Synthesis of aromatic and heteroaromatic oligoamides on methoxypoly(ethylene glycol) as solubilizing polymer support

Article abstract of DOI:10.1039/a904289j

A protecting-group-free procedure for the synthesis of short carbo- and heteroaromatic oligoamide chains on MeO-PEG as solubilizing support is introduced. Starting from nitrocarboxylic acids, oligoamides of carboxylic acids derived from N-methylpyrrole, N-methylimidazole and aniline are synthesized that contain up to five arene units. The polymer support facilitates work up procedures and markedly improves the otherwise poor solubility of the products. Each coupling step is monitored by 1H-NMR spectroscopy without cleavage of the product from the polymeric support.

Full text of DOI:10.1039/a904289j

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Synthesis of aromatic and heteroaromatic oligoamides on
methoxypoly(ethylene glycol) as solubilizing polymer support
Burkhard Konig,* Ulrich Papke and Martin Rodel
Institut fur Organische Chemie Universitat Regensburg, D-93040, Regensburg, Germany
Received (in Freiburg, Germany) 17th May 1999, Accepted 15th November 1999
A protecting-group-free procedure for the synthesis of short carbo- and heteroaromatic oligoamide chains on
MeO-PEG as solubilizing support is introduced. Starting from nitrocarboxylic acids, oligoamides of carboxylic
acids derived from N-methylpyrrole, N-methylimidazole and aniline are synthesized that contain up to Ðve arene
units. The polymer support facilitates work up procedures and markedly improves the otherwise poor solubility of
the products. Each coupling step is monitored by 1H-NMR spectroscopy without cleavage of the product from the
polymeric support.
Heteroaromatic oligoamides containing N-methylpyrrole (Py)
and N-methylimidazole (Im) amino acids are an essential part
of the structure of DNA-binding natural products, such as
netropsin1 or distamycin.2 Inspired by these compounds and
their properties, Dervan, Wemmer and others have developed
synthetic heteroaromatic oligoamides that bind sequence spe-
ciÐcally to DNA.3 The recently reported fascinating results of
highly speciÐc binding at nanomolar concentrations4 and in
vivo gene regulation5 by such compounds makes their future
application in gene therapy or biotechnology very likely.
Baird and Dervan have provided a procedure for the synthesis
of heteroaromatic oligoamides by automated solid phase syn-
thesis, by which even extended oligoamides are available in
almost every desirable combination using Boc-protected het-
eroaromatic amino acids as building blocks.6
We report here the synthesis of short heteroaromatic oli-
goamides on a soluble polymer support.7 A protecting-group-
free procedure using methoxypoly(ethylene glycol) (MeO-
PEG-OH), 1, with an average molecular weight of 5000 g
mol~1 as an inexpensive support8 provides practical access to
oligoamides for the synthesis of DNA binding agents or other
purposes. Readily available nitrocarboxylic acids are used as
the starting material. They are reduced to the corresponding
amine after being successfully coupled to the support. It is not
intended to provide a competing procedure to the reported
automated solid phase synthesis6 of extended oligoamides:
the well known restrictions of the MeO-PEG support in the
synthesis of large peptides9 and the difficulty of automa-
tization limit the synthesis to short oligoamides. However,
synthesis on a MeO-PEG-OH solid support does o†er some
advantages: the handling and characterization of insoluble
oligoamides is facilitated, commercially or readily available
nitro compounds are employed as starting materials and every
reaction step can be monitored by NMR without cleavage of
the oligoamide from the polymer. This promotes the opti-
mization of the coupling conditions for each step, which is
usually required because of the signiÐcant di†erences in reacti-
vity of aromatic and heteroaromatic amino acids in amide
bond formation. We provide here general procedures for oli-
goamide synthesis on a liquidÈsolid support and illustrate the
feasibility of the synthetic route by some examples.
ester linkage using standard conditions (Scheme 1). For puriÐ-
cation the polymer-bound product 3 is precipitated by addi-
tion of Et O and collected by Ðltration (see general procedure
2
2 in the Experimental section). The excess of acid chloride is
removed by washing with ether. In the next step the nitro
group is reduced with HCOONH ÈPd/C in methanol solu-
4
tion for 1 h at room temperature (see general procedure 1 in
the Experimental section). The catalyst is removed by Ðl-
tration over Celite and Et O is added to precipitate both the
2
amine and excess HCOONH . The solid is dissolved in
4
dichloromethane leaving behind excess HCOONH and the
obtained solution is used directly in the next reaction step.
4
Reaction with 2 leads to the polymer-bound amide 4 with
quantitative loading of the polymer, which is determined by
NMR spectroscopy (vide infra). Repetition of the reduction-
coupling cycle gives diamide 7, but the loading of the polymer
decreases to 55%. A polymer loading of 83% is obtained with
compound 5,10 which illustrates that the ester linkage of the
heteroarene chain to MeO-PEG is not fully stable under the
coupling conditions.11 Introduction of the next pyrrole yields
pure triamide 9, but the loading of the support decreases to
39%. Finally, the oligoamides are cleaved from the polymer
support by treatment with base, which provides 812 and 10 as
carboxylic acids in good yield (see general procedure 4 in the
Experimental section).
Fig. 1 shows part of the 1H-NMR spectra of 3 (top), 4
(middle) and 7 (bottom), making the growth of the oligoamide
chain visible. Resonance signals of N-methyl groups suc-
cessively appear, indicating the incorporation of a new pyrrole
ring. Comparison of the integral of each signal with the
methoxy resonance of MeO-PEG (d \ 3.37), which is used as
an internal standard, allows the determination of reaction
yields and polymer loading.
A particular advantage of oligoamide synthesis on a liquidÈ
solid support is the possibility to control the success of coup-
ling without cleavage from the polymer. This is illustrated by
the synthesis of N-methylimidazole N-methylpyrrole diamide,
15, in Scheme 2. Though the nitrocarboxylic acid 11 can be
coupled to the preceding amine, the reaction of compound 12,
after reduction, with 6 is not successful. The low reactivity of
the imidazole amine group in amide formation under stan-
dard conditions has been observed previously.6 To obtain 14
the use of 136 in the amide coupling is required, which was
conÐrmed by the analysis of the polymer-bound reaction pro-
ducts by NMR.
Results and discussion
In the Ðrst step 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chlo-
ride, 2,10 is quantitatively bound to MeO-PEG-OH (1) via an
Starting from the corresponding nitrocarboxylic acids new
aromatic or heteroaromatic amino acids, which have not been
New J. Chem., 2000, 24, 39È45
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000
39

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Fig. 1 Part of the 1H-NMR (400 MHz, CDCl ) spectrum of
3
polymer-bound N-methylpyrrole oligoamides. From top to bottom:
compounds 3, 4 and 7.
ring. Again, the success of amide formation for each step is
monitored by NMR. Compounds in which one amide linkage
is replaced by a urea moiety, such as 23, are obtained from the
reaction (Scheme 4) with nitroisocyanates (20).
Extended aromatic oligoamides are known for their low
solubility in organic solvents.13 The unique properties of the
MeO-PEG support facilitates the handling and character-
Scheme 1
used for the synthesis of oligoamides so far, can be introduced.
This is illustrated (Scheme 3) by the reaction of m-nitrobenzoic
acid, 16-OH, which leads to the synthesis of an analog, 19, of
the distamycin amide core in which the central N-
methylpyrrole unit is replaced by a 1,3-disubstituted benzene
Scheme 2
40
New J. Chem., 2000, 24, 39È45

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Scheme 3
Scheme 5
ization of such compounds markedly, as shown by the synthe-
sis of 30, 31 and 35 (see Schemes 5 and 6). With nitrobenzoic
acids as building blocks for oligoamide synthesis we observed
a constant quantitative loading of the polymer support and
complete conversion for all coupling and reduction steps up to
the tetraamide 34. The growth of the aromatic oligoamide
chain is monitored by the 1H-NMR resonances of the amide
signals of compounds 26, 28, 32 and 34 (Fig. 2, from top to
bottom).
Conclusion
In summary we have presented a simple and a†ordable pro-
cedure for the synthesis of short heteroaromatic and aromatic
oligoamides. The described synthesis on MeO-PEG as solid
support combines the convenience of solid phase procedures,
such as simpliÐed work up and removal of excess coupling
reagents, with the advantages of solution reactions, such as
short reaction times and the use of heterogeneous catalysts.
Starting from readily available nitrocarboxylic acids, carbo-
and heteroaromatic oligoamides with up to Ðve arene units
Scheme 4
New J. Chem., 2000, 24, 39È45
41

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Experimental
General
NMR spectra were recorded at 400 (1H) and 100 (13C) MHz
in [D]-chloroform solutions unless otherwise stated. The
multiplicity of the 13C signals was determined with the DEPT
technique and are denoted as (]) for CH or CH, and (C
)
3
quat
for quaternary carbons. Direct inlet EI mass spectra were
recorded at 70 eV on a double focusing sector Ðeld instrument
(Finnigan MAT, MS8430). The source temperature was set to
200 ¡C. High resolution experiments were performed at a
resolution of 10 000 (10% valley) by peak matching. In some
cases where molecular ion intensities were too low for exact
mass determination characteristic fragment ions (e.g., M`
[ CO ) were used instead. The percentage of polymer
2
loading with oligoamide product was determined from com-
parison of the integrals of the 1H-NMR resonance of the ter-
minal MeO-PEG methoxy group and a signiÐcant signal of
the oligoamide residue. Py and Im indicate pyrrole and imid-
azole amino acids, respectively. HOBt Æ H O stands for
2
hydroxybenzotriazole and DIEA for N,N-diisopropylethyla-
mine. mPh and pPh denote 1,3- and 1,4-benzoic amino acid,
respectively.
General procedure 1 (GP 1) for the reduction step
The MeO-PEG-bound nitro compound was dissolved in
methanol (not more than 100 ml). For large-scale reactions a
minimum amount of dichloromethane had to be added until
all of the solid was dissolved. Excess HCOONH and 10%
4
palladium on carbon were added, and the reaction mixture
was stirred for 1 h at room temperature. The start of the reac-
tion was indicated by the evolution of gas. In cases where this
could not be observed the reaction mixture was heated with a
heat gun for a short period. After 1 h at room temperature the
catalyst was removed by Ðltration over Celite and Et O was
2
added (250È1000 ml depending on the scale of the reaction) to
precipitate the generated MeO-PEG-bound amine and excess
Scheme 6
HCOONH . The solid was collected by suction and dissolved
4
in dichloromethane leaving behind excess HCOONH , which
were obtained, whereby neither protecting groups, nor expen-
sive chemicals or special apparatus are necessary. The synthe-
sis of libraries of oligoamides from nitrocarboxylic acids may
be envisaged. We hope that the reported procedure will make
heteroaromatic and aromatic oligoamides more widely avail-
able and stimulate their application in biotechnology or
separation techniques, such as new stationary chromatog-
raphy phases.14
4
was Ðltered o†. The obtained solution is directly used in GP 2
or GP 3.
General procedure 2 (GP 2) for coupling with acid chlorides
To the solution obtained from GP 1 or to a solution of MeO-
PEG-OH in dichloromethane, an excess of pyridine and 3È5
equiv. of the appropriate acid chloride were added and the
reaction mixture was stirred for 12 h. The product was pre-
cipitated by addition of Et O and collected by Ðltration. The
2
polymer was redissolved and precipitated twice for puriÐ-
cation, then dried in vacuo.
General procedure 3 (GP 3) for the coupling step with activated
acids
The appropriate acid (3È5 equiv.) was activated with DCC
and HOBt Æ H O (1.0 equiv. of each, corresponding to the
2
amount of acid) in DMF (25 ml) for 4 h. To this reaction
mixture the solution obtained from GP 1 was added, followed
by an excess of DIEA. After 12 h stirring at room temperature
the reaction mixture was Ðltered and the product was precipi-
tated by addition of Et O, and collected by Ðltration. The
2
polymer was redissolved, precipitated twice and dried in
vacuo.
General procedure 4 (GP 4) for the cleavage of oligoamide
from the polymer
Fig. 2 Amide proton resonance region of the 1H-NMR spectrum
The MeO-PEG-bound oligoamide was dissolved in 10 ml of
aqueous 2 N NaOH and stirred at room temperature for 12 h.
(400 MHz. CDCl ) of polymer-bound aromatic oligoamides. From
3
top to bottom: compounds 26, 28, 32 and 34. * denotes a noise signal.
42
New J. Chem., 2000, 24, 39È45

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The solution was acidiÐed with HCl, the precipitated oligo-
amide was collected by Ðltration and dried in vacuo.
(C ), 162.0 (C ). MS (EI) m/z (%) \ 492 (100) [M
quat
quat
[ CO ]`, 397 (18), 275 (49), 153 (36). HRMS: C
H
N O ,
2
23 24
8
5
[M [ CO ]` \ 492.1865 ^ 2 ppm.
2
Syntheses and product characterization
MeO-PEG–Py–Im–NO (12). Compound 3 (1.0 g, 0.2
2
MeO-PEG–Py–NO (3). MeO-PEG-OH (1, 50.0 g, 10.0
mmol) was reduced using GP 1 (HCOONH : 0.5 g, 7.9 mmol;
2
4
mmol) was allowed to react with 2 (5.67 g, 30.0 mmol) follow-
Pd/C: 100 mg) and was afterwards allowed to react with 11
ing GP 2 (pyridine: 10 ml) to yield 3 with quantitative loading
of the polymer. 1H-NMR: d \ 3.99 (s, 3H), 7.43 (d, 4J \ 2.0
Hz, 1H), 7.68 (d, 4J \ 2.0 Hz, 1H).
(136 mg, 0.8 mmol) following GP 3 (DCC: 247 mg, 1.2 mmol;
HOBt Æ H O: 162 mg, 1.2 mmol; DIEA: 1 ml) to yield 12 with
2
87% loading of the polymer. 1H-NMR: d \ 3.92 (s, 3H), 4.21
(s, 3H), 6.98 (d, 4J \ 2.0 Hz, 1H), 7.41 (d, 4J \ 2.0 Hz, 1H),
MeO-PEG–Py–Py–NO (4). Compound 3 (5.0 g, 1.0 mmol)
7.93 (s, 1H), 9.29 (s, 1H).
2
was reduced using GP 1 (HCOONH : 1.0 g, 15.9 mmol;
4
Pd/C: 100 mg) and subsequently allowed to react with 2 (567
MeO-PEG–Py–Im–Py–NO (14). Compound 3 (0.5 g, 0.2
2
mg, 3.0 mmol) following GP 2 (pyridine: 1 ml) to yield 4 with
quantitative loading of the polymer. 1H-NMR: d \ 3.90 (s,
3H), 4.03 (s, 3H), 7.05 (d, 4J \ 2.0 Hz, 1H), 7.45 (d, 4J \ 2.0
Hz, 1H), 7.60 (d, 4J \ 2.0 Hz, 1H), 7.68 (d, 4J \ 2.0 Hz, 1H),
8.98 (s, 1H).
mmol) was reduced using GP 1 (HCOONH : 0.9 g, 14.3
4
mmol; Pd/C: 50 mg) followed by reaction with 13 (88 mg, 0.3
mmol) according to GP
3 (DCC: 62 mg, 0.3 mmol;
HOBt É H O: 46 mg, 0.3 mmol; DIEA: 1 ml) to yield 14 with
2
61% loading of the polymer. 1H-NMR: d \ 3.92 (s, 3H), 4.05
(s, 3H), 4.10 (s, 3H), 6.89 (m, 1H), 7.44 (m, 1H), 7.48 (m, 1H),
7.49 (m, 1H), 7.64 (m, 1H), 9.05 (s, 1H), 9.16 (s, 1H).
MeO-PEG–Py–Py–Py–NO (7). Compound 3 (1.0 g, 0.2
2
mmol) was reduced using GP 1 (HCOONH : 0.5 g, 7.9 mmol;
4
Pd/C: 120 mg) and subsequently allowed to react with 5 (175
HO C–Py–Im–Py–NO (15). Compound 7 (293 mg, 0.054
2
2
mg, 0.6 mmol) following GP 3 (DCC: 124 mg, 0.6 mmol;
mmol) was treated according to GP 4 and yielded 10 mg
HOBt Æ H O: 92 mg, 0.6 mmol; DIEA: 1 ml) to yield 7 with
(0.024 mmol) of 15 (73%) as a yellow solid. Mp: 220 ¡C.
2
83% loading of the polymer. 1H-NMR: d \ 3.90 (s, 3H), 3.95
IR(KBr): l \ 3428, 1672, 1572 cm~1. UV(CH CN): j
(log
3
max
(s, 3H), 4.05 (s, 3H), 6.86 (d, 4J \ 2.0 Hz, 1H), 6.91 (s, 1H), 7.32
(s, 1H), 7.46 (d, 4J \ 1.5 Hz, 1H), 7.50 (d, 4J \ 1.5 Hz, 1H),
7.60 (d, 4J \ 1.5 Hz, 1H), 8.51 (s, 1H), 9.18 (s, 1H).
e) \ 192 (2.36), 236 (2.21), 292 (2.20) nm. 1H-NMR (400 MHz,
DMSO-d ): d \ 3.83 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.93 (d,
6
4J \ 2.0 Hz, 1H), 7.40 (d, 4J \ 1.9 Hz, 1H), 7.57 (s, 1H), 7.76
(d, 4J \ 2.0 Hz, 1H), 8.20 (d, 4J \ 2.0 Hz, 1H), 10.08 (s, 1H),
HO C–Py–Py–Py–NO (8)12. Compound 7 (400 mg, 0.074
10.80 (s, 1H). 13C-NMR (100 MHz, DMSO-d ): d \ 36.4 (]),
2
2
6
37.0 (]), 37.6 (]), 107.8 (]), 108.5 (]), 120.0 (C ), 120.6
quat
mmol) was treated according to GP 4 and yielded 21 mg (0.05
mmol) of 8 (70%) as a yellow solid. IR(KBr): l \ 3408, 2953,
(]), 122.0 (C ), 126.3 (C ), 126.8 (]), 128.4 (]), 134.0
quat
quat
1665, 1438 cm~1. UV(CH CN): j
(log e) \ 240 (4.36), 296
(C ), 135.6 (C ), 145.3 (C ), 157.1 (C ), 159.4 (C ),
3
max
quat
quat
quat
quat
quat
(4.43) nm. 1H-NMR (400 MHz, DMSO-d ): d \ 3.82 (s, 3H),
162.0 (C ). MS (EI) m/z (%) \ 414 (9) [M [ 1]`, 399 (100).
6
quat
3.86 (s, 3H), 3.96 (s, 3H), 6.85 (d, 4J \ 1.9 Hz, 1H), 7.05 (d,
4J \ 1.8 Hz, 1H), 7.26 (d, 4J \ 1.6 Hz, 1H), 7.42 (d, 4J \ 1.8
Hz, 1H), 7.59 (d, 4J \ 1.9 Hz, 1H), 8.18 (d, 4J \ 1.8 Hz, 1H),
9.94 (s, 1H), 10.28 (s, 1H), 12.16 (s, 1H). 13C-NMR (100 MHz,
MeO-PEG–Py–mPh–NO (17). Compound 3 (1.24 g, 0.25
2
mmol) was reduced using GP 1 (HCOONH : 0.33 g, 5.2
4
mmol; Pd/C: 120 mg) followed by reaction with m-
DMSO-d ): d \ 36.1 (]), 36.2 (]), 37.5 (]), 104.6 (]), 107.6
nitrobenzoic acid (16-OH, 567 mg, 3.0 mmol) according to GP
6
(]), 108.4 (]), 118.7 (]), 119.6 (C ), 120.3 (]), 121.5 (C ),
3 (DCC: 155 mg, 0.75 mmol; HOBt É H O: 115 mg, 0.75
quat
quat
quat
2
122.6 (C ), 122.9 (C ), 126.3 (C ), 128.3 (]), 133.8 (C ),
mmol; DIEA: 1 ml) to yield 17 with 86% loading of the
quat
quat
quat
quat
quat
156.9 (C ), 158.3 (C ), 162.0 (C ). MS (EI) m/z (%) \ 370
polymer. 1H-NMR: d \ 3.93 (s, 3H), 7.02 (d, 4J \ 2.0 Hz, 1H),
7.59 (d, 4J \ 2.0 Hz, 1H), 7.67 (t, 3J \ 8.0 Hz, 1H), 8.35 (m,
1H), 8.42 (m, 1H), 8.90 (m, 1H), 9.48 (s, 1H).
quat
(74) [M [ CO ]`, 275 (100).
2
MeO-PEG–Py–Py–Py–Py–NO (9). Compound 7 (620 mg,
2
0.12 mmol) was reduced using GP 1 (HCOONH : 0.45 g, 7.1
MeO-PEG–Py–mPh–Py–NO (18). Compound 17 (760 mg,
4
2
mmol; Pd/C: 50 mg) and subsequently allowed to react with 6
0.15 mmol) was reduced using GP 1 (HCOONH : 0.45 g, 7.1
4
(63 mg, 0.37 mmol) following GP 3 (DCC: 77 mg, 0.37 mmol;
mmol; Pd/C: 50 mg) and then allowed to react with 6 (76 mg,
0.45 mmol) following GP 3 (DCC: 93 mg, 0.45 mmol;
HOBt Æ H O: 57 mg, 0.37 mmol; DIEA: 1 ml) to yield 9 with
2
39% loading of the polymer. 1H-NMR: d \ 3.89 (s, 3H), 3.95
HOBt É H O: 69 mg, 0.45 mmol; DIEA: 1 ml) to yield 18 with
2
(s, 3H), 3.97 (s, 3H), 4.05 (s, 3H), 6.87 (m, 2H), 6.94 (m, 1H),
7.40 (m, 1H), 7.45 (m, 2H), 7.56 (m, 1H), 7.60 (m, 1H), 8.75 (s,
1H), 9.33 (br s, 2H).
56% loading of the polymer. 1H-NMR: d \ 3.92 (s, 3H), 4.07
(s, 3H), 6.90 (d, 4J \ 2.0 Hz, 1H), 7.44 (t, 3J \ 7.9 Hz, 1H),
7.57 (d, 4J \ 1.9 Hz, 1H), 7.65 (m, 2H), 7.70 (m, 1H), 8.09 (m,
1H), 8.15 (m, 1H), 9.01 (s, 1H), 9.14 (s, 1H).
HO C–Py–Py–Py–Py–NO (10). Compound 9 (754 mg,
2
2
0.137 mmol) was treated according to GP 4 and yielded 20 mg
(0.037 mmol) of 10 (82%) as a yellow solid. Mp: 245 ¡C
(decomp.). IR (KBr): l \ 3427, 1701, 1648 cm~1.
HO C–Py–mPh–Py–NO (19). Compound 18 (510 mg,
2
2
0.094 mmol) was treated according to GP 4 and gave 20 mg
(0.05 mmol) of 19 (92%) as a yellow solid. Mp: 225 ¡C
UV(CH CN): j
(log e) \ 192 (4.49) 240 (4.43), 300 (4.50),
(decomp).
IR(KBr):
l \ 3402,
1677,
1315
cm~1.
3
max
nm. 1H-NMR (400 MHz, DMSO-d ): d \ 3.82 (s, 3H), 3.85 (s,
UV(CH CN): j
(log e) \ 276 (4.47), 240 (4.42), 214 (4.44),
6
3
max
3H), 3.87 (s, 3H), 3.97 (s, 3H), 6.86 (d, 4J \ 1.8 Hz, 1H), 7.06
192 (4.42) nm. 1H-NMR (400 MHz, DMSO-d ): d \ 3.85 (s,
6
(m, 2H), 7.25 (d, 4J \ 1.5 Hz, 1H), 7.28 (d, 4J \ 1.5 Hz, 1H),
7.43 (d, 4J \ 1.8 Hz, 1H), 7.62 (d, 4J \ 1.9 Hz, 1H), 8.19 (d,
4J \ 1.7 Hz, 1H), 9.91 (s, 1H), 10.00 (s, 1H), 10.33 (s, 1H).
3H), 3.98 (s, 3H), 6.91 (d, 4J \ 1.4 Hz, 1H), 7.49 (m, 2H), 7.66
(d, 3J \ 7.6 Hz, 1H), 7.77 (d, 4J \ 1.6 Hz, 1H), 7.93 (d,
3J \ 8.0 Hz, 1H), 8.24 (m, 2H), 10.31 (s, 1H), 10.32 (s, 1H),
13C-NMR (100 MHz, DMSO-d ): d \ 36.1 ( ] ), 36.1 (]),
12.23 (br s, 1H). 13C-NMR (100 MHz, DMSO-d ): d \ 36.2
6
6
(]), 37.6 (]), 108.6 (]), 108.8 (]), 119.6 (]), 119.8 (C ),
quat
36.2 (]), 37.5 (]), 104.6 (]), 104.8 (]), 107.7 (]), 108.4 (]),
118.6 (]), 118.7 (]), 119.5 (C ), 120.3 (]), 121.5 (C ),
120.6 (]), 122.3 (]), 122.6 (C ), 122.9 (]), 126.0 (C ),
quat
quat
quat
quat
quat
122.2 (C ), 122.6 (C ), 122.7 (C ), 123.0 (C ), 126.3
128.7 (]), 128.8 (]), 133.9 (C ), 135.2 (C ), 138.9 (C ),
quat
(C ), 128.2 (]), 133.8 (C ), 156.9 (C ), 158.4 (C ), 158.5
quat quat quat quat
quat
quat
quat
quat
quat
158.6 (C ), 161.9 (C ), 163.6 (C ). MS (EI) m/z (%) \ 411
quat
quat
quat
New J. Chem., 2000, 24, 39È45
43

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(8) [M]`, 367 (100), 272 (84), 153 (36), 107 (20), 95 (22).
react with 24 (1.53 g, 8.25 mmol) following GP 2 (pyridine: 1.2
ml) to yield 29 with quantitative loading of the polymer. 1H-
NMR: d \ 7.46 (t, 3J \ 7.9 Hz, 1H), 7.79 (d, 3J \ 7.8 Hz, 1H),
7.92 (d, 3J \ 8.7 Hz, 2H), 8.01 (d, 3J \ 10.2 Hz, 2H), 8.3È8.4
(m, 6H), 9.44 (s, 1H), 10.04 (s, 1H).
HRMS: C
H
N O , [M]` \ 411.1175 ^ 2 ppm.
19 17
5 6
MeO-PEG–Py–mNHCONHPh–NO (21). Compound 3
2
(1.17 g, 0.23 mmol) was reduced using GP 1 (HCOONH : 0.5
4
g, 7.9 mmol; Pd/C: 60 mg) and then allowed to react with
HO C–pPh–pPh–pPh–NO (30). Compound 28 (4.55 g,
3-nitrophenyl isocyanate (20, 192 mg, 1.17 mmol) to yield 21
with 82% loading of the polymer. For puriÐcation the product
2
2
0.84 mmol) was treated according to GP 4 to yield 295 mg
(0.73 mmol) of 30 (86%) as a white solid. Mp: [300 ¡C.
was precipitated three times with Et O. 1H-NMR: d \ 3.89 (s,
2
IR(KBr): ln \ 3336, 1524, 1320 cm~1. UV(CH CN): j
(log
3H), 6.73 (d, 4J \ 2.0 Hz, 1H), 7.26 (d, 4J \ 1.8 Hz, 1H), 7.39
3
max
e) \ 196 (4.70), 298 (4.52) nm. 1H-NMR (400 MHz, DMSO-
(t, 3J \ 8.1 Hz, 1H), 7.78 (m, 1H), 7.85 (m, 1H), 8.04 (br s, 1H),
8.41 (m, 1H), 8.54 (s, 1H).
d ): d \ 8.08 (s, 4H), 8.09 (m, 2H), 8.16 (m, 2H), 8.31 (m, 2H),
6
8.46 (m, 2H), 10.61 (s, 1H), 10.97 (s, 1H). 13C-NMR (100 MHz,
MeO-PEG–Py–mNHCONHPh–Py–NO (22). Compound
DMSO-d ): d \ 119.6 (]), 119.8 (]), 123.7 (]), 126.0 (C ),
2
21 (0.65 g, 0.13 mmol) was reduced using GP 1 (HCOONH :
4
6
quat
quat
128.9 (]), 129.4 (]), 130.0 (C ), 130.3 (]), 140.4 (C ),
quat
142.1 (C ), 143.5 (C ), 149.4 (C ), 164.4 (C ), 165.4
quat quat quat quat
(C ), 167.3 (C ). MS (EI): m/z (%) \ 405 (8) [M]`, 269
quat quat
(100), 150 (19), 121 (18), 104 (16), 92 (10), 76 (9). HRMS:
0.5 g, 7.9 mmol; Pd/C: 50 mg) and was afterwards allowed to
react with 6 (66 mg, 0.39 mmol) following GP 3 (DCC: 80 mg,
0.39 mmol; HOBt É H O: 60 mg, 0.39 mmol; DIEA: 1 ml) to
2
yield 22 with 62% loading of the polymer. 1H-NMR: d \ 3.87
C
C
H
N O , [M]` \ 405.0955 ^ 2 ppm. Elem. anal.
21 15
3 6
(s, 3H), 4.02 (s, 3H), 6.70 (m, 1H), 7.2È7.3 (m, 3H), 7.42 (m, 1H),
7.53 (d, 4J \ 1.8 Hz, 1H), 7.61 (m, 1H), 7.68 (m, 1H), 7.74 (m,
1H), 7.92 (s, 1H), 8.72 (s, 1H).
H
N O : calcd. C 62.22, H 3.73, N 10.37; found C 62.24,
21 15
3 6
H 3.70, N 10.19%.
HO C–pPh–mPh–pPh–NO (31). Compound 29 (6.9 g, 1.28
2
2
mmol) was treated according to GP 4 to yield 454 mg (1.12
HO C–Py–mNHCONHPh–Py–NO (23). Compound 22
2
2
mmol) of 31 (88%) as a white solid. Mp: [300 ¡C. IR(KBr):
(285 mg, 0.053 mmol) was treated according to GP 4 and
yielded 12 mg (0.028 mmol) of 23 (86%) as a yellow solid. Mp:
230 ¡C. IR(KBr): l \ 3408, 1676, 1547, 1314 cm~1.
l \ 3315, 1645, 1526, 1323 cm~1. UV(CH CN): j
(log
3
max
e) \ 194 (4.65), 216 (4.46), 278 (4.47) nm. 1H-NMR (400 MHz,
DMSO-d ): d \ 7.57 (t, 3J \ 8.0 Hz, 1H), 7.76 (d, 3J \ 7.3
UV(CH CN): j
(log e) \ 256 (4.58), 216 (4.38), 192 (4.31)
6
3
max
Hz, 1H), 7.94 (m, 4H), 8.06 (m, 1H), 8.24 (m, 2H), 8.35 (s, 1H),
nm. 1H-NMR (400 MHz, DMSO-d ): d \ 3.81 (s, 3H), 3.91 (s,
6
8.40 (m, 2H), 10.61 (s, 1H), 10.81 (s, 1H). 13C-NMR (100 MHz,
3H), 6.65 (d, 4J \ 2.1 Hz, 1H), 7.15È7.25 (m, 3H), 7.29 (m, 1H),
DMSO-d ): d \ 119.5 (]), 120.2 (]), 123.3 (]), 123.6 (]),
7.73 (d, 4J \ 2.0 Hz, 1H), 7.93 (m, 1H), 8.22 (d, 4J \ 1.7 Hz,
1H), 8.30 (s, 1H), 8.66 (s, 1H), 10.09 (s, 1H). 13C-NMR (100
6
125.7 (C ), 128.9 (]), 129.3 (]), 130.3 (]), 135.4 (C ),
quat
quat
139.0 (C ), 140.3 (C ), 143.3 (C ), 149.3 (C ), 164.1
MHz, DMSO-d ): d \ 36.1 (]), 37.6 (]), 107.7 (]), 108.5
quat
(C ), 165.9 (C ), 167.0 (C ). MS (EI): m/z (%) \ 405 (6)
quat quat quat
[M]`, 269 (100), 150 (17), 121 (20), 104 (12), 92 (8), 76 (10).
quat
quat
quat
6
(]), 109.9 (]), 113.4 (]), 113.5 (]), 119.1 (]), 119.8 (C ),
quat
quat
122.7 (C ), 126.3 (C ), 126.8 (]), 128.8 (]), 133.8 (C ),
quat
quat
quat
HRMS:
anal. C
62.01, H 3.71, N 10.07%.
C
H
N O , [M]` \ 405.0955 ^ 2 ppm. Elem.
139.0 (C
), 140.4 (C ), 152.3 (C ), 158.4 (C ), 162.0
21 15
3 6
quat
quat
quat
H
N O : calcd. C 62.22, H 3.73, N 10.37; found C
(C ). MS (FAB~): m/z (%) \ 425 (4) [M [ 1]~, 306 (100).
21 15
3 6
quat
MeO-PEG–pPh–NO (25). 1 (50.0 g, 10.0 mmol) was
2
MeO-PEG–pPh–pPh–pPh–mPh–NO (32). Compound 28
allowed to react with 4-nitrobenzoyl chloride (24, 9.25 g, 50.0
2
(2.65 g, 0.49 mmol) was reduced using GP 1 (HCOONH : 1.0
4
mmol) following GP 2 (pyridine: 5 ml) to yield 25 with quan-
titative loading of the polymer. 1H-NMR: d \ 8.27 (m, 4H).
g, 15.9 mmol; Pd/C: 100 mg) and was afterwards allowed to
react with 16-Cl (454 mg, 2.45 mmol) following GP 2
(pyridine: 1.0 ml) to yield 32 with quantitative loading of the
polymer. 1H-NMR: d \ 7.68 (t, 3J \ 8.0 Hz, 1H), 7.96 (d,
3J \ 8.7 Hz, 2H), 8.1 (m, 10H), 8.31 (m, 1H), 8.74 (d, 3J \ 7.8
Hz, 1H), 9.04 (m, 1H), 10.05 (s, 1H), 10.19 (s, 1H), 10.81 (s, 1H).
MeO-PEG–pPh–pPh–NO (26). Compound 25 (11.5 g, 2.3
2
mmol) was reduced using GP 1 (HCOONH : 1.5 g, 23.8
4
mmol; Pd/C: 100 mg) followed by reaction with 24 (2.13 g,
11.5 mmol) according to GP 2 (pyridine: 1.6 ml) to yield 26
with quantitative loading of the polymer. 1H-NMR: d \ 7.93
(d, 3J \ 8.8 Hz, 2H), 8.05 (d, 3J \ 8.6 Hz, 2H), 8.31 (m, 4H),
9.69 (s, 1H).
HO C–pPh–pPh–pPh–mPh–NO (33). Compound 32 (920
2
2
mg, 0.167 mmol) was treated according to GP 4 to yield 60
mg (0.115 mmol) of 33 (69%) as a white solid. Mp: [300 ¡C.
IR(KBr): l \ 3325, 1650, 1519, 1321 cm~1. UV(CH CN): j
MeO-PEG–pPh–mPh–NO (27). Compound 25 (11.5 g, 2.3
3
max
2
(log e) \ 192 (4.39), 216 (4.33), 306 (4.37) nm. 1H-NMR (400
mmol) was reduced using GP 1 (HCOONH : 1.5 g, 23.8
4
MHz, DMSO-d ): d \ 7.88 (t, 3J \ 8.0 Hz, 1H), 7.9È8.1 (m,
mmol; Pd/C: 100 mg) and was afterwards allowed to react
6
12H), 8.46 (m, 2H), 8.84 (m, 1H), 10.45 (s, 1H), 10.48 (s, 1H),
with 3-nitrobenzoyl chloride (16-Cl, 2.13 g, 11.5 mmol) follow-
ing GP 2 (pyridine: 1.6 ml) to yield 27 with quantitative
loading of the polymer. 1H-NMR: d \ 7.70 (t, 3J \ 8.0 Hz,
1H), 7.97 (d, 3J \ 8.8 Hz, 2H), 8.05 (d, 3J \ 8.8 Hz, 2H), 8.38
(m, 1H), 8.50 (m, 1H), 8.99 (m, 1H), 9.74 (s, 1H).
10.87 (s, 1H). 13C-NMR (100 MHz, DMSO-d ): d \ 119.3
6
(]), 119.7 (]), 122.5 (]), 125.3 (C ), 126.3 (]), 128.58 (]),
quat
128.63 (]), 129.0 (C ), 129.6 (C ), 130.1 (]), 130.2 (]),
quat
quat
quat
134.2 (]), 135.9 (C
), 141.9 (C ), 142.5 (C ), 143.3
quat
quat
(C ), 147.7 (C ), 163.6 (C ), 165.1 (C ), 165.2 (C ),
quat
quat
quat
quat
quat
MeO-PEG–pPhÈpPhÈpPhÈNO (28). Compound 26 (8.25
166.9 (C ). MS (EI): m/z (%) \ 524 (2) [M]`, 507 (2), 480
(4), 388 (72), 286 (36), 269 (60), 150 (100), 120 (51), 104 (41), 76
2
quat
g, 1.65 mmol) was reduced using GP 1 (HCOONH : 1.5 g,
4
23.8 mmol; Pd/C: 100 mg) and was afterwards allowed to
(38). HRMS:
ppm. Elem. anal. C
N 10.33; found C 62.23, H 3.98, N 9.80%.
C
H
N O , [M [ CO ]` \ 480.1429 ^ 5
27 20
4
5
2
react with 24 (1.53 g, 8.25 mmol) following GP 2 (pyridine: 1.2
ml) to yield 28 with quantitative loading of the polymer. 1H-
NMR: d \ 8.00 (m, 8H), 8.28 (d, 3J \ 8.8 Hz, 2H), 8.38 (d,
3J \ 8.8 Hz, 2H), 9.53 (s, 1H), 10.18 (s, 1H).
H
N O (H O): calcd. C 61.99, H 4.09,
28 20
4
7
2
MeO-PEG–pPh–pPh–pPh–mPh–pPh–NO
(34). Com-
2
pound 32 (1.9 g, 0.35 mmol) was reduced using GP 1
MeO-PEG–pPh–mPh–pPh–NO (29). Compound 27 (8.25
(HCOONH : 1.0 g, 15.9 mmol; Pd/C: 100 mg) and then
2
4
g, 1.65 mmol) was reduced using GP 1 (HCOONH : 1.5 g,
4
allowed to react with 24 (320 mg, 1.73 mmol) following GP 2
23.8 mmol; Pd/C: 100 mg) and was afterwards allowed to
(pyridine: 1.0 ml) to yield 34 with quantitative loading of the
44
New J. Chem., 2000, 24, 39È45

View Article Online
2
3
F. Arcamone, S. Penco, O. Orezzi, V. Nicolella and A. Pirelli,
Nature (L ondon), 1964, 203, 1064.
polymer. 1H-NMR: d \ 7.80 (d, 3J \ 7.5 Hz, 1H), 7.92 (d,
3J \ 8.1 Hz, 1H), 7.97 (d, 3J \ 8.6 Hz, 2H), 8.1 (m, 11H), 8.25
(m, 3H), 8.43 (d, 3J \ 8.6 Hz, 2H), 9.89 (s, 1H), 9.91 (s, 1H),
10.12 (s, 1H), 10.55 (s, 1H).
M. Mrksich, W. S. Wade, T. J. Dwyer, B. H. Geierstanger, D. E.
Wemmer and P. B. Dervan, Proc. Natl. Acad. Sci. U.S.A., 1992,
89, 7586D. S. Johnson and D. L. Boger, in Comprehensive Supra-
molecular Chemistry, eds. J. Atwood, J. E. D. Davies, D. D. Mac-
nicol, F. Vogtle, J.-M. Lehn and Y. Murakami, Pergamon Press,
Oxford, 1996, vol. 4, p. 73 and cited references. P. E. Nielsen,
Chem. Eur. J., 1997, 3, 505 and cited references. G. Jia, H. Iida
and J. W. Lown, Chem. Commun., 1999, 119.
HO C–pPh–pPh–pPh–mPh–pPh–NO (35). Compound 34
2
2
(1160 mg, 0.207 mmol) was treated according to GP 4 to yield
100 mg (0.156 mmol) of 35 (75%) as a brownish solid. Mp:
[300 ¡C. IR(KBr): l3307, 1648, 1518, 1321 cm~1.
4
5
(a) J. W. Trauger, E. E. Baird and P. B. Dervan, Nature (L ondon),
1996, 382, 559; (b) J. M. Turner, E. E. Baird and P. B. Dervan, J.
Am. Chem. Soc., 1997, 119, 7636; (c) S. E. Swalley, E. E. Baird and
P. B. Dervan, Chem. Eur. J., 1997, 3, 1600; (d) S. E. Swalley, E. E.
Baird and P. B. Dervan, J. Am. Chem. Soc., 1997, 119, 6953.
J. M. GottesÐeld, L. Nealy, J. W. Trauger, E. E. Baird and P. B.
Dervan, Nature (L ondon), 1997, 387, 202.
UV(CH CN):
j
(log e) \ 194 (4.60), 252 (4.38) nm.
3
max
1H-NMR (400 MHz, DMSO-d ): d \ 7.59 (t, 3J \ 7.9 Hz,
6
1H), 7.79 (d, 3J \ 7.9 Hz, 1H), 7.9È8.1 (m, 13H), 8.24 (m, 2H),
8.40 (m, 3H), 10.45 (s, 1H), 10.46 (s, 1H), 10.61 (s, 1H), 10.81 (s,
1H), 12.74 (br s, 1H). 13C-NMR (100 MHz, DMSO-d ):
6
d \ 119.3 (]), 119.4 (]), 120.1 (]), 123.2 (]), 123.5 (]),
6
7
8
E. E. Baird and P. B. Dervan, J. Am. Chem. Soc., 1996, 118, 6141.
B. Konig and M. Rodel, Chem. Commun., 1998, 605.
123.6 (]), 125.2 (C ), 128.6 (]), 128.8 (]), 129.0 (C ),
quat
quat
129.2 (]), 130.1 (]), 135.3 (C
), 138.9 (C ), 140.2 (C ),
For the use of polyethylene glycol as a support in synthesis, see:
M. Mutter, H. Hagenmaier and E. Bayer, Angew. Chem., 1971,
83, 883; Angew. Chem., Int. Ed. Engl., 1971, 10, 811; R. N. V.
Pillai and M. Mutter, Top. Curr. Chem., 1982, 106, 119; com-
binatorial libraries: H. Han, M. M. Wolfe, S. Brenner and K. D.
Janda, Proc. Natl. Acad. Sci. U.S.A., 1995, 92, 6419.
quat
142.4 (C ), 142.5 (C ), 143.4 (C ), 149.2 (C ), 164.0
quat quat quat quat
(C ), 165.1 (C ), 165.2 (C ), 165.7 (C ), 166.9 (C ).
quat
quat
quat
quat
quat
quat
quat
MS (EI): m/z (%) \ 599 (0.1) [M [ CO ]`, 507 (2), 286 (18),
269 (16), 167 (21), 150 (35), 120 (100). Elem. anal.
2
C
H
N O (H O): calcd. C 63.54, H 4.11, N 10.59; found C
9
D. J. Gravert and K. D. Janda, Chem. Rev., 1997, 97, 489.
35 25
5
8
2
63.46, H 4.04, N 10.08%.
10 J. W. Lown and K. Krowicki, J. Org. Chem., 1985, 50, 3774.
11 This limitation of PEG supports has been described for other
peptide syntheses earlier. For examples, see ref. 9.
12 (a) J. S. Taylor, P. G. Schultz and P. B. Dervan, T etrahedron,
1984, 40, 457; (b) M. Bialer, B. Yagen and R. Mechoulam, T etra-
hedron, 1978, 34, 2389.
13 (a) H. Bredereck and H. von Schuh, Chem. Ber., 1948, 81, 215; (b)
S. Gould and D. A. Laufer, J. Magn. Reson., 1979, 34, 37.
14 B. Konig, H. Buchholz, M. Rodel and M. Schulze, DE Pat. 198
05 431.9, 1998; European, Japanese and US patents pending.
Acknowledgements
This work was supported by the Fonds der Chemischen
Industrie. M.R. thanks the Land Niedersachsen, Germany, for
a graduate fellowship.
References
1
A. C. Finlay, F. A. Hochstein, B. A. Sobin and F. X. Murphy, J.
Am. Chem. Soc., 1951, 73, 341.
Paper a904289j
New J. Chem., 2000, 24, 39È45
45