H, furan ring proton), 5.41 (dq, J = 9.52, 7.32 Hz, 1 H, C-H),
1.54 (d, J = 7.32 Hz, 3 H, Cb-H3). MS (LSI-MS): m/z = 412
[M + H]+.
(23) The association constant (Ka) was obtained by using the
following equation: Ka = a/{(1 – a)([G] – a[H])}, where a =
(d – d0)/(dmax – d0), d0 is the initial chemical shift (host amide
proton), d is the chemical shift at each titration point, and dmax
is the chemical shift when the receptor is entirely bound (see
ref.21). The titrations were usually repeated several times to
attain error limits as low as possible. The average association
constant was determined from the values of each titration
point and the standard deviations are specified.
(24) (a) Jones, R. W.; Barry, A. L.; Gavan, T. L.; Washington, J.
A. II In Manual of Clinical Microbiology, 4th ed.; Lennette,
E. H.; Balows, A.; Hausler, W. J. Jr.; Shadomy, H. J., Eds.;
American Society for Microbiology: Washington DC, 1985,
972–977. (b) Lalitha, N.; Annapurna, J.; Iyenger, D. S.;
Bhalerao, U. T. Arzneim. Forsch. (Drug Res.) 1991, 41, 827.
(25) The details of the biological studies will be published
separately.
Selected physical data of 2c: Rf = 0.5 (silica, 8% MeOH in
CHCl3); [a]D29 –36.4 (c 0.055, MeOH). 1H NMR (200 MHz,
DMSO-d6): d = 8.17 (d, J = 10.41 Hz, 1 H, NH), 6.98 (d,
J = 2.97 Hz, 1 H, furan ring proton), 6.49 (d, J = 2.97 Hz, 1
H, furan ring proton), 4.91 (dd, J = 10.41, 9.66 Hz, 1 H, Ca-
H), 2.04 (m, 1 H, Cb-H), 1.04 (d, J = 6.69 Hz, 3 H, Cg-H3),
0.86 (d, J = 6.69 Hz, 3 H, Cg-H¢3). MS (ESI): m/z = 496 [M
+ H]+, 518 [M + Na]+, 519 [M + Na + H]+.
Selected physical data of 2d: Rf = 0.5 (silica, 7% MeOH in
CHCl3); [a]D29 –100.0 (c 0.070, MeCN). 1H NMR (200
Synlett 2004, No. 14, 2484–2488 © Thieme Stuttgart · New York