Linear and cyclic amides with a thiophene backbone: Ultrasound-promoted synthesis and crystal structures

Article abstract of DOI:10.1021/jo3017605

A full synthetic study of linear and cyclic thiophene oligoamides has been carried out. The combination of an ultrasonic technique to diminish the intramolecular backfolding of longer oligoamide chains, therefore enhancing the accessibility of the carboxy

Full text of DOI:10.1021/jo3017605

Article
pubs.acs.org/joc
Linear and Cyclic Amides with a Thiophene Backbone: Ultrasound-
Promoted Synthesis and Crystal Structures
Thien H. Ngo, Hulya Berndt, Dieter Lentz, and Hans-Ulrich Reissig*
̈
Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, D-14195 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A full synthetic study of linear and cyclic thiophene oligoamides has been carried out. The combination of an
ultrasonic technique to diminish the intramolecular backfolding of longer oligoamide chains, therefore enhancing the accessibility
of the carboxylic acid, and T3P as coupling reagent led to shorter reaction time and higher yields for both linear and cyclic
oligoamides. By controlling the degree of dilution, macrocyclic amides with different sizes can selectively be prepared. Different
crystal structures of cyclic thiophene oligoamides were also analyzed.
Scheme 1. Synthesis of 5-Aminothiophenecarboxylic Acids
INTRODUCTION
■
Due to their high stability, amide bonds have been chosen by
nature as a linkage for the construction of its basic structures,
e.g., proteins and glycoconjugates to amino acids.1 In the field of
peptidomimetics, numerous research groups have dedicated
their full focus to the development of methodologies for
mimicking the vital processes of nature. The discovery of
biological activities of some natural products built up by amide
bonds, e.g. those extracted from marine plants,2,3 shows the
importance of these investigations. For example, cyclopeptides
containing five-membered heterocycles such as the antitumor
trunkamide A4−6 and the cytotoxic ascidiacyclamide2,7,8 (both
from the Lissoclinum class of cyclic peptides) play an
undeniably important role in nature, as they are found in
many of these marine organisms. The alternating sequence of
heterocyclic rings and amino acid units which characterize these
structures has led to speculation that the metabolites may have
a role to play in vivo as host agents for metal transport, and/or
that metals may act as templates in their biological assembly
from the constitutive amino acids and heterocyclic rings.9 The
importance of this research area has encouraged us to search for
optimal methods for the synthesis of oligopeptides containing
heterocycles in their backbones.
The synthetic pathway described above affords new
opportunities to prepare a variety of linear and cyclic
oligoamides containing thiophene moieties. These oligopep-
tides can be compared to the better known meta-substi-
tuted36,37 (or para-substituted)38−40 phenyl peptidomimetics,
but the heterocyclic structure may result in different properties
over a wide area of interest, e.g., these oligoamides could act as
ligands for metal cations, and the extra coordination might
enhance or inhibit some biological activities. The more
conformationally rigid structure due to the aryl groups could
be an advantage for efficient and flexible synthetic access to
both linear and cyclic peptide analogues; in the case of a
cyclopeptide, the rigidity could lead to a better fit for the host−
guest interaction.
Within our group, the synthesis of 5-aminothiophenecarbox-
ylic acids via the three-component Gewald reaction10−15 has
been explored16,17 using 2-siloxycyclopropanecarboxylates A as
aldehyde equivalents B (Scheme 1).18−35 This process gave
direct access to the unnatural amino acids C containing a
thiophene backbone, which can be considered as isosteres to
the natural dipeptides D.
For peptide bond formation, the traditional synthetic
methodology (under conventional stirring) involves the
Received: August 18, 2012
Published: September 26, 2012
© 2012 American Chemical Society
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Scheme 2. Synthesis of Linear Thienyl Amides 2a−c with Different Coupling Reagents
reaction of carboxylic acids with amines in the presence of
peptide coupling reagents.41 New techniques such as micro-
wave-assisted peptide couplings have been widely reported in
recent decades, both in solution42−45 and on solid phase.46,47
But another phenomenon has drawn our attention, namely
ultrasonication. Sonochemistry using energy from cavitation
bubbles to promote chemical reactions has already been known
for more than 70 years.48 It has regained more attention in
recent decades due to the availability of reliable ultrasonic
equipment and offers some advantages over conventional
procedures, such as shorter reaction times and higher yields. To
our knowledge, only a few examples have been reported that
Table 1. Reaction Conditions for the Synthesis of Linear
Oligoamides
coupling
a
reaction
conditions
yield
(%)
entry acid amine
reagent
product
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1b
2b
2b
1a
1a
1a
1a
1a
1a
1a
1a
1a
BOP, DMAP
TFFH, DMAP
TFFH, DIPEA
HATU, DIPEA
EDCI·HCl
24 h
3 d
2a
2a
2a
2a
2a
2a
2a
3a
3a
−
−
3 d
68
32
81
87
80
69
57
24 h
24 h
24 h
24 h
24 h
24 h
PyBroP, DIPEA
T3P, Et3N
EDCI·HCl
PyBroP, 2,4,6-
collidine
employ ultrasound activation in peptide synthesis.49−53
A
second aspect concerns propylphosphonic anhydride T3P,
which has gained our interest because it offers several
advantages over other traditional coupling reagents, e.g., higher
yields, low toxicity, easy workup, and short reaction times.54−57
In the previous report, we described the preparation of linear
and cyclic thiophene oligoamides with the backbone formed
between an aliphatic carboxylic acid derived from C and the
notoriously unreactive 5-amino group of the thiophene ring,
using EDCI·HCl (see footnote in Table 1) as coupling reagent
(Scheme 2).17 The described synthesis gave easy access to
linear oligomers, though a clear trend of decreasing yields was
observed for higher homologues (from 81% to 61%). In
addition, the macrocyclization proved to be inefficient using the
described procedure (1−18% yield). In the current work, we
report a detailed study of the synthesis of linear and cyclic
thiophene oligoamides, employing a variety of coupling
reagents under both conventional reaction conditions and
ultrasonication. This report discloses that ultrasound activation
combined with T3P as the peptide coupling reagent is the best
choice for our systems, leading to strong improvements and
allowing for the synthesis of compounds previously regarded as
“difficult”.
10
11
12
2b
2b
2b
1a
2c
2c
T3P, Et3N
24 h
2 d
3a
4a
4a
33
61
59
EDCI·HCl
PyBroP, 2,4,6-
collidine
24 h
13
14
15
16
17
18
19
20
21
22
2b
2b
2b
3b
3b
1b
1b
1b
1b
1b
2c
1a
2c
1a
2c
1a
2c
3c
4c
2c
T3P, Et3N
T3P, Et3N
T3P, Et3N
T3P, Et3N
T3P, Et3N
T3P, Et3N
T3P, Et3N
T3P, Et3N
T3P, Et3N
EDCI·HCl
24 h
4a
3a
4a
4a
5
38
b
30 min
77
b
60 min
75
b
20 min
11
b
60 min
38
b
5 min
2a
3a
4a
5
98
b
20 min
quant.
92
b
15 min
b
6 min
94
b
2 h
3a
68
a
EDCI·HCl = N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hy-
drochloride, BOP = benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate, TFFH = N,N,N′,N′-tetramethyl-
fluoroformamidinium hexafluorophosphate, DMAP
(dimethylamino)pyridine, DIPEA = N,N-diisopropylethylamine,
HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate, PyBroP = bromotripyrrolidinophosphonium
= 4-
b
hexafluorophosphate. Ultrasonic activation.
RESULTS AND DISCUSSION
■
To investigate the effect of the different coupling reagents on
extended chains, the amino and carboxylic acid moieties of
dimer 2a were deprotected selectively either by saponification
with lithium hydroxide or by hydrogenolysis employing
palladium (black) to obtain 2b and 2c, respectively (Scheme
2).17 These building blocks were then used for the chain
elongation. When the synthesis of 3a was carried out starting
from monomer 1a and dimer 2b, the yield dropped for all
coupling reagents (Scheme 3, Table 1: entries 8−10). This
trend continues further with the preparation of the linear
tetramer 4a by peptide coupling, starting from 2b and 2c
(entries 11−13). When the yields of the di-, tri-, and tetramers
prepared by different coupling reagents were compared, one
could clearly observe that the yields decreased for higher
oligomers, from 87% to 59% for PyBroP (entries 6, 9, 12) and
81% to 61% for EDCI·HCl (entries 5, 8, 11), respectively. This
To construct thiophene oligoamides via a sequence of peptide
couplings, monomers with unprotected amino and carboxylic
acid moieties, respectively 1a and 1b, were prepared according
to the literature procedures.17 Different coupling reagents were
employed to carry out the peptide coupling, affording the dimer
2a (Scheme 2, Table 1). No desired product 2a was observed
when BOP or TFFH was used in the presence of DMAP
(entries 1 and 2). By replacing DMAP with DIPEA, 68% of 2a
could be isolated with TFFH as coupling reagent (entry 3) and
32% with HATU (entry 4). These observations clearly show
that not only does the coupling reaction play an important role
but the type of amine base also seems to considerably influence
the efficiency of the amide bond formation. The best yields
were obtained with PyBroP/DIPEA, EDCI·HCl, and T3P/
Et3N (up to 87%, entries 5−7).
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Scheme 3. Synthesis of Trimer 3a, Tetramer 4a, and Pentamer 5
effect was observed more distinctly with the use of T3P where
the yield dropped from 80% to 33%, although most of the
starting material was recovered. The unreacted precursors did
not seem to contribute further to the desired coupling, even
when the reaction time was extended or additional reagent T3P
was added.
Scheme 4. Chain Elongation of Oligomeric Amides 3a, 4a,
and 5 with Monomer 1b Bearing the Free Carboxyl Group
This observation might be a result of the possible
conformation of the longer chain compounds. The active
carboxylic acid moiety could be shielded by intramolecular
folding and thus be less accessible to the coupling reagent,
hence resulting in less efficient couplings. To support this
hypothesis, ultrasonic activation was applied during the reaction
to overcome this proposed intramolecular folding. The
decrease in yield for longer amide chains is most apparent in
the case of T3P as coupling reagent (Table 1, entries 7, 10, and
13). Therefore, T3P was chosen as the coupling reagent for a
further optimization process. Under ultrasonification and using
T3P as coupling reagent, the yields of trimer 3a and tetramer
4a were enhanced to 77% and 75%, respectively (entries 14 and
15). As expected, the effect of ultrasonic activation is less
distinct when the prolongation was extended to higher
oligomer chains (tetramer 4a and pentamer 5), starting from
free carboxylic trimeric precursor 3b. The yields dropped to
11% and 38%, respectively (entries 16 and 17). Entries 14−17
clarify that the size of the oligomer with the free amino group
does not impact the yield much; however, the length of the
precursor with the free carboxylic acid does appear to have a
significant effect.
These observations seem to confirm our hypothesis that
deactivation of the carboxylic group for amide coupling is due
to intramolecular backfolding of the longer chain. Therefore,
we changed our strategy and carried out the extension of the
oligomer chain by successive peptide couplings with only
monomer 1b containing the unprotected carboxylic moiety
(Scheme 4). Under the same reaction conditions used
previously, the yields were enhanced in all cases up to
quantitative (entries 18−21). The reaction times were also
reduced from 1−2 days (without sonification) to 5−20 min.
Ultrasonication not only appears to unfold the oligomeric
chain, leading to a better accessibility of the functional groups,
but it also accelerates the coupling reaction itself. The latter can
be explained by the high cavitation energy from ultrasonication,
which easily overcomes the activation energy barrier. The
concentration plays an important role during sonification. The
T3P-mediated peptide coupling occurred much faster (only 5−
20 min) when high concentrations were applied while in the
case of high dilution, ultrasonification did not speed up the
reaction compared to conventional stirring.
Next we questioned whether the improvement of yields was
only a result of the sonification effect and the choice of a
suitable monomer (free carboxyl vs amino groups). To have a
better understanding, diamide 3a was prepared under the
optimized procedure above, but with EDCI·HCl as coupling
reagent. The reaction resulted in the desired product 3a with
68% yield (entry 22). Longer reaction times did not lead to the
completion of the transformation. Therefore, we can conclude
that the procedure using T3P as coupling reagent combined
with ultrasonification gives the optimal reaction conditions for
the synthesis of thiophene oligoamides. This optimized
procedure for amide coupling has been applied to synthesize
oligoamides containing more conventional amino amides. The
obtained results are very promising but out of the scope of this
work and will be reported in the near future.
The high occurrence of macrocyclic oligoamides in nature
encouraged our search for optimal cyclization conditions for
linear amide chains or starting from single monomers.58−60
With the tri- and tetramer chains in hand, a range of
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Scheme 5. Synthesis of Macrocyclic Amides 6−9
macrocycles can potentially be prepared by intramolecular
cyclization. Similar to the above couplings, the macrocycliza-
tions were subjected to an optimization process with different
coupling reagents and reaction conditions. As reported in our
preliminary study, EDCI·HCl-mediated macrocyclization of
tetramer 4d at a concentration of 0.004 mol/L gave after three
days 18% of the desired cyclic tetramer 6 with traces of cyclic
octamer 8 (Scheme 5, Table 2, entry 1).17 When PyBroP with
DIPEA was employed as coupling reagent, no cyclic tetramer 6
was obtained (entry 2), and only in the presence of 2,4,6-
collidine could 3% of octamer 8 be isolated (entry 3). The
combination of TFFH and DIPEA gave a low yield for 6
(12%), but no formation of 8 was observed (entry 4), while
TFFH with 2,4,6-collidine led to the formation of both
macrocycles 6 (3%) and 8 (3%, entry 5). With 2,4,6-collidine as
base, dimerization seemed to occur faster than the cyclization
leading to a higher yield of final cyclic octamer 8. We then used
T3P as coupling reagent with and without ultrasonication.
When the mixture of 4d and T3P was added dropwise to the
stirring solution of Et3N over one day followed by conventional
stirring for an additional three days, 31% of cyclic tetramer 6
and 16% of octamer 8 were obtained (entry 6). This protocol
created in situ a highly diluted solution leading to the expected
considerably higher yield of the smaller macrocycle. By
ultrasound activation of the entire mixture of precursor, T3P,
and Et3N, the reaction time for both intermolecular and
intramolecular amide interaction was decreased, and very much
to our pleasure the yields of 6 and 8 were strongly enhanced to
37% and 50%, respectively (entry 7). Starting from 4d, the
combination of the pseudo high dilution and ultrasonication
influenced the yields to the advantage of the cyclic tetramer 6
(46%) over the octamer 8 (21%). The high dilution and fast
reaction activation by ultrasound apparently favored cyclization
of the linear oligomers before they could dimerize.
Table 2. Reaction Conditions for Macrocyclization
linear
concn
product
(yield)
a
entry
117
oligomer
reagents
(mol/L)
time
3 d
4d
4d
4d
EDCI·HCl
0.004
0.004
0.004
6 (18%)
8 (traces)
2
3
PyBroP,
DIPEA
5 d
3 d
6 (0%)
8 (0%)
PyBroP,
2,4,6-
collidine
6 (0%)
8 (3%)
4
5
4d
4d
TFFH,
DIPEA
0.004
0.004
4 d
3 d
6 (12%)
8 (0%)
TFFH,
2,4,6-
collidine
6 (3%)
8 (3%)
b
6
4d
4d
4d
3d
3d
3d
3d
3d
T3P, Et3N
T3P, Et3N
T3P, Et3N
≤0.0002
1 d + 3 d
2 h
6 (31%)
8 (16%)
c
7
0.00025
≤0.0009
0.004
6 (37%)
8 (50%)
d
8
2 h + 2 h
5 d
6 (46%)
8 (21%)
9
TFFH,
DIPEA
7 (0%)
9 (0%)
1017
11
12
13
EDCI·HCl
T3P, Et3N
T3P, Et3N
T3P, Et3N
0.004
3 d
7 (1%)
9 (0%)
b
≤0.0004
4 d + 1 d
2 h + 2 h
1 h (gel)
7 (27%)
9 (0%)
d
0.0008
7 (33%)
9 (6%)
c
0.027
7 (26%)
9 (32%)
a
b
See footnote in Table 1 for abbreviations. Dropping of activated
linear oligomers into a stirring Et3N solution in CH2Cl2 followed by
c
d
stirring at rt. Sonification of the mixture. Dropwise addition of
activated linear oligomers in Et3N solution in CH2Cl2 under
ultrasound activation followed by additional sonification.
While in the case of tetrapeptide 4d TFFH-mediated
cyclization gave 12% of the cyclic derivative, no cyclic tri-,
hexa-, or nonamer was observed during the cyclization of linear
trimer 3d (Scheme 5, Table 2, entry 9). Even in a highly diluted
reaction mixture, the EDCI·HCl activation of 3d did not lead to
intramolecular macrocyclization. Only 1% of the cyclic hexamer
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7 was obtained (entry 10).17 The yield of 7 was increased to
27% when the slow addition method was applied in the
presence of T3P under conventional stirring (entry 11). For the
first time a cyclic nonamer 9 was isolated with 6% yield when
we combined the dropwise addition protocol with ultra-
sonification, and 33% of the hexacyclic peptide 7 was also
isolated (entry 12). When the concentration was raised to 0.027
mol/L, gel formation took place after 1 h of sonification. A
higher concentration of the reaction mixture led to a more
efficient formation of nonamer 9, resulting in a yield of 32%
with 26% of the hexamer 7 (entry 13). These observations
confirm the trend as described above. With higher concen-
tration, the reaction occurred faster and was more selective for
larger macrocycles.
solvent systems. With the first solvent system (hexane−
dichloromethane), two molecules of CH2Cl2 were incorporated
within the cavity, whereas 1,2-dichloroethane was too large and
only found around the molecule. The distortion of the inner
tert-butoxycarbonyl group out of the cavity plane created
enough space for CH2Cl2 to fill the opposite sites of the cavity.
As shown in Figure 2, a possible hydrogen bond can be formed
between the hydrogens of dichloromethane and the sulfur
atoms S3 and S3i of the macrocycle.
In the dichloromethane and 1,2-dichoroethane solvates of
compound 7 exist further voids of 560 and 438 Å3, respectively,
which are filled by disordered solvent molecules. The electron
density of these molecules was taken into account using the
program SQEEZE as integrated in the PLATON program
package. The positions of these voids in the unit cell are
depicted in Figure 3 using ball and stick and space-filling
models.
CRYSTALLOGRAPHIC DATA
■
In our previous work, the crystal structure of tetrameric amide
6 was reported as a molecule with a central core close to a
square (angles of 84.9° and 95.1°), in which the sp3-hybridized
carbon atoms C5−C11−C5i−C11i form the corners.17 The
cavity within the macrocycles was occupied by one hexane
molecule, employed as solvent for crystallization.
CONCLUSION
■
An efficient synthetic protocol has been developed for the
preparation of linear and cyclic oligoamides containing
thiophene moieties. Via a sequence of peptide couplings with
monomeric amino acids containing a free carboxylic acid
moiety, linear peptide chains were obtained with very high to
quantitative yields. The combination of T3P as coupling
reagent and ultrasonification proved to be the optimal reaction
conditions for a fast and high-yielding amide coupling. This
optimized procedure was applied to prepare cyclic amides. The
yields of the macrocycles with different sizes were selectively
raised by varying the concentration of the reaction mixture. As
expected, high dilution led to good yields of smaller
macrocycles, e.g., cyclic tetra- and hexamers, while increased
concentrations selectively gave higher quantities of cyclic octa-
and nonamers. Crystal structures of macrocyclic hexamer 7
revealed a chairlike solid-state structure with the central tert-
butoxycarbonyl groups filling the rectangular cavity.
Two different solvent systems were applied to crystallize
hexameric amide 7, namely slow diffusion of hexane into the
solution of 7 in CH2Cl2 and slow evaporation of 1,2-
dichloroethane as solvent. Compared to macrocycle 6, the
crystal structure of the hexameric amide 7 obtained from slow
evaporation of 1,2-dichloroethane showed a nearly chairlike
structure with a rectangular void with the angles of 87.3° and
93.7° (Figure 1). Taking the sp3-hybridized carbon atoms C5,
EXPERIMENTAL SECTION
■
1
General. H and 13C NMR spectra were recorded on commercial
250, 400, and 700 MHz instruments in CDCl3 solution, and chemical
shifts (δ) are reported in parts per million (ppm) referenced to
tetramethylsilane or the internal (NMR) solvent signals. Detailed
NMR peak assignments were obtained by analysis of DEPT, HSQC,
and COSY NMR spectra. The high resolution mass spectra were
obtained with an ESI-TOF spectrometer. Silica gel (0.040−0.063 mm)
was used for column chromatography. Melting points are not
corrected. X-ray crystallography: Single crystals for the X-ray
diffraction experiment were selected using a microscope and mounted
on the top of a glass fiber. Crystallographic data were collected using a
diffractometer using Mo Kα radiation (λ = 0.71073 Å, graphite
monochromator) at 133 K. Ultrasound bath with 35 kHz, 100%
power, was used for syntheses.
Figure 1. X-ray structure of hexameric amide 7 obtained from slow
evaporation of 1,2-dichloroethane (top view).
C11, C5i, and C11i for its four corners, the cavity had side
lengths of 7.4 (C5−C11) and 14.1 Å (C5−C11i). The chair
structure was derived from the direction in which the four tert-
butoxycarbonyl substituents are oriented. In pairs, they are
aimed in opposite directions (Figure 1). Interestingly, the cavity
of the macrocycle was not occupied by a solvent molecule but
by the opposed tert-butoxycarbonyl groups connected to the
C14 and C14i carbons (Figure 1). Due to sterical hindrance,
these ester groups did not lie in the same plane but above and
below the rectangle plane with an angle of 12.8° to 18.5°.
As mentioned above, two small differences were observed
between the two crystal structures of 7 obtained by different
The compounds 1a, 1b, 2b, 2c, 3c, 3d, 4c, and 4d have been
prepared according to the literature procedure.16,17
General Procedure for T3P-Mediated Peptide Couplings
under Ultrasonication (Scheme 4, Table 1; entries 18−21). To a
solution of amine (1 equiv) in CH2Cl2 were added carboxylic acid 1b
(1.2 equiv), T3P (2 equiv), and triethylamine (2 equiv). The mixture
was activated in the ultrasound bath at rt (5−20 min) under Ar
atmosphere, and the completion was followed by TLC. The crude
solution was washed with water (three times) and brine. After drying
of the organic layer with Na2SO4, the solvent was evaporated under
reduced pressure. Pure oligomers were obtained after purification by
column chromatography (silica gel).
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Figure 2. Top view (a) and side view (b) of macrocycle 7 containing two CH2Cl2 molecules in its cavity.
Figure 3. Packing of macrocycle 7 crystallized from CH2Cl2/hexane (a) and 1,2-dichloroethane (b).
Dimer 2a. According to general procedure, 60 mg of 1a (0.22
mmol) and 103 mg of 1b (0.26 mmol) in CH2Cl2 (5 mL) afforded
after 5 min sonification 143 mg of dimer 2a (143 mg, 98%); eluent
15% EtOAc in hexane; spectroscopic and physical properties agree
with previously published data.17
Trimer 3a. According to general procedure, 100 mg of 2c (0.20
mmol) and 92 mg of 1b (0.24 mmol) in CH2Cl2 (5 mL) afforded after
20 min sonification quantitative yield of trimer 3a (173 mg); eluent
30% EtOAc in hexane; spectroscopic and physical properties agree
with previously published data.17
Tetramer 4a. According to general procedure, 107 mg of 3c (0.14
mmol) and 92 mg of 1b (0.17 mmol) in CH2Cl2 (5 mL) afforded after
15 min sonification tetramer 4a (147 mg, 92%); eluent 10% EtOAc in
CH2Cl2; spectroscopic and physical properties agree with previously
published data.17
General Saponification Procedure of Methyl Esters. To a
solution of the ester (1 equiv) in THF/H2O (3:2) was added LiOH
(3−4 equiv). The mixture was stirred at rt, and the completion was
followed by TLC. After acidification by HCl (1 M) to pH 2, EtOAc
was added, and the solution was washed with water and brine and
dried with Na2SO4. The solvent was evaporated under reduced
pressure. Purification by column chromatography (silica gel, 9:1
CH2Cl2:MeOH) afforded pure carboxylic acid as a colorless solid.
Deprotected Trimer 3b. According to general saponification
procedure, 400 mg of 3a (0.45 mmol) and 33 mg of LiOH (1.38
mmol) in a mixture of THF/H2O (16 mL) afforded carboxylic acid 3b
(345 mg, 88%) as colorless solid; mp 164−166 °C; HRMS (ESI+)
calcd for C41H47N3O12S3Na 892.2220; found 892.2194; 1H NMR (400
MHz, CDCl3, 25 °C, TMS): δ = 11.26 (s, 1H, NH); 11.20 (s, 1H,
NH); 10.34 (s, 1H, NH); 7.41−7.33 (m, 5H, Ph); 7.08 (s, 1H,
thioph); 7.07 (s, 1H, thioph); 6.96 (s, 1H, thioph); 5.23 (s, 2H,
CH2Ph); 3.85 (s, 4H, CH2); 3.73 (s, 2H, CH2COO); 1.542, 1.515,
1.511 (3s, each 9H, t-Bu); 13C NMR (101 MHz, CDCl3, 25 °C,
TMS): δ = 166.73, 166.70 (CONH); 164.9, 164.8 (CO2t-Bu); 153.0
(Cbz); 149.9, 147.6, 147.4 (SCN); 135.5, 128.7, 128.66, 128.62 (Ph),
125.3, 124.4, 124.2 (thiophene), 124.6, 124.0, 123.1 (SCCH2); 115.0,
114.6, 113.5 (CCO2t-Bu); 81.9 (t-Bu); 68.1 (CH2Ph); 37.05, 37.04,
37.00 (CH2); 28.41, 28.37, 28.35 (t-Bu).
Procedure for Macrocyclizations (Scheme 5, Table 2). Cyclic
Octamer 6. To an activated solution of Et3N (20 μL, 0.14 mmol) in
CH2Cl2 (70 mL) in an ultrasound bath was added dropwise, over 2 h,
a mixture of linear tetramer 4d (69 mg, 0.071 mmol) and T3P (45 mg,
0.14 mmol). The solution was sonificated for an additional 2 h. The
crude solution was washed with water and brine. After drying the
organic layer with Na2SO4, the solvent was evaporated under reduced
pressure. Pure macrocycle 6 (31 mg, 46%) was obtained as a yellow
solid after purification by column chromatography (silica gel, eluent
1% MeOH in CH2Cl2). The spectroscopic and physical properties of
Pentamer 5. According to general procedure, 100 mg of 4c (0.10
mmol) and 48 mg of 1b (0.12 mmol) in CH2Cl2 (5 mL) afforded after
6 min sonification pentamer 5 (128 mg, 94%) as colorless solid; mp
190−192 °C; eluent 10% EtOAc in CH2Cl2; HRMS (ESI+) calcd for
1
C64H75N5O18S5K 1400.3342; found 1400.3316; H NMR (400 MHz,
CDCl3, 25 °C, TMS): δ = 11.26 (s, 1H, NH); 11.23 (s, 2H, NH);
11.19 (s, 1H, NH); 10.34 (s, 1H, NH); 7.42−7.34 (m, 5H, Ph); 7.08−
7.07 (m, 4H, thioph); 6.94 (s, 1H, thioph); 5.24 (s, 2H, CH2Ph); 3.84
(s, 8H, CH2); 3.71 (s, 3H, OMe); 3.68 (s, 2H, CH2COO); 1.54, 1.52,
1.51 (3s, 9H, 27H, 9H, t-Bu); 13C NMR (101 MHz, CDCl3, 25 °C,
TMS): δ = 170.8 (CO2Me); 166.64, 166.61, 166.57 (CONH); 164.88,
164.86, 164.76 (CO2t-Bu); 153.0 (Cbz); 149.9, 147.6, 147.3 (SCN);
135.5 (Ph); 128.8, 128.7, 128.6 (Ph); 125.3, 125.0, 124.5 (CHthioph);
124.4, 124.33, 124.31 (SCCH2); 123.7 (CHthioph); 123.1 (SCCH2);
114.97, 114.96, 114.5, 113.5 (CCO2t-Bu); 81.89, 81.87, 81.82, 81.7 (t-
Bu); 68.1 (CH2Ph); 52.5 (OMe); 37.1, 37.0, 35.0 (CH2); 28.42, 28.37
(t-Bu).
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Article
cyclic tetramer 6 agree with previously published data.17 A 14 mg
amount of 8 (21%) was obtained during this experiment.
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T3P (32 mg, 0.10 mmol), and Et3N (14 μL) in CH2Cl2 (200 mL) was
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A 3 mg amount of 9 (6%) was obtained during this experiment. Two
different solvent systems were employed to obtain crystals from 7,
namely by slow diffusion of hexane into the solution of 7 in CH2Cl2
and by slow evaporation of 1,2-dichloroethane as solvent.
Cyclic Nonamer 9. A solution of tetramer 3d (100 mg, 0.136
mmol), T3P (87 mg, 0.273 mmol), and Et3N (38 μL, 0.273 mmol) in
CH2Cl2 (5 mL) was activated in the ultrasound bath at rt for 1 h. The
crude solution was washed with water and brine. After drying the
organic layer with Na2SO4, the solvent was evaporated under reduced
pressure. Pure macrocycle 9 (31 mg, 32%) was obtained as an orange-
red solid after purification by column chromatography (silica gel,
eluent 4:1 EtOAc/hexane). Mp 135−137 °C; HRMS (ESI+) calcd for
C99H117N9O27S9Na 2175.5477; found 2175.5482; 1H NMR (250
MHz, CDCl3, 25 °C, TMS): δ = 11.22 (s, 9H, NH); 7.06 (s, 9H,
thioph); 3.83 (s, 18H, CH2); 1.49 (s, 81H, t-Bu); 13C NMR (176
MHz, CDCl3, 25 °C, TMS): δ = 166.6, 164.9 (CON); 147.7 (SCN);
124.7 (SCCH2); 124.3 (CHthioph); 115.0, 110.14 (CCO2t-Bu); 82.0 (t-
Bu); 37.0 (CH2); 28.4 (t-Bu). A 25 mg amount of 7 (26%) was
obtained during this experiment.
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■
S
* Supporting Information
Crystallographic data of macrocycle 7 and H and 13C NMR
1
spectra of new compounds 3b, 5, 8, and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Hans.Reissig@Chemie.FU-Berlin.de.
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■
The authors thank the Alexander von Humboldt Foundation
for a postdoctoral fellowship for T. H. Ngo, and Bayer
HealthCare for generous support. We gratefully acknowledge
support of H. Berndt by the Deutsche Forschungsgemeinschaft
(GKR 788). We also thank Dr. U. K. Wefelscheid for making us
familiar with T3P, and Archimica GmbH for providing this
crucial reagent.
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