Improving the efficiency of forming 'unfavorable' products: Eight-residue macrocycles from folded aromatic oligoamide precursors

Article abstract of DOI:10.1055/s-0029-1217173

Oligoamide macrocycles consisting of eight meta-linked benzene residues were synthesized based on the cyclization of aromatic oligoamide precursors having folded backbones rigidified by three-center hydrogen bonds. An alternative route based on the conden

Full text of DOI:10.1055/s-0029-1217173

LETTER
1437
Improving the Efficiency of Forming ‘Unfavorable’ Products: Eight-Residue
Macrocycles from Folded Aromatic Oligoamide Precursors
E
ight-Residue
h
M
acrocycle
u
fromFolde
l
dArom
i
atic
O
l
a
igoamide
P
n
recursors g Zou,a Youzhou He,a Yongan Yang,a Yi Zhao,a Lihua Yuan,a Wen Feng,*a Kazuhiro Yamato,b Bing Gong*b
a
College of Chemistry, Key Laboratory for Radiation Physics and Technology of Ministry of Education,
Institute of Nuclear Science and Technology, Sichuan University, Chengdu, 610064, P. R. of China
Fax +86(28)85418755; E-mail: wfeng9510@scu.edu.cn
Department of Chemistry, University at Buffalo, The State University of New York at Buffalo, Buffalo, NY 14260, USA
Fax +1(716)64568002243; E-mail: bgong@buffalo.edu
b
Received 11 February 2009
precursors having rigidified, folded backbones enforced
by three-center intramolecular hydrogen bonds.
Abstract: Oligoamide macrocycles consisting of eight meta-linked
benzene residues were synthesized based on the cyclization of aro-
matic oligoamide precursors having folded backbones rigidified by
three-center hydrogen bonds. An alternative route based on the con-
densation of pentadimeric diamine and trimeric diacid provided the
cyclic octamer in 75% yield using EDCI/HOBt as the coupling re-
agent.
As part of our ongoing interest in the construction of func-
tional oligoamide macrocycles, we started to sythesize
six-residue macrocycles such as 3a that carries olefinic
side chains based on procedures we reported.11 During
this investigation, we observed the presence of a trace
amount of an eight-residue macrocycle in the reaction
mixture, in addition to the expected six-residue macro-
cyle.
Key words: macrocycles, synthesis, hydrogen bonds, folding oli-
goamides, cyclizations
In this paper we probe conditions under which the forma-
tion of this otherwise unfavorable eight-residue macro-
cycle could be improved. We first investigated the one-
step condensation of the corresponding monomeric diacid
chloride and diamine at various temperatures. An alterna-
tive strategy that led to the preparation of the same mac-
rocycle in significantly enhanced yields was also
examined.
Macrocyclization facilitated by noncovalent interactions,
such as hydrogen bonding, has attracted increasing atten-
tion for constructing well-defined structures.1 Among
known strategies such as templation2 and high dilution,2,3
for forming macrocycles, especially those with shape-
persistency4 that have great potentials as scaffolds for var-
ious applications,5–7 macrocyclization assisted by hydro-
gen bonding stands out due to its high efficiency.
Macrocyclization facilitated by intramolecular H-bonding
has allowed the construction of macrocylces having vari-
ous lumens. For instance, by locking diamide precursors
into a cis conformation within a framework containing a
2,6-disubstitutedpyridyl unit, reacting acid chloride and
amino groups were brought into close proximity for
cyclization, which led to a macrocylce in 88% yield that
was in sharp contrast to a much lower yield of 30% in the
absence of intramolecular H-bonds.8 Taking advantage of
folded conformations of uncyclized precursors, which
was enforced by intramolecular hydrogen bonding via sta-
bilization of imine bonds, a 14-membered macrocycle
was obtained by the condensation of ethylene diamine and
dialdehyde.9 The directionality of hydrogen bonds also
led to the formation of macrocyclic trimer even in a highly
polar solvent at high temperature (100 °C).10 A discovery
made by us provided an efficient means to the formation
of a series of six-residue, cavity-containing oligoamide
macrocycles in over 80% yield based on the condensation
of simple monomeric diamines and diacid chlorides.11
The high efficiency demonstrated by our system was be-
lieved to be due to the cyclization of reactive oligomeric
As shown in Scheme 1, the coupling of diamine 1 (1
equiv) with diacid chloride 2 (1 equiv) following the pre-
viously reported procedure in the presence of triethyl-
amine at –20 °C led to 3a as the major product in a yield
of 65%. A trace amount of a cyclic species (<1%), which
was indicated by a signal {m/z = 2577.1 [M + K+]} in the
MALDI-TOF spectrum, was also detected. This minor
product was initially assumed to be the dimeric aggregate
of a four-residue macrocycle resembling calix[4]arenes,
but was soon found to be more consistent with the eight-
residue macrocycle 4a. Subsequent reaction of 1 and 2b
also led to the detection of macrocycle 4b in the crude
product {m/z = 1807.5 [M + Na+]}, again in a very low
yield (<5%). The presence of 4a and 4b as minor products
in these one-step reactions prompted us to investigate the
possibility of optimizing the formation of macrocycles
larger than the six-residue ones.
Due to the folded (rigidified) conformation of the oligo-
meric precursors and intermediates, which belong to a
class of folded oligomers whose folding has been well
established by us12 to be enforced by highly favorable
intramolecular three-center hydrogen bonds, the cycliza-
tion of oligoamide precursors with lengths beyond six res-
idues would be hampered because of the strain associated
with macrocyclic products with twisted backbone and the
SYNLETT 2009, No. 9, pp 1437–1440
x
x.
x
x.
2
0
0
9
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217173; Art ID: S01909ST
© Georg Thieme Verlag Stuttgart · New York

1438
S. Zou et al.
LETTER
R:
a (CH2)9CH=CH2
b CH2CH2OMe
c (CH2CH2O)3Me
MeO
H2N
OMe
NH2
RO
OR
+
ClOC
COCl
1
2
Et3N–CH2Cl2
MeO
OR
OMe
OR
NH
HN
MeO
OMe
OR
H
N
RO
H
N
O
O
OR HN
NH OR
OMe
OMe
MeO
O
O
O
O
RO
H
OR
H
O
O
NH
HN
+
MeO
C
N
O
O
N
O
N
C
RO
MeO
OMe
OR
O
O
O
N
H
HN
NH
RO
RO
OMe
H
OMe
RO
OR
MeO
OMe
4a trace
3a 65%, –20 °C
3b 80%, –20 °C
3c 67%, –15 °C
40%, 20 °C
4b <5%
4c 9%
23%
Scheme 1 Macrocyclization based on the condensation of monomeric diamine 1 and diacid chlorides 2
increased entropic barriers associated with the formation and polymers of higher molecular weights. Although re-
of larger macrocycles. Furthermore, reaction steps lead- mained to be characterized, these linear oligomers and
ing to the direct precursors of macrocycles with more than polymers are interesting since they should fold into helical
six meta-linked residues are discouraged because of steric conformations containing hydrophilic holes, channels
hindrance associated with the rigidified backbones of the running down their long axes. In addition, at 20 °C, higher
reacting oligmeric intermediates lead to these long oligo- concentration seems to facilitate the formation of the
mers.
eight-residue 4c. For example, the yield reached 30% at
50 mM.
The above analysis agrees with the observed low yields of
4a and 4b. Thus it seems that rigidification of the oligo- That the yield of the eight-residue macrocycle 4c could in-
meric intermediates and precursors of expanded macro- deed be improved under different conditions led to a fur-
cycles such as 4a and 4b is the major reason for the low ther investigation on the possibility of optimizing the
efficiencies observed for their formation. We then rea- corresponding macrocyclization using an alternative strat-
soned that by adopting conditions under which the confor- egy. One straightforward approach involves adopting a
mational flexibility of the oligoamide backbones gets synthetic route that excludes the formation of the six-
enhanced, the entropic and steric barriers associated with
Table 1 Temperature Effect on Yields of 3c and 4ca
the formation of macrocycles larger than the six-residue
ones should be alleviated. Based on this consideration, di-
acid chloride 2c was treated with diamine 1 at various
temperatures in CHCl3. The results are listed in Table 1.
Temp (°C)
Yield of 3c (%)
Yield of 4c (%)
–30
–15
0
70
67
56
40
37b
32c
22
17
<5
9
1
Analyzing the crude reaction mixture by H NMR and
subsequent isolation of the product revealed that the
yields of the six-residue macrocycle 3c kept decreasing
with increasing temperature. In contrast, the yields of
macrocycle 4c increased from <5% to 23% as the temper-
ature was raised from –30 to 20 °C. However, the yields
of 4c declined at higher temperature, with 7% at 40 °C and
less than 5% at –30 °C. The fact that an optimum temper-
ature exists for forming 4c suggests that in this system dif-
ferent reactions are competing at different temperature
range, which provides a potential strategy for maximizing
the yield of an otherwise unfavorable product. Indeed, at
12
23
30b
20c
7
20
40
60
<5
a Initial concentration: 10 mM, 20 °C.
60 °C, besides 3c (17%) and 4c (<5%) isolated, the major- b 50 mM.
ity of the reaction mixture seemed to be linear oligomers
c 100 mM.
Synlett 2009, No. 9, 1437–1440 © Thieme Stuttgart · New York

LETTER
Eight-Residue Macrocycles from Folded Aromatic Oligoamide Precursors
1439
MeO
OMe
The above strategy, which involves the coupling of oligo-
mers, is quite flexible. Other synthetic routes can be sim-
ilarly designed. For example, eight-residue macrocycles
such as 4c may also be obtained by coupling trimeric di-
acid such as 7 with monomeric diamine 1. This possibility
was tested by treating the diacid chloride 9 with diamine
1, from which macrocycle 4c was obtained in a yield of
TgO HN
NH OTg
TgO
OTg
a)
O
O
80%
MeOOC
COOH
TgO
OTg
COOMe
COOMe
6
5
1
40%. The MALDI-TOF and H NMR spectra indicated
MeO
OMe
that the crude mixture comprised 4c, along with unreacted
starting material, and other acylic species.
OTgHN
NH OTg
b)
c) 75%
d) 93%
8
95%
O
O
TgO
OTg
COOH
8a R = NO2
COOH
7
route A
MeO
OMe
TgO HN
NH OTg
O
O
TgO
HN
OTg
NH
e)
+
O
R
O
4c
7
Figure 1 The MALDI-TOF spectra of (a) the reaction mixture, and
(b) purified 4c, based on route A.15 Calculated value for the
C120H168N8NaO48[M + Na+] ion of 4c: 2512.08.
75%
MeO
OMe
R
OMe
OMe
In summary, we have investigated the formation of oli-
goamide macrocycles 4 consisting of eight meta-linked
benzene residues. Although six-residue macrocyle pre-
dominated in the one-step coupling reaction of monomer-
ic diamine and diacid chloride at low temperature, the
yields of eight-residue macrocycles can be improved at
higher temperatures. The enhanced yields of the otherwise
unfavorable eight-residue macrocycles from the one-step
condensation reaction can be attributed to the increased
flexibility of the folded oligomeric intermediates and pre-
cursors at elevated temperatures. An alternative coupling
route based on the coupling of pentameric diamine 8b and
trimeric diacid 7, which precluded the six-residue macro-
cycle from forming, led to the eight-residue 4c in a signif-
icantly improved yield. This work has presented strategies
that allow the augmentation of an unfavorable product ei-
ther by tuning reaction conditions or by adopting an alter-
native synthetic route. The approach described here
should be of value to the preparation of macrocycles that
would be difficult to obtain under regular conditions.
8b R = NH2
route B
MeO
OMe
TgO HN
NH OTg
MeO
H2N
OMe
NH2
f)
40%
O
O
+
4c
TgO
OTg
COCl
COCl
1
9
Scheme 2 Reagents and conditions: a) (i) (COCl)2, CH2Cl2; (ii) 1,
Et3N, r.t.; b) NaOH, H2O–MeOH, reflux; c) 2,4-dimethoxy-5-nitro-
aniline, Ph3PCl2, 45 °C; d) H2, Pd/C; e) EDCI/HOBt, 7, r.t. f) (i)
(COCl)2, CH2Cl2; (ii) 1, Et3N, r.t.
residue macrocycles. One such route is shown in
Scheme 2, involving the coupling of pentameric diamine
8b and trimeric diacid 7.
The combination of 8b and 7 cannot lead to six-residue
macrocycle 3c. Instead, only the eight-residue macrocycle
4c or longer oligomers are possible products. Starting
from monomethyl ester acid 5, trimeric diacid 7 was ob-
tained by coupling diamine 1 with 5 followed by hydro-
lyzing the formed trimeric dimethyl ester 6. Pentameric
diamine 8b was prepared by the catalytic hydrogenation
of the corresponding dinitro compound 8a, which was ob-
tained from the reaction between 7 and 4-dimethoxy-5-
nitroaniline,13 using triphenylphosphine dichloride
(Ph3PCl2) as the coupling reagent. By coupling trimeric
diacid 7 with pentameric diamine 8b at 28 °C using EDCI/
HOBt as the coupling reagent, macrocycle 4c was isolated
in a yield of 75%.14 That macrocycle 4c was formed as the
dominant product from this reaction was demonstrated by
MALDI-TOF (Figure 1), which revealed a very strong
and distinct signal even for the reaction mixture.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (No. 20774059 and No. 20672078), the National Science
Foundation of the USA (CHE-0314577), and Analytical & Testing
Center of Sichuan University for NMR analysis.
References and Notes
(1) Gloe, K. In Macrocyclic Chemistry: Current Trends and
Future Perspectives; Springer: Dordrecht, 2005.
(2) McCallien, D. W. J.; Sanders, J. K. M. J. Am. Chem. Soc.
1995, 117, 6611.
Synlett 2009, No. 9, 1437–1440 © Thieme Stuttgart · New York

1440
S. Zou et al.
LETTER
Na] calcd for C120H168N8NaO48: 2513.0882; found:
(3) (a) Knops, P.; Sendhoff, N.; Mekelburger, H. B.; Voegtle, F.
Top. Curr. Chem. 1992, 161, 1. (b) Rossa, L.; Voegtle, F.
Top. Curr. Chem. 1983, 113, 1.
2513.0955.
Compound 6: 1H NMR (400 MHz, CDCl3): d = 9.75 (s, 2 H),
9.37 (s, 1 H), 8.88 (s, 2 H), 6.63 (s, 2 H), 6.55 (s, 1 H), 4.40
(t, J = 4.8 Hz, 4 H), 4.25 (t, J = 4.8 Hz, 4 H), 4.00 (t, J = 4.8
Hz, 4 H), 3.94 (t, J = 4.8 Hz, 4 H), 3.92 (s, 6 H), 3.84 (s, 6
H), 3.80 (t, J = 4.8 Hz, 4 H), 3.68 (m, 12 H), 3.58 (m, 12 H),
3.47 (q, 4 H), 3.37 (s, 6 H), 3.32 (s, 6 H). ESI-HRMS: m/z
[M + H] calcd for C54H81N2O24: 1141.5179; found:
1141.5125.
(4) (a) Bazzicalupi, C.; Bencini, A.; Bianchi, A.; Danesi, A.;
Faggi, E.; Giorgi, C.; Santarelli, S.; Valtancoli, B. Coord.
Chem. Rev. 2008, 252, 1052. (b) Müller, T. J. J.; Bunz,
U. H. F. Functional Organic Materials – Synthesis,
Strategies and Applications; Wiley-VCH: Weinheim, 2007,
225. (c) Zhang, W.; Moore, J. S. Angew. Chem. Int. Ed 2006,
45, 4416. (d) Zhao, D.; Moore, J. S. Chem. Commun. 2003,
807. (e) MacLachlan Mark, J. Pure Appl. Chem. 2006, 78,
873. (f) Grave, C.; Schlüter, A. D. Eur. J. Org. Chem. 2002,
3075.
(5) (a) Höger, S.; Meckenstock, A.-D. Chem. Eur. J. 1999, 5,
1686. (b) Martell, A. E.; Perutka, J.; Kong, D. Coord. Chem.
Rev. 2001, 216, 55.
(6) (a) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc.
1996, 118, 1019. (b) Seo, S. H.; Jones, T. V.; Seyler, H.;
Peters, J. O.; Kim, T. H.; Chang, J. Y.; Tew, G. N. J. Am.
Chem. Soc. 2006, 128, 9264. (c) Pasini, D.; Ricci, M. Curr.
Org. Synth. 2007, 4, 59.
(7) Helsel, A. J.; Brown, A. L.; Yamato, K.; Feng, W.; Yuan,
L. H.; Clements, A. J.; Harding, S. V.; Szabo, G.; Shao,
Z. F.; Gong, B. J. Am. Chem. Soc. 2008, 130, 15784.
(8) Carver, F. J.; Hunter, C. A.; Shannon, R. J. J. Chem. Soc.,
Chem.Commun. 1994, 1277.
(9) Owston, P. G.; Peters, R.; Ramsammy, E.; Tasker, P. A.;
Trotter, J. J. Chem. Soc., Chem. Commun. 1980, 1218.
(10) Jiang, H.; Leger, J.-M.; Guionneau, P.; Huc, I. Org. Lett.
2004, 6, 2985.
(11) (a) Yuan, L. H.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu,
D. G.; Guo, H.; Gong, B. J. Am. Chem. Soc. 2004, 126,
11120. (b) Sanford, A. R.; Yuan, L. H.; Feng, W.; Yamato,
K.; Flowers, R. A.; Gong, B. Chem. Commun. 2005, 4720.
(12) (a) Gong, B. Acc. Chem. Res. 2008, 41, 1376. (b) Yuan, L.
H.; Zeng, H. Q.; Yamato, K.; Sanford, A. R.; Feng, W.;
Atreya, H. S.; Sukumaran, D. K.; Szyperski, T.; Gong, B.
J. Am. Chem. Soc. 2004, 126, 16528. (c) Gong, B.; Zeng, H.
Q.; Zhu, J.; Yuan, L. H.; Han, Y. H.; Cheng, S. Z.;
Furukawa, M.; Parra, R. D.; Kovalevsky, A. Y.; Mills, J. L.;
Skrzypczak-Jankun, E.; Martinovic, S.; Smith, R. D.; Zheng,
C.; Szyperski, T.; Zeng, X. C. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 11583. (d) Zhu, J.; Parra, R. D.; Zeng, H.;
Skrzypczak-Jankun, E.; Zeng, X. C.; Gong, B. J. Am. Chem.
Soc. 2000, 122, 4219.
Compound 7: 1H NMR (400 MHz, CDCl3): d = 9.57 (s, 2 H),
9.21 (s, 1 H), 8.96 (s, 2 H), 6.65 (s, 2 H), 6.41 (s, 1 H), 4.48
(t, J = 4.8 Hz, 4 H), 4.33 (t, J = 4.8 Hz, 4 H), 4.01 (t, J = 4.8
Hz, 4 H), 3.87 (s, 6 H), 3.84 (t, J = 4.8 Hz, 4 H), 3.71 (m, 8
H), 3.63 (m, 8 H), 3.57 (m, 12 H), 3.47 (m, 4 H), 3.37 (s, 6
H), 3.32 (s, 6 H).13C NMR (100 MHz, CDCl3): d = 164.8,
161.2, 160.9, 160.7, 145.6, 138.1, 120.1, 116.1, 111.4, 98.2,
94.4, 71.9, 71.8, 70.6, 70.5, 70.5, 70.4, 70.3, 69.4, 69.2, 69.0,
68.5, 58.9, 58.8, 55.8. ESI-HRMS: m/z [M – H] calcd for
C52H75N2O24: 1111.4710; found: 1111.4769.
Compound 8a: 1H NMR (400 MHz, CDCl3): d = 9.88 (s, 2
H), 9.65 (s, 2 H), 9.20 (s, 3 H), 8.98 (s, 2 H), 6.63 (s, 2 H),
6.56 (s, 1 H), 6.47 (s, 2 H), 4.49 (t, J = 4.8 Hz, 4 H), 4.36 (t,
J = 4.8 Hz, 4 H), 4.07 (s, 6 H), 3.96 (t, J = 4.8 Hz, 4 H), 3.92
(d, 12 H), 3.76 (t, J = 4.8 Hz, 4 H), 3.70 (t, J = 4.8 Hz, 4 H),
3.64 (t, J = 4.8 Hz, 4 H), 3.56 (m, 12 H), 3.46 (m, 12 H), 3.31
(s, 12 H). 13C NMR (100 MHz, CDCl3): d = 161.6, 160.1,
160.0, 153.8, 151.0, 146.3, 137.0, 121.4, 120.6, 117.4,
115.3, 114.6, 97.7, 95.6, 95.2, 71.8, 70.7, 70.6, 70.6, 70.5,
70.4, 70.3, 69.4, 69.1, 69.0, 58.9, 56.7, 56.5, 56.1. ESI-
HRMS: m/z [M + H] calcd for C68H93N6O30: 1473.5936;
found: 1473.5927.
Compound 8b: prepared from hydrogenation of its dinitro
compound 8a in 90% yield. 1H NMR (400 MHz, DMSO-d6):
d = 10.07 (s, 2 H), 10.02 (s, 2 H), 9.32 (s, 1 H), 8.91 (s, 2 H),
7.90 (s, 2 H), 7.10 (s, 2 H), 6.96 (s, 1 H), 6.75 (s, 2 H), 4.63
(s, 8 H), 4.03 (s, 6 H), 4.01–3.98 (m, 8 H), 3.91 (s, 6 H), 3.84
(s, 6 H), 3.65 (m, 8 H), 3.60–3.40 (m, 8 H), 3.36 (m, 8 H),
3.23 (s, 6 H), 3.21 (s, 6 H), 3.16–3.10 (m, 8 H).(15)
Procedure For Macrocyclization
Route A
A mixture of 7 (23.7 mg, 0.021 mmol), EDCI (10.2 mg,
0.053 mmol), and HOBt (7.3 mg, 0.054 mmol) in CH2Cl2
(10 mL) was stirred at r.t. for 50 min and then 8b (30.0 mg,
0.021 mmol) was added. The mixture was stirred at 28 °C
overnight. After washing with H2O, the residue was
subjected to chromatography (CHCl3–MeOH, 5:1) to afford
the product 4c as an off-white solid (37.5 mg, 75%).
Route B
The diacid chloride (0.020 mmol), prepared from diacid 7
and (COCl)2 in CH2Cl2, was added to the diamine 1 (0.020
mmol) in the presence of Et3N in 0.5 h. The mxiture was
stirred 6 h. After washing with 10% HCl, the residue was
recrystallized several times from acetone to provide 4c in
40% yield.
(13) Yuan, L. H.; Sanford, A. R.; Feng, W.; Zhang, A. M.; Zhu,
J.; Zeng, H. Q.; Yamato, K.; Li, M. F.; Ferguson, J. S.; Gong,
B. J. Org. Chem. 2005, 70, 10660.
(14) Selected Spectroscopic Data of Compounds 4–8
Compound 4c: 1H NMR (400 MHz, 95% CDCl3–5%
CD3OD): d = 10.00 (s, 4 H), 9.90 (s, 4 H), 9.40 (s, 2 H), 9.23
(s, 2 H), 9.00 (s, 2 H), 8.70 (s, 2 H), 6.80 (s, 2 H), 6.69 (s, 2
H), 6.50 (s, 4 H), 4.47 (s, 16 H), 3.99–3.43 (m), 3.28 (s, 24
H). MS (MALDI-TOF): m/z calcd for C120H168N8NaO48
[M + Na]: 2512.08; found: 2512.1. ESI-HRMS: m/z [M +
Synlett 2009, No. 9, 1437–1440 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.