A proline-based macrocyclic amide with S4 symmetry

Article abstract of DOI:10.1246/cl.2008.10

A new square-shaped macrocyclic amide was prepared from N-(4-amino-2-nitrophenyl)proline (ANPP). The two enantiomers of ANPP were connected in an alternating sequence and then cyclized to the corresponding macrocyclic tetramer with S₄ symmetry. In this design, there is a central cavity approximately 7 A in diameter and rigid aromatic rings and intramolecular hydrogen bonding help to reduce the conformational flexibility of the molecule. Copyright

Full text of DOI:10.1246/cl.2008.10

10
Chemistry Letters Vol.37, No.1 (2008)
A Proline-based Macrocyclic Amide with S4 Symmetry
Hee Choon Ahn, Sun-mi Yun, and Kihang Choiꢀ
Department of Chemistry and Center for Electro- and Photo-Responsive Molecules,
Korea University, Seoul 136-701, Korea
(Received October 4, 2007; CL-071099; E-mail: kchoi@korea.ac.kr)
R2
2-NPP R1 = H, R2 = NO2
ANPP R1 = NH2, R2 = NO2
4-APP R1 = NH2, R2 = H
A new square-shaped macrocyclic amide was prepared from
N-(4-amino-2-nitrophenyl)proline (ANPP). The two enantiom-
ers of ANPP were connected in an alternating sequence and then
cyclized to the corresponding macrocyclic tetramer with S4 sym-
N
R1
O2N
CO2H
H
˚
metry. In this design, there is a central cavity approximately 7 A
N
N
N
in diameter and rigid aromatic rings and intramolecular hydro-
gen bonding help to reduce the conformational flexibility of
the molecule.
O
NO2
O
O
N
O
R1
HN
3
5
NH
6
N
H
N
O2N
N
O
O
Macrocycles have been widely used in molecular recogni-
tion studies, and many synthetic receptors for biologically and
environmentally important molecules and ions have been con-
structed on the basis of macrocyclic scaffolds.1 Macrocyclic
structures are effective in reducing conformational flexibility
and providing preorganized ligand binding sites when compared
to their acyclic analogues. In particular, cyclic amides have re-
ceived much attention as ideal candidates for novel macrocyclic
scaffolds;2 both symmetrical and unsymmetrical macrocycles
can be synthesized from amino acid monomers in a stepwise
manner, and the rigid amide bonds between the monomers not
only reduce conformational flexibility but also provide the mac-
rocycles potential sites for inter- or intramolecular hydrogen-
bonding interactions.
N
N
O
H
2-NPP phenylamide
R1, R2 = H
NO2
R2
1
Figure 1. Conformational preference of 2-NPP phenylamide
and structure of the cyclic tetramer of ANPP. The hydrogen
bonds stabilizing the lowest conformer of 2-NPP phenylamide
are indicated by dashed lines.
Recently, we have reported that N-(2-nitrophenyl)proline
(2-NPP) amides of primary amines have conformational prefer-
ence for the intramolecular hydrogen bonds connecting the
amide hydrogen, proline nitrogen, and nitro oxygen atoms.3 A
simple modeling study on 2-NPP phenylamide showed that the
same bifurcated hydrogen bonding could also stabilize the low-
est energy conformation of 2-NPP amides of aromatic amines.
Because of the reduced conformational flexibility and the or-
thogonal arrangement of the two aromatic rings within 2-NPP
phenylamide (Figure 1), we reasoned that N-(4-amino-2-nitro-
phenyl)proline (ANPP) might be used as a building block to con-
struct a new square-shaped macrocyclic amide.
Simple conformational search studies showed that the ho-
mochiral linear tetramer of ANPP would prefer a helical confor-
mation to a cyclic one and the corresponding cyclic tetramer
with C4 symmetry would have large ring strain (data not shown).
On the other hand, the linear tetramer with an alternating se-
quence of (R)- and (S)-ANPP monomers would prefer a cyclic
conformation so that macrocycle 1 with S4 symmetry would
have much lower ring strain.4
Figure 2. Lowest energy conformation of the cyclic tetramer of
ANPP: a side view drawn with depth cues (left) and a top view
with CPK representation (right). Progressively darker shades of
gray represent H, C, O, and N, respectively.
has been widely used as a macrocyclic scaffold in molecular
recognition studies.6 In the center of macrocycle 1, there is a
˚
cavity approximately 7 A in diameter. Because the amide and
nitro groups are located at the sterically congested corners, the
cavity is lined mostly with the four phenyl rings.
The macrocycle synthesis began with the preparation of the
two ANPP enantiomers (Scheme 1). (S)- and (R)-2 were synthe-
sized from the nucleophilic substitution reaction of Boc-protect-
ed 4-fluoro-3-nitroaniline7 with L- and D-proline, respectively
(Boc = tert-butoxycarbonyl). The corresponding amine compo-
nent was prepared by protection of the carboxyl group as
its methyl ester and deprotection of the amine group under acidic
condition. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-
Cl) was used as the coupling reagent to synthesize the dimer that
was in turn converted into 3 or 4 by removal of the Boc group or
hydrolysis of the methyl ester group, respectively. These two
dimers with a free amine or carboxyl group were coupled togeth-
To obtain a detailed picture of the macrocycle, we per-
formed a Monte Carlo conformation search.5 The lowest energy
conformation of macrocycle 1 has S4 symmetry, as expected,
(Figure 2) and the other low-energy conformations show only
minor variations in the ring puckering of the proline moieties
outside the molecule. The dimensions of the macrocycle are
˚
about 10 ꢁ 10 A and similar to those of ꢀ-cyclodextrin, which
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.1 (2008)
11
NHR2
NHR2
ing that the molecule has a long rotational correlation time pre-
sumably because of its large size.9 Synthesis of another macro-
cycle was attempted by using (R)- and (S)-N-(4-aminophenyl)-
proline (4-APP) as monomers. However, the corresponding tet-
rameric precursor showed very low solubility in common
organic solvents and test reactions for the cyclization yielded in-
separable mixtures. It seems that the intramolecular interactions
between the nitro and amide groups of macrocycle 1 prevent in-
termolecular hydrogen bonding and thus reduce aggregation.
In summary, we have shown that a new macrocyclic amide
can be synthesized from proline-based amino acids. In this
square-shaped cyclic tetramer, the two enantiomers of ANPP
are connected in an alternating sequence and the overall struc-
ture has S4 symmetry. Incorporation of rigid aromatic rings
and preorganization through intramolecular hydrogen bonding
allowed to control the conformational flexibility of this large
macrocycle. We are currently working on the development
of various synthetic receptors based on this novel macrocyclic
scaffold.
NHBoc
a
d
R1O2C
O2N
O2N
O
O2N
N
CO2R1
N
N
F
N
H
NO2
e
(S)-2 R1 = H, R2 = Boc
R1 = CH3, R2 = Boc
1 = H, R2 = Boc
R1 = CH3, R2 = H
b,c
1 = CH3, R2 = H
R
3
4
R
f
O2N
N
H
N
N
O
CO2CH3
BocHN
NO2
g
h-j
3 + 4
1
NH
O
O2N
O
N
N
N
H
NO2
Scheme 1. Reagents and conditions: (a) L-proline, NaHCO3,
H2O, EtOH, reflux, 80%; (b) MeI, K2CO3, DMF, 93%; (c)
TFA, CH2Cl2; (d) (R)-2, BOP-Cl, DIEA, CH2Cl2, 87%; (e)
LiOH, H2O, MeOH, THF, 96%; (f) TFA, CH2Cl2; (g) BOP-
Cl, DIEA, CH2Cl2, 73%; (h) LiOH, H2O, MeOH, THF, 94%;
(i) TFA, CH2Cl2; (j) BOP-Cl, DIEA, THF, 30%. TFA = tri-
fluoroacetic acid, DIEA = N,N-diisopropylethylamine.
This work was partly supported by a Korea University Grant
and the Korea Science and Engineering Foundation through
CRM of Korea University.
References and Notes
1
a) J. W. Steed, J. L. Atwood, Supramolecular Chemistry, Wiley,
Chichester, 2000. b) J.-M. Lehn, Supramolecular Chemistry: Con-
cepts and Perspectives, Wiley-VCH, Weinheim, 1995.
a) H. Ishida, M. Suga, K. Donowaki, K. Ohkubo, J. Org. Chem.
1995, 60, 5374. b) S. Kubik, R. Goddard, R. Kirchner, D. Nolting,
J. Seidel, Angew. Chem., Int. Ed. 2001, 40, 2648. c) K. Choi,
A. D. Hamilton, J. Am. Chem. Soc. 2003, 125, 10241. d) T. K.
Chakraborty, S. Tapadar, S. K. Kumar, Tetrahedron Lett. 2002,
43, 1317. e) D. Mink, S. Mecozzi, J. Rebek, Jr., Tetrahedron Lett.
1998, 39, 5709. f) C. Boss, P. H. Rasmussen, A. R. Wartini, S. R.
Waldvogel, Tetrahedron Lett. 2000, 41, 6327. g) G. Haberhauer,
T. Oeser, F. Rominger, Chem. Commun. 2004, 2044. h) G.
Haberhauer, A. Pinter, T. Oeser, F. Rominger, Eur. J. Org. Chem.
2007, 1779. i) H. Jiang, J.-M. Leger, P. Guionneau, I. Huc, Org. Lett.
2004, 6, 2985. j) P. S. Shirude, E. R. Gillies, S. Ladame, F. Godde,
K. Shin-Ya, I. Huc, S. Balasubramanian, J. Am. Chem. Soc. 2007,
129, 11890. k) I. Azumaya, T. Okamoto, F. Imabeppu, H.
Takayanagi, Tetrahedron 2003, 59, 2325. l) S. Jayaprakash, G.
Pattenden, M. S. Viljoen, C. Wilson, Tetrahedron 2003, 59, 6637.
H. C. Ahn, K. Choi, Org. Lett. 2007, 9, 3853.
2
3
4
For cyclic amides with an alternating sequence of L- and D-ꢁ-amino
acids, see: D. T. Bong, T. D. Clark, J. R. Granja, M. R. Ghadiri,
Angew. Chem., Int. Ed. 2001, 40, 988.
5
Spartan’06 (Wavefunction, Inc.) was used for the calculations. A
Monte Carlo conformation search was performed using the MMFF
force field to find the lowest energy conformation, which was then
used as an initial structure for the geometry optimization using the
semiempirical AM1 model.
Figure 3. NOESY spectrum of macrocycle 1 in DMSO-d6. The
1H signals were assigned on the basis of their chemical shifts and
splitting patterns. The mixing time was set as 300 ms with
6
7
J. Szejtli, Chem. Rev. 1998, 98, 1743.
Y. Kuramoto, Y. Ohshita, J. Yoshida, A. Yazaki, M. Shiro, T. Koike,
J. Med. Chem. 2003, 46, 1905.
1
400 MHz H NMR frequency.
er to afford the tetramer. Sequential deprotection of the N- and
C-terminal groups gave the linear precursor that was cyclized
to macrocycle 1 under high dilution condition (1 mM) to mini-
mize linear oligomer formation.
The structure of the macrocycle was initially confirmed by
its simplified NMR spectrum and finally by high-resolution mass
spectrometry.8 A NOESY experiment showed all the expected
NOEs between adjacent protons (Figure 3), and the diagonal
and cross peaks in the 2D spectrum have the same signs indicat-
8
Spectral data of macrocycle 1: 1H NMR (400 MHz, DMSO-d6) ꢂ
10.08 (s, 4H), 7.90 (d, 4J ¼ 2:6 Hz, 4H), 7.62 (dd, 3J ¼ 9:3 Hz,
4J ¼ 2:6 Hz, 4H), 6.94 (d, 3J ¼ 9:3 Hz, 4H), 4.38–4.41 (m, 4H),
3.38–3.42 (m, 4H), 3.07–3.11 (m, 4H), 2.38–2.42 (m, 4H), 1.84–
2.01 (m, 12H); 13C NMR (100 MHz, DMSO-d6) ꢂ 167.0, 137.4,
136.6, 128.8, 125.1, 117.9, 115.7, 62.8, 51.5, 31.6, 24.3; HRMS
(FAB) m=z: ½M þ Hꢂþ calcd for C44H45N12O12, 933.3280; found
933.3276.
9
J. Keeler, Understanding NMR Spectroscopy, Wiley, Chichester,
2005.
Published on the web (Advance View) November 27, 2007; doi:10.1246/cl.2008.10