Synthesis of geometrically constrained unsymmetrical bis(polyamides) related to the antiviral distamycin

Article abstract of DOI:10.1002/1099-0690(200006)2000:11<2095::AID-EJOC2095>3.0.CO;2-J

Analysis of the structural and stereochemical requirements for the strict DNA base-sequence recognition of (AT)₄ and (AT)₅, respectively, for the oligopeptide minor-groove binding agents netropsin (I) and distamycin (II) leads to proposals for the rational structure modification for altered base recognition. In this paper we report the synthesis of unsymmetrical imidazo-pyrrolo-bis(polyamides), structurally related to the natural antiviral agents distamycin, and bearing either unnatural (25-27) or natural (31-33) termini linked by a flexible or rigid linker. This is the first report of the synthesis of an imidazole-bearing structure with either dimethylaminopropyl or amidinium termini in the linked bis(polyamides).

Full text of DOI:10.1002/1099-0690(200006)2000:11<2095::AID-EJOC2095>3.0.CO;2-J

FULL PAPER
Synthesis of Geometrically Constrained Unsymmetrical Bis(polyamides)
Related to the Antiviral Distamycin
Sanjay K. Sharma,[a] Manju Tandon,[a] and J. William Lown*[a]
Keywords: Antiviral agents / DNA recognition / Distamycin / Polyamides / Unsymmetrical polyamides
Analysis of the structural and stereochemical requirements
for the strict DNA base-sequence recognition of (AT)4 and
(AT)5, respectively, for the oligopeptide minor-groove bind-
imidazo-pyrrolo-bis(polyamides), structurally related to the
natural antiviral agents distamycin, and bearing either un-
natural (25−27) or natural (31−33) termini linked by a flex-
ing agents netropsin (I) and distamycin (II) leads to proposals ible or rigid linker. This is the first report of the synthesis of
for the rational structure modification for altered base recog- an imidazole-bearing structure with either dimethylamino-
nition. In this paper we report the synthesis of unsymmetrical
propyl or amidinium termini in the linked bis(polyamides).
Introduction
severe; this is manifested by a trend of weaker binding with
higher homologs.[6] One solution to this phasing problem is
to synthesize extended bis(polyamides) tethered by a linker
of appropriate dimensions.[7]
Antiviral chemotherapy continues to be one of the most
important means of controlling viral diseases.[1] One of the
most challenging problems in the use of drugs in the treat-
ment of human diseases is specificity. Recently, it has be-
come evident that DNA-sequence selectivity is an import-
ant component contributing to the cytotoxic potency of
several chemotherapeutic agents.[2] Therefore, the question
arises as to whether one could tailor the binding preference
of DNA binding agents to particular base sequences and
thereby produce new drugs that might prove effective clinic-
ally and might complement efforts in the antisense or triple
helix antigene area. Netropsin (I)[3] and distamycin (II)[4]
(Figure 1) have served as prototype DNA-sequence selective
minor-groove binding agents. However, in an attempt to
bind longer sequences of DNA the empirical (n ϩ 1) rule[5]
cannot be extended indefinitely because, as the number of
repeating units increases, the mismatching becomes more
Studies conducted in our group on murine leukemic re-
trovirus (MuLV),[8] HIV-1 integrase[9] and Okazaki frag-
ments[10] have shown that the inclusion of a flexible polyme-
thylene or fumaryl linker, or a para arrangement of dista-
mycin moieties on either benzene or pyridine, confers in
vitro inhibitory activities against HIV-1 and HIV-2 inte-
grase in nanomolar concentrations[9] and comparable po-
tency against the other targets. However, because of the
presence of unnatural dimethylaminopropyl termini (ini-
tially employed for reasons of chemically stability), these
linked polyamides have limited cellular uptake and hence
low in vivo selectivity and limited clinical application. En-
couraged by the high potency and selectivity in vitro, how-
ever, we have designed new unsymmetrical bis(polyamides)
containing an imidazole moiety on one side of these active
linkers and pyrrole on the other side so as to refine the
drug targeting of the proviral U3LTR region.[9] Imidazole
is introduced for the first time in the bis(polyamides) to
change base-site recognition selectively from AT to GC in
the minor groove of B-DNA[11] in order to permit targeting
of mixed DNA sequences and to thereby investigate the ef-
fect of DNA sequence selectivity on drug efficacy. These
unsymmetrical polyamides were also synthesized with
either dimethylaminopropyl or amidinium termini in order
to explore their potential against HIV type 1 and FIV inte-
grase in vitro and in vivo.
Results and Discussion
Figure 1. Netropsin (I), Distamycin (II)
[a]
Department of Chemistry, University of Alberta,
Compounds 1 and 2 were synthesized by the reported
procedure.[12] Subsequent condensation with 3-(dimethyl-
amino)propylamine or 3-aminopropionitrile fumarate in
Edmonton, AB, Canada T6G 2G2
Fax: (internat.) ϩ 1-780/492-8231
E-mail: annabella.wiseman@ualberta.ca
Eur. J. Org. Chem. 2000, 2095Ϫ2103
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0611Ϫ2095 $ 17.50ϩ.50/0
2095

S. K. Sharma, M. Tandon, J. W. Lown
FULL PAPER
Scheme 2. a ϭ SOCl2, MeOH, 90%; b ϭ NaClO2, H2NSO3H,
H2O, 80%
commercially available while pyridine-2,5-dicarboxylic acid
5-methyl ester (IV) was synthesized by the reported proced-
ure.[13a] Terephthalic acid monomethyl ester was synthe-
sized by a new and convenient strategy (Scheme 2). 4-Car-
boxybenzaldehyde (available commercially) was converted
into the 4-formylbenzoic acid methyl ester (11) in 90% yield
by reaction with SOCl2 in MeOH. This reaction was fol-
lowed by sodium chlorite and sulfamic acid-mediated
Swern oxidation affording terephthalic acid monomethyl es-
Scheme 1.
a
ϭ
H2N(CH2)3N(CH3)2 or H2NCH2CH2CN -
0.5HOOCCHϭCHCOOH, THF, 90%; b ϭ H2, Pd/C, MeOH, 1 or
2, 80%
THF gave the compounds 3؊6 (Scheme 1). A Pd/C-facilit- ter (12) in 80% yield. This procedure is convenient and
ated reduction of 3 and coupling with 1 resulted in a dipyr- straightforward and proceeds with higher yields than the
role unit which was again reduced by Pd/C and coupled earlier methods.[13b]Ϫ[13d] Catalytic reduction of 8 afforded
with 1 to give 7. Compounds 8؊10 were synthesized in a an unstable amine, which was coupled with the acid group
similar manner. Fumaric acid monoethyl ester (III) was of the linker III, catalyzed by DCC/HOBt in anhydrous
Table 1. Synthesis of unsymmetrical bispolyamide
2096
Eur. J. Org. Chem. 2000, 2095Ϫ2103

Geometrically Constrained Bis(polyamides) Related to the Antiviral Distamycin
Table 2. Substitution on intermediates and unsymmetrical products
FULL PAPER
DMF, to give an intermediate 13 in 40% yield. Interme- those of Baksheev et al.[14c] that the first step of the reaction
diates 14 and 15 were synthesized similarly from tere- of the cyano group, i.e. formation of the imino ester with
phthalic acid monomethyl ester (12) and pyridine-2,5-dicarb- an alcohol in the presence of hydrogen chloride, is com-
oxylic acid monomethyl ester (IV), respectively (Table 1 and pleted in 90 min, and that longer reaction times promote
2). However, when the same strategy was applied for coup- side reactions resulting in lower yields. The imino ester re-
ling the reduced product of 10 with the acid end of the acts readily with ammonia in ethanolic solution within 1 h
linker III, the coupling afforded low yields and, because of at ambient temperature to afford amidinium termini.
the high polarity of the intermediate, it was very difficult to
purify, thereby further lowering the overall yield.
Conclusions
Therefore, we reduced compound 9 in a similar way and
coupled the resulting amine with the acid functionalities of
the linker III to afford intermediate 16 in 40% yield. Inter-
mediates 17 and 18 were synthesized similarly by coupling
the acid group of the linker terephthalic acid monomethyl
ester (12) or pyridine-2,5-dicarboxylic acid monomethyl es-
ter (IV), respectively. The ester linkages in 13؊18 were then
hydrolyzed with ethanolic sodium hydroxide, and the cor-
responding sodium salt of the acids were acidified with
Dowex-Hϩ resin to afford the acid intermediates 19؊24.
The synthesis of the unsymmetrical polyamides was ac-
complished by coupling the appropriate unstable amine, ob-
tained from the Pd/C reduction of 7 with the acid func-
tionality of 19, catalyzed by DCC/HOBt in dry DMF, to
give the unsymmetrical imidazo-pyrrolo-bis(polyamide) 25,
bearing a dimethylaminopropyl terminus, in 44% yield. The
bis(polyamides) 26 and 27 were synthesised similarly from
21 and 23 respectively (Table 1 and 2). The reduced amine
of 10 was similarly coupled with 20 to afford the imidazo-
pyrrolo-bis(polyamide) 28, with a propionitrile terminus, as
were 29 and 30 from 22 and 24 coupled with the reduced
amine of 10. Compounds 28Ϫ30 were subjected to a modi-
fied Pinnar reaction[14] to give 31Ϫ33, respectively, with
Encouraged by the high in vitro potency and selectivity
of the symmetrical pyrrolo-bis(polyamides) with unnatural
dimethylaminopropyl termini against HIV-1 and HIV-2
integrase, leukemic retrovirus (MuLv) and Okazaki frag-
ments, we designed and synthesised imidazo-pyrrolo-bis-
(polyamides) 25؊31 linked by the geometrically con-
strained linkers III, IV and 12. Imidazole in the extended
polyamides is incorporated for the first time for the recogni-
tion of GC sequences in the minor groove of B-DNA.
These unsymmetrical bis(polyamides) are synthesised with
the unnatural termini 25؊27 and also with the natural ami-
dinium termini 31؊33. In the course of this work tere-
phthalic acid monomethyl ester (12) is synthesised by a new
and convenient route. These compounds are currently un-
dergoing biological evaluation at the NIH.
Experimental Section
General: Melting points were determined with an electrothermal
melting point apparatus and are uncorrected. All chemicals used
were of reagent grade. Dimethylformamide (DMF), methanol
natural amidinium termini. Our observations agree with (MeOH) and tetrahydrofuran (THF) were of anhydrous grade pro-
Eur. J. Org. Chem. 2000, 2095Ϫ2103 2097

S. K. Sharma, M. Tandon, J. W. Lown
FULL PAPER
cured from Aldrich Chemical Co. and were used without further
purification. Freshly distilled dichloromethane was used. Ϫ The
progress of the reactions was monitored by thin layer chromato-
graphy using precoated silica gel 60F 254, E. Merck TLC plates
visualizing under UV light. Ϫ 1H NMR spectra were recorded with
a Bruker (300 MHz) spectrometer with tetramethylsilane (TMS) as
internal standard on the δ scale. Multiplicity of resonance peaks
are indicated as singlet (s), broad singlet (br s), doublet (d), quadru-
plet (q), triplet (t) and multiplet (m). Ϫ Mass-spectrometric analysis
was performed by positive-mode electrospray ionization with Mic-
romass ZapSpec Hybrid Sector-TOF.
(CN), 36.4 (NϪCH3), 34.8 (NCH2CH2CN), 17.2 (CH2CH2CN).Ϫ
HRMS: calcd. for C8H10N5O3 224.078; found 224.078 (Mϩ ϩ H,
100%); calcd. C 41.18, H 8.21, N 30.03; found C 41.15, H 8.30,
N 30.09.
N-[(3-(Dimethylamino)propyl]-1-methyl-4-[(1-methyl-4-nitropyrrole-
2-carboxamido)pyrrole-2-carboxamido]pyrrole-2-carboxamide (7). ؊
General Procedure: Catalytic hydrogenation using Pd/C (10%,
400 mg) of compound 3 (1.00 g, 378 mmol) in DMF/MeOH (1:1,
v/v) afforded an unstable amine which was dried, in order to re-
move traces of MeOH, and redissolved in dry DMF maintained at
0 °C and a solution of 1 (1.03 g, 378 mmol) in anhydrous THF
(10 mL) was added to it slowly. The reaction mixture was slowly
brought to room temperature and stirred at this temperature for
18 h. The solvent was removed in vacuo and the residue was puri-
fied on silica gel CH2Cl2/MeOH/NH4OH (80:20:0.5).This gave a
dipyrrolodicarboxamide intermediate which was again reduced and
allowed to react with 1 in a similar way as above to give a crude
product of the triamide which was purified on a silica gel column
using CH2Cl2/MeOH/NH4OH (80:20:2) as eluent to afford pure
N-[3-(Dimethylamino)propyl]-1-methyl-4-nitropyrrole-2-carbox-
amide (3). ؊ General Procedure: A solution of 3-dimethylamino-
propylamine (0.45 mL, 3.68 mmol) in anhydrous tetrahydrofuran
was added slowly to a stirred solution of 1 (1.00 g, 3.68 mmol) at
0 °C and then the temperature of the reaction was raised to room
temperature after complete addition. Stirring was continued for an
additional 2 h. Evaporation of the solvent and crystallization of the
product in hexane/CH2Cl2 (3:1, v/v) afforded pure 3, 96% yield, as
1
1
pale yellow needles, m.p. 120Ϫ122 °C. Ϫ H NMR ([D6]DMSO):
7, 78% yield, as a yellow powder, m.p. 118Ϫ121 °C. Ϫ H NMR
δ ϭ 1.59 (q, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 2.15 (s, 6 H,
N(CH3)2), 2.25 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.15 (dt, J ϭ
6.0 Hz, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.95 (s, 3 H, NϪCH3),
7.45 (d, J ϭ 2.0 Hz, 1 H, PyH), 8.15 (d, J ϭ 2.0 Hz, 1 H, PyH),
8.45 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2). Ϫ 13C NMR
([D6]DMSO): δ ϭ 161.1 (CϭO), 133.7, 128.1, 123.2, 107.5(PyϪC),
56.3 (NCH2CH2CH2N), 44.3 [N(CH3)2], 37.4 (NϪCH3), 37.1
([D6]DMSO): δ ϭ 1.60 (q, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 2.16
[s, 6 H, N(CH3)2], 2.28 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.18
(t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.78 (s, 3 H, NϪCH3), 3.86
(s, 3 H, NϪCH3), 3.90 (s, 3 H, NϪCH3), 6.84 (d, J ϭ 2.0 Hz, 1 H,
PyϪH), 7.04 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.14 (d, J ϭ 2.0 Hz, 1
H, PyϪH), 7.20 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.25 (d, J ϭ 2.0 Hz,
1 H, PyϪH), 7.38 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.09 (t, J ϭ 6.0 Hz,
1 H, CONHCH2CH2CH2N), 9.90 (s, 1 H, CONH), 10.02 (s, 1 H,
CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 161.1, 158.3, 156.9 (Cϭ
O), 133.7, 128.1, 126.2, 123.0, 122.9, 122.0, 121.4, 118.5, 117.8,
107.6, 104.5, 104.1 (PyϪC), 56.4 (NCH2CH2CH2N), 44.2
[N(CH3)2], 37.4 (NϪCH3), 36.7 (CH2CH2CH2N), 36.1, 35.9
(NϪCH3), 26.4 [CH2N(CH3)2]. Ϫ HRMS: calcd. for C23H31N8O5
499.241; found 499.241 (Mϩ ϩ H, 100%); calcd. C 55.40, H 6.07,
N 22.48; found C 55.9, H 6.13, N 22.53.
(CH2CH2CH2N), 26.4 [CH2N(CH3)2].
Ϫ HRMS: calcd. for
C11H19N4O3 255.145; found 255.146 (Mϩ ϩ H, 100%); calcd. C
51.94, H 7.14, N 22.04; found C 51.97, H 7.15, N 22.10.
The following compounds were prepared using this procedure.
N-[3-(Dimethylamino)propyl]-1-methyl-4-nitroimidazole-2-carbox-
amide (4): 98% yield, as pale yellow needles, m.p. 132 °C. Ϫ 1H
NMR ([D6]DMSO): δ ϭ 1.76 (q, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N),
2.28 [s, 6 H, N(CH3)2], 2.40 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N),
3.15 (dt, J ϭ 7.0 Hz, J ϭ 6.0 Hz, 2 H, CH2CH2CH2N), 4.12 (s,
3 H, NϪCH3), 7.75 (s, 1 H, Im 5-H), 8.40 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2CH2). Ϫ 13C NMR ([D6]DMSO): δ ϭ 157.5 (Cϭ
O), 144.2, 137.7, 126.3, (ImϪC), 56.5 (NCH2CH2CH2N), 44.7
[N(CH3)2], 37.1 (CH2CH2CH2N), 36.4 (NϪCH3), 26.5
[CH2N(CH3)2]. Ϫ HRMS: calcd. for C10H18N5O3 256.140; found
256.140 (Mϩ ϩ H, 100%); calcd. C 47.03, H 6.72, N 27.44; found
C 47.10, H 6.74, N 27.63.
The following compounds were prepared in a similar way.
N-[(3-(Dimethylamino)propyl]-1-methyl-4-[(1-methyl-4-nitroimid-
azole-2-carboxamido)imidazole-2-carboxamido]imidazole-2-carbox-
1
amide (8): 80% yield, as a yellow powder, m.p. 212Ϫ215 °C. Ϫ H
NMR ([D6]DMSO): δ ϭ 1.70 (q, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N),
2.25 [s, 6 H, N(CH3)2], 2.40 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N),
3.26 (t, J ϭ 7.0 Hz, 2 H, CH2CH2ϪCH2N), 3.96 (s, 3 H, NϪCH3),
4.05 (s, 3 H, NϪCH3), 4.07 (s, 3 H, NϪCH3), 7.50 (s, 1 H, Im 5-
H), 7.68 (s,
1 H, Im 5-H), 8.40 (t, J ϭ 6.0 Hz, 1 H,
N-(2-Cyanoethyl)-1-methyl-4-nitropyrrole-2-carboxamide (5): Syn-
CONHCH2CH2CH2N), 8.65 (s, 1 H, Im 5-H), 9.70 (s, 1 H,
CONH), 10.30 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ
158.6, 155.5, 155.3 (CϭO), 144.6, 137.3, 135.0, 134.8, 134.7, 133.7,
127.0, 116.1, 113.8 (ImϪC), 56.9 (NCH2ϪCH2CH2N), 45.0
[N(CH3)2], 37.1 (CH2CH2CH2N), 36.6, 35.4, 35.3 (NϪCH3), 26.9
[CH2NϪ(CH3)2]. Ϫ HRMS: calcd. for C20H28N11O5 502.227;
found 502.227 (Mϩ ϩ H, 100%); calcd. C 47.88, H 5.43, N 30.73;
found C 47.90, H 5.50, N 30.90.
thesized using 3-aminopropionitrile fumarate in 92% yield, as pale
yellow needles, m.p. 118Ϫ120 °C. Ϫ H NMR ([D6]DMSO): δ ϭ
1
2.75 (t,
J ϭ 6.0 Hz, 2 H, CH2CH2CN), 3.45 (q, 2 H,
NHCH2CH2CN), 3.95 (s, 3 H, NCH3), 7.45 (d, J ϭ 2.0 Hz, 1 H,
PyϪH), 8.17 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.85 (t, J ϭ 6.0 Hz, 1
H, COϪNHCH2CH2CN). Ϫ 13C NMR ([D6]DMSO): δ ϭ 171.3
(CϭO), 133.7, 128.4, 123.4 (PyϪC), 119.3 (CN), 107.9 (PyϪC),
50.3 (NϪCH3), 31.8 (NCH2CH2CN), 21.8 (CH2CH2CN). Ϫ
HRMS: calcd. for C9H11N4O3 223.081; found 223.083 (Mϩ ϩ H,
100%); calcd. C 48.63, H 4.54, N 25.22; found C 48.64, H 4.57,
N 26.23.
N-(2-Cyanoethyl)-1-methyl-4-[(1-methyl-4-nitropyrrole-2-carbox-
amido)pyrrole-2-carboxamido]pyrrole-2-carboxamide (9): 75% yield,
1
as a yellow powder, m.p. 284Ϫ287 °C. Ϫ H NMR ([D6]DMSO):
N-(2-Cyanoethyl)-1-methyl-4-nitroimidazole-2-carboxamide
90% yield, as pale yellow needles, m.p. 133Ϫ135 °C. Ϫ H NMR
(6): δ ϭ 2.75 (t, J ϭ 6.0 Hz, 2 H, CH2CH2CN), 3.45 (q, 2 H,
NHCH2CH2CN), 3.81 (s, 3 H, NCH3), 3.91 (s, 3 H, NϪCH3), 4.00
1
([D6]DMSO): δ ϭ 2.45 (t, J ϭ 6.0 Hz, 2 H, CH2CH2CN), 3.25 (q, (s, 3 H, NCH3), 6.92 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.15 (d, J ϭ
2 H, NHCH2CH2CN), 3.85 (s, 3 H, NϪCH3), 8.25 (s, 1 H, Im 5-
2.0 Hz, 1 H, PyϪH), 7.22 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.31 (d,
H), 8.85 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN). Ϫ 13C NMR J ϭ 2.0 Hz, 1 H, PyϪH), 7.60 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.21
([D6]DMSO): δ ϭ 157.8 (CϭO), 143.3, 137.0, 126.3 (ImϪC), 119.0 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.25 (t, J ϭ 6.0 Hz, 1 H,
2098
Eur. J. Org. Chem. 2000, 2095Ϫ2103

Geometrically Constrained Bis(polyamides) Related to the Antiviral Distamycin
FULL PAPER
CONHCH2CH2ϪCN), 9.95 (s, 1 H, CONH), 10.23 (s, 1 H, using CH2Cl2/MeOH/NH4OH (80:20:2) as eluent to give 13, 44.5%
CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 175.7, 172.6, 171.2 (Cϭ 1H NMR
yield as yellow powder, m.p. 208Ϫ210 °C.
Ϫ
O), 148.0, 142.4, 140.5, 137.2, 136.5, 136.4, 135.7, 133.6, 132.9, ([D6]DMSO): δ ϭ 1.30 (t, J ϭ 7.0 Hz, 3 H, COOCH2CH3), 1.76
132.6, 121.8, 118.9 (PyϪC), 118.8 (CN), 51.7, 50.4, 50.2 (NϪCH3), (q, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 2.42 [s, 6 H, N(CH3)2], 2.60
31.9 (NCH2CH2CN), 22.7 (CH2CH2CN). Ϫ HRMS: calcd. for (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.28 (t, J ϭ 7.0 Hz, 2 H,
C21H23N8O5 467.1791; found 467.1788 (Mϩ ϩ H, 100%); calcd. C
54.06, H 4.76, N 24.03; found C 54.09, H 4.81, N 25.01.
CH2CH2CH2N), 3.90 (s, 3 H, NCH3), 4.05 (s, 3 H, NCH3), 4.07
(s, 3 H, NCH3), 4.20 (q, J ϭ 7.0 Hz, 2 H, COOCH2CH3), 6.72 (d,
J ϭ 1.5 Hz, 1 H, vinylic CH), 7.30 (d, J ϭ 1.5 Hz, 1 H, vinylic
CH), 7.55 (s, 1 H, Im 5-H), 7.68 (s, 1 H, Im 5-H), 7.70 (s, 1 H, Im
5-H), 8.44 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 9.68 (s, 1
H, CONH), 9.78 (s, 1 H, CONH), 11.14 (s, 1 H, CONH). Ϫ 13C
NMR ([D6]DMSO): δ ϭ 164.5, 165.3, 158.6, 155.5, 155.3 (CϭO),
144.6, 137.3, 135.0, 134.8, 134.7, 133.7 (ImϪC), 134.5, 132.6 (CHϭ
CH), 127.0, 116.1, 113.8 (ImϪC), 60.9 (COCH2CH3), 56.9
(NCH2CH2CH2N), 45.0 [N(CH3)2], 37.1 (CH2CH2CH2N), 36.6,
35.4, 35.3 (NϪCH3), 26.9 [CH2N(CH3)2], 13.9 (CH2CH3). Ϫ
HRMS: calcd. for C26H36N11O6 598.284; found 598.286 (Mϩ ϩ H,
100%); calcd. C 52.24, H 5.91, N 25.79; found C 52.31, H 4.14,
N 25.81.
N-(2-Cyanoethyl)-1-methyl-4-[(1-methyl-4-nitroimidazole-2-carbox-
amido)imidazole-2-carboxamido]imidazole-2-carboxamide (10): 77%
yield, as a yellow powder, m.p. 269Ϫ271 °C. Ϫ 1H NMR
([D6]DMSO): δ ϭ 2.79 (t, J ϭ 6.0 Hz, 2 H, CH2CH2CN), 3.49 (q,
2 H, NHϪCH2CH2CN), 3.99 (s, 3 H, NϪCH3), 4.01 (s, 3 H,
NϪCH3), 4.05 (s, 3 H, NCH3), 7.55 (s, 1 H, Im 5-H), 7.65 (s, 1 H,
Im 5-H), 8.55 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN), 8.65 (s, 1
H, Im 5-H), 9.55 (s, 1 H, CONH), 10.65 (s, 1 H, CONH). Ϫ 13C
NMR ([D6]DMSO): δ ϭ 157.6, 155.2, 155.0 (CϭO), 144.3, 137.0,
134.8, 134.6, 133.8, 133.4 (ImϪC), 119.1 (CN), 116.8, 113.8, 113.1
(ImϪC), 36.6 (NϪCH3), 35.2 (NCH2CH2CN), 17.4 (CH2CH2CN).
Ϫ HRMS: calcd. for C18H20N11O5 470.1648; found 470.1663 (Mϩ
ϩ H, 100%); calcd. C 46.04, H 4.08, N 32.83; found C 46.14, H
4.10, N 32.89.
The following compounds were prepared by this method.
Benzamide 14: 40% yield, as a yellow powder, m.p. 222Ϫ225 °C. Ϫ
1H NMR ([D6]DMSO): δ ϭ 1.76 (q, J ϭ 7.0 Hz, 2 H,
CH2CH2CH2N), 2.24 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 2.30 [s,
Methyl 4-Formylbenzoate (11): To 4-formylbenzoic acid (1.00 g,
7.24 mmol) in dry methanol (200 mL) thionyl chloride (6.00 mL,
7.24 mmol) was added dropwise at 0 °C until all of the compound 6 H, N(CH3)2], 3.20 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.92 (s,
dissolved. The reaction mixture was slowly brought to room tem-
perature and then stirred for 2 h. The solvent was removed in va-
cuo, by coevaporation with dichloromethane (2 ϫ 100 mL) to re-
move the excess of thionyl chloride to afford 11, 90% yield, m.p.
3 H, NCH3), 3.95 (s, 3 H, ArCϪOOCH3), 4.00 (s, 3 H, NϪCH3),
4.05 (s, 3 H, NϪCH3), 7.55 (s, 1 H, Im 5-H), 7.66 (s, 1 H, Im 5-
H), 7.68 (s, 1 H, Im 5-H), 8.12 (dd, J ϭ 10 Hz, 4 H, phenylic H),
8.40 (t, J ϭ 6.0 Hz, 1 H, CONH؊CH2CH2CH2N), 9.65 (s, 1 H,
64Ϫ65 °C (ref.[13d] 61Ϫ63 °C). Ϫ1H NMR ([D6]DMSO): δ ϭ 4.00 CONH), 9.75 (s, 1 H, CONH), 11.02 (s, 1 H, CONH). Ϫ 13C NMR
(s, 3 H, ArCOOCH3), 7.95 (d, J ϭ 10 Hz, 2 H, ArH), 8.15 (d, 2
([D6]DMSO): δ ϭ 167.7, 167.8, 158.6, 155.5, 155.3 (CϭO), 144.7,
H, J ϭ 10 Hz, ArH), 10.05 (s, 1 H, ArCHO). Ϫ 13C NMR 137.2, 135.0, 134.9, 134.7, 133.5 (ImϪC), 133.3 (Ar C-4), 133.5
([D6]DMSO): δ ϭ 52.7 (OCH3), 129.7 (C-2, C-6), 129.6 (C-3, C- (ArC-1), 129.6 (ArC-2 and C-6), 129.4 (ArC-3 and C-5), 127.3,
5), 134.2 (C-4), 134.8 (C-1), 165.5 (ArCOOCH3), 192.6 (CHO). Ϫ
EI; m/z (%): 164.04 (33.45), 149.02 (100.00), 133.02 (53.26), 121.02
116.3, 113.5 (ImϪC), 56.4 (NCH2CH2CH2N), 52.5 (OCH3), 45.2
[N(CH3)2], 37.3 (CH2CH2CH2N), 36.7, 35.3, 35.2 (NϪCH3), 26.4
(19.54), 105.03 (15.16), 77.03 (12.73), 65.03 (18.62), 51.02 (11.56). [CH2ϪN(CH3)2]. Ϫ HRMS: calcd. for C29H36N11O6 634.284;
Ϫ C9H8O3: calcd. C 65.85, H 4.91, found C 65.79, H 4.97.
found 634.284 (Mϩ ϩ H, 100%); calcd. C 54.95, H 5.57, N 24.32;
found C 54.93, H 5.63, N 24.37.
Methyl Terephthalate (12): To a solution of 11 (150 mg, 0.91 mmol)
and sulfamic acid (150 mg, 1.09 mmol) in water (10 mL) was added
a solution of sodium chlorite (98 mg, 1.09 mmol) in water (1 mL). 241Ϫ244 °C. Ϫ H NMR ([D6]DMSO): δ ϭ 2.08 (q, J ϭ 7.0 Hz,
Pyridinecarboxamide 15: 39% yield, as a yellow powder, m.p.
1
The reaction mixture was stirred at room temperature for 1 h. The
acid precipitated was collected to afford 12, 80% yield, m.p.
218Ϫ220 °C. Ϫ 1H NMR ([D6]DMSO): δ ϭ 3.95 (s, 3 H, Ar-
2 H, CH2CH2CH2N), 2.84 [s, 6 H, N(CH3)2], 3.15 (t, J ϭ 7.0 Hz,
2 H, CH2ϪCH2CH2N), 3.48 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N),
3.92 (s, 3 H, NCH3), 3.95 (s, 3 H, ArCOOCH3), 4.10 (s, 3 H,
COOCH3), 4.5Ϫ5.00 (br s, 1 H, ArCOOH), 8.03 (d, 4 H, ArH). Ϫ NϪCH3), 4.15 (s, 3 H, NϪCH3), 7.24 (s, 1 H, Im 5-H), 7.40 (s, 1
13C NMR ([D6]DMSO): δ ϭ 52.3 (OCH3), 129.7 (C-2, C-6), 129.6
H, Im 5-H), 7.42 (s, 1 H, Im 5-H), 8.35 (d, J ϭ 7.0 Hz, 1 H, pyridyl
(C-3, C-5), 133.3 (C-4), 134.7 (C-1), 165.5 (ArCOOCH3), 167.8 3-H), 8.40 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 8.75 (dd,
(COOH). Ϫ EI; m/z (%): 180.04 (25.29), 149.02 (78.42), 133.02 J ϭ 7.0 Hz and J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.34 (d, J ϭ 2.0 Hz,
(10.50), 121.02 (19.09), 104.02 (8.88), 76.03 (19.45), 69.13 (100.00),
51.02 (10.88). Ϫ C9H8O4: calcd. C 60.0, H 4.48, found C 61.2,
H 4.83.
1 H, pyridyl 6-H), 9.65 (s, 1 H, CONH), 9.75 (s, 1 H, CONH),
11.02 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 165.7, 164.3,
158.6, 155.5, 155.3 (CϭO), 144.7, 137.0, 135.2, 134.9, 134.7, 133.3
(ImϪC), 151.4, 150.1, 138.5, 129.1, 124.6 ( pyridyl C), 127.3, 116.3,
113.3 (ImϪC), 56.4 (NCH2CH2CH2N), 53.8 (OCH3), 45.2
[N(CH3)2], 37.2 (CH2CH2CH2N), 36.2, 35.3, 35.2 (NϪCH3), 26.4
[CH2N(CH3)2]. Ϫ HRMS: calcd. for C28H34N12O6 635.280; found
635.281 (Mϩ ϩ H, 100%); calcd. C 52.97, H 5.40, N 26.49; found
C 52.99, H 5.45, N 26.63.
Fumaramide 13. ؊ General Procedure: Catalytic hydrogenation us-
ing Pd/C (10%, 0.15 g) of compound 8 (0.28 g, 0.56 mmol) in
DMF/MeOH (1:1, v/v, 15 mL) afforded an unstable amine which
was dried, in order to remove traces of MeOH, and redissolved
in dry DMF (10 mL). Then fumaric acid monoethyl ester (81 mg,
0.56 mmol) and 1-hydroxybenzotriazole (108 mg, 0.79 mmol) were
added to this solution, followed by the addition of a solution of 1,3-
dicyclohexylcarbodiimide (166 mg, 0.79 mmol) in anhydrous DMF
Fumaramide 16: 47% yield, as a yellow powder, m.p. 223Ϫ225 °C.
Ϫ
1H NMR ([D6]DMSO): δ ϭ 1.30 (t, J ϭ 7.0 Hz, 3 H, CO-
(2 mL). The reaction mixture was stirred at room temperature for OCH2CH3), 2.75 (t, J ϭ 6.0 Hz, 2 H, CH2CH2CN), 3.45 (q, 2 H,
18 h under argon. TLC examination of the reaction mixture at this
time showed the formation of the product. The solvent was re-
moved in vacuo and the residue was purified on a silica gel column
NHCH2CH2CN), 3.81 (s, 3 H, NϪCH3), 3.91 (s, 3 H, NϪCH3),
4.00 (s, 3 H, NϪCH3), 4.20 (q, J ϭ 7.0 Hz, 2 H, COOCH2ϪCH3),
6.72 (d, J ϭ 1.5 Hz, 1 H, vinylic CH), 6.92 (d, J ϭ 2.0 Hz, 1 H,
Eur. J. Org. Chem. 2000, 2095Ϫ2103
2099

S. K. Sharma, M. Tandon, J. W. Lown
FULL PAPER
PyϪH), 7.15 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.22 (d, J ϭ 2.0 Hz, 1 4.03 (s, 3 H, NϪCH3), 4.00Ϫ5.00 (br s, 1 H, ArCOOH), 6.66 (d,
H, PyϪH), 7.30 (d, J ϭ 1.5 Hz, 1 H, vinylic CH), 7.31 (d, J ϭ J ϭ 1.5 Hz, 1 H, vinylic CH), 7.06 (d, J ϭ 1.5 Hz, 1 H, vinylic
2.0 Hz, 1 H, PyϪH), 7.60 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.21 (d, CH), 7.20 (s, 1 H, Im 5-H), 7.65 (s, 1 H, Im 5-H), 7.68 (s, 1 H, Im
2.0 Hz, H, PyϪH), 8.25 (t, 6.0 Hz, H, 5-H), 8.40 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 9.65 (s, 1
CONH؊CH2CH2CN), 9.95 (s, 1 H, CONH), 10.23 (s, 1 H, H, CONH), 9.75 (s, 1 H, CONH), 11.00 (s, 1 H, CONH). Ϫ 13C
CONH), 11.02 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ
NMR ([D6]DMSO): δ ϭ 164.6, 165.3, 158.7, 155.4, 155.3 (CϭO),
165.6, 165.5, 164.3, 158.5, 155.4 (CϭO), 148.0, 142.4, 140.5, 137.4, 144.5, 137.3, 135.0, 134.6, 134.5, 133.7 (ImϪC), 134.5, 132.6 (CHϭ
136.8, 136.4, 135.7 (PyϪC), 134.6, 134.3 (CHϭCH), 133.6, 132.9, CH), 127.2, 116.3, 113.4 (ImϪC), 56.9 (NCH2CH2CH2N), 45.2
J
ϭ
1
J
ϭ
1
132.6, 121.6, 119.6 (PyϪC), 119.8 (CN), 60.8 (COCH2CH3), 51.7, [N(CH3)2], 37.3 (CH2CH2CH2N), 36.6, 35.5, 35.4 (NϪCH3), 26.8
51.4, 50.4 (NϪCH3), 32.6 (NCH2CH2CN), 22.8 (CH2CH2CN), [CH2N(CH3)2]. Ϫ HRMS: calcd. for C24H32N11O6 570.252; found
13.8 (COCH2CH3). Ϫ HRMS: calcd. for C27H31N8O6 563.235; 570.251 (Mϩ ϩ H, 100%); calcd. C 50.59, H 5.49, N 27.06; found
found 563.237 (Mϩ ϩ H, 100%); calcd. C 57.63, H 5.38, N 19.93;
C 50.27, H 5.34, N 26.89.
found C 56.93, H 5.41, N 20.01.
The following compounds were prepared by this procedure.
Fumaramide 20: 86% yield, as light yellow solid, m.p. 265Ϫ269 °C.
Benzamide 17: 44% yield, as a yellow powder, m.p. 219Ϫ223 °C. Ϫ
1H NMR ([D6]DMSO): δ ϭ 2.78 (t, J ϭ 6.0 Hz, 2 H, CH2CH2CN),
3.49 (q, 2 H, NHCH2CH2CN), 3.83 (s, 3 H, NϪCH3), 3.92 (s, 3
H, NϪCH3), 3.97 (s, 3 H, ArCOOCH3), 4.05 (s, 3 H, NϪCH3),
6.93 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.20 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.21 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.37 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.65 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.15 (dd, J ϭ 10 Hz, 4 H,
phenylic), 8.22 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.25 (t, J ϭ 6.0 Hz, 1
H, CONHCH2CH2CN), 10.01 (s, 1 H, CONH), 10.23 (s, 1 H,
CONH), 11.05 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ
164.7, 164.5, 165.2, 158.5, 155.3 (CϭO), 148.0, 142.4, 140.3, 137.2,
136.5, 136.4, 135.7, 133.6, 132.6, 132.4 (PyϪC), 133.3, 132.1, 129.6,
129.4 ( ArϪC), 121.3, 118.9 (PyϪC), 118.8 (CN), 52.6 (OCH3),
51.7, 50.4, 50.2 (NϪCH3), 31.9 (NCH2CH2CN), 22.7
(CH2CH2CN). Ϫ HRMS: calcd. for C30H31N8O6 599.235; found
599.234 (Mϩ ϩ H, 100%); calcd. C 60.18, H 5.05, N 18.73; found
C 60.67, H 4.95, N 17.93.
Ϫ
1H NMR ([D6]DMSO): δ ϭ 2.75 (t, J ϭ 6.0 Hz, 2 H,
CH2CH2CN), 3.48 (q, 2 H, NHCH2CH2CN), 3.82 (s, 3 H,
NϪCH3), 3.87 (s, 3 H, NϪCH3), 4.03 (s, 3 H, NϪCH3), 4.35Ϫ5.12
(s, 1 H, CHCOOH), 6.74 (d, J ϭ 1.5 Hz, 1 H, vinylic CH), 6.89 (d,
J ϭ 2.0 Hz, 1 H, PyϪH), 7.10 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.25
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.32 (d, J ϭ 1.5 Hz, 1 H vinylic CH),
7.33 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.59 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
8.26 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.29 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2CN), 9.98 (s, 1 H, CONH), 10.27 (s, 1 H, CONH),
11.07 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 165.6, 165.4,
164.3, 158.7, 155.4 (CϭO), 148.1, 142.4, 140.2, 137.4, 136.8, 136.4,
135.7 (PyϪC), 134.4, 134.3 (CHϭCH), 133.4, 132.9, 132.4, 121.6,
119.5 (PyϪC), 119.8 (CN), 51.7, 51.4, 50.4 (NϪCH3), 32.4
(NCH2CH2CN), 22.6 (CH2CH2CN).
Ϫ HRMS: calcd. for
C25H27N8O6 535.204; found 535.207 (Mϩ ϩ H, 100%); calcd. C
56.16, H 4.91, N 20.97; found C 55.13, H 4.67, N 20.57.
Pyridinecarboxamide 18: 37% yield, as a yellow powder, m.p.
267Ϫ271 °C. Ϫ 1H NMR ([D6]DMSO): δ ϭ 2.77 (t, J ϭ 6.0 Hz, 2
H, CH2CH2CN), 3.43 (q, 2 H, NHCH2CH2CN), 3.78 (s, 3 H,
NϪCH3), 3.91 (s, 3 H, NϪCH3), 3.99 (s, 3 H, ArCOOCH3), 4.05
(s, 3 H, NϪCH3), 6.93 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.15 (d, J ϭ
2.0 Hz, 1 H, PyϪH), 7.29 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.35 (d,
J ϭ 2.0 Hz, 1 H, PyϪH), 7.65 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.25
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.27 (t, J ϭ 6.0 Hz, 1 H,
CONH؊CH2CH2CN), 8.39 (d, J ϭ 7.0 Hz, 1 H, pyridyl 3-H), 8.79
(dd, J ϭ 7.0 Hz, J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.38 (d, J ϭ 2.0 Hz,
1 H, pyridyl 6-H), 10.01 (s, 1 H, CONH), 10.27 (s, 1 H, CONH),
11.15 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 164.6, 165.5,
164.3, 158.5, 155.4 (CϭO), 151.3, 150.2, 137.3, 129.2, 124.6 (pyri-
dyl C), 148.0, 142.3, 140.5, 137.2, 136.5, 136.4, 135.7, 133.6, 132.9,
132.6, 121.8, 118.9 (PyϪC), 118.8 (CN), 53.6 (OCH3), 51.7, 50.4,
50.2 (NϪCH3), 31.9 (NCH2CH2CN), 22.7 (CH2CH2CN). Ϫ
HRMS: calcd. for C29H30N9O6 600.231 found 600.231 (Mϩ ϩ H,
100%); calcd. C 58.08, H 4.88, N 21.03; found C 58.02, H 4.79,
N 20.97.
Benzamide 21: 90% yield, as a yellow solid, m.p. 227Ϫ229 °C. Ϫ
1H NMR ([D6]DMSO):
δ ϭ 1.70 (q, J ϭ 7.0 Hz, 2 H,
CH2CH2CH2N), 2.26 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 2.35 [s,
6 H, N(CH3)2], 3.25 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.98 (s,
3 H, NϪCH3), 4.01 (s, 3 H, NϪCH3), 4.05 (s, 3 H, NϪCH3),
4.15Ϫ5.00 (s, 1 H, ArCOOH), 7.57 (s, 1 H, Im 5-H), 7.68 (s, 1 H,
Im 5-H), 7.73 (s, 1 H, Im 5-H), 8.15 (dd, J ϭ 10 Hz, 4 H, phenylic),
8.42 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 9.71 (s, 1 H,
CONH), 9.75 (s, 1 H, CONH), 11.05 (s, 1 H, CONH). Ϫ 13C NMR
([D6]DMSO): δ ϭ 167.7, 167.4, 158.5, 155.5, 155.1 (CϭO), 144.6,
137.2, 135.1, 134.7, 134.6, 133.5 (ImϪC), 133.3, 133.5, 129.6, 129.4
(ArϪC), 127.3, 116.3, 113.4 (ImϪC), 56.2 (NCH2CH2CH2N), 45.4
[N(CH3)2], 37.2 (CH2CH2CH2N), 36.7, 35.4, 35.2 (NϪCH3), 26.3
[CH2N(CH3)2]. Ϫ HRMS: calcd. for C28H34N11O6 620.268; found
620.270 (Mϩ ϩ H, 100%); calcd. C 54.26, H 5.37, N 24.87; found
C 53.97, H 4.99, N 24.67.
Benzamide 22: 80% yield, as a light brown solid, m.p. 281Ϫ283 °C.
Ϫ
1H NMR ([D6]DMSO): δ ϭ 2.75 (t, J ϭ 6.0 Hz, 2 H,
Fumaramide 19. ؊ General Procedure: An ethanolic solution of 13
CH2CH2CN), 3.46 (q, 2 H, NHCH2CH2CN), 3.87 (s, 3 H,
(0.10 g, 0.16 mmol) was treated with 1  aqueous sodium hydroxide NϪCH3), 3.93 (s, 3 H, NϪCH3), 4.05 (s, 3 H, NϪCH3), 4.13 (s, 1
(4 mL), and the mixture was stirred at reflux for 18 h. A chromato-
graphic examination of this reaction mixture showed the formation
of the corresponding sodium salt of the acid and complete disap-
pearance of the ester. The solvent was removed in vacuo, the res-
idue was dissolved in water (30 mL) and acidified to pH ϭ 2 using
Dowex-Hϩ resin. The resin was collected and the aqueous phase
was freeze-dried to afford 80 mg of 19, 89% yield, as a yellow solid,
H, ArCOOH), 6.96 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.18 (d, J ϭ
2.0 Hz, 1 H, PyϪH), 7.27 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.34 (d,
J ϭ 2.0 Hz, 1 H, PyϪH), 7.64 (d, J ϭ 2.0ϪHz, 1 H, PyϪH), 8.15
(dd, J ϭ 10 Hz, 4 H, phenylic), 8.17 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
8.22 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN), 9.93 (s, 1 H,
CONH), 10.17 (s, 1 H, CONH), 11.05 (s, 1 H, CONH). Ϫ 13C
NMR ([D6]DMSO): δ ϭ 164.6, 164.5, 165.1, 158.4, 155.3 (CϭO),
m.p. 208Ϫ210 °C (dec.). Ϫ 1H NMR ([D6]DMSO): δ ϭ 1.80 (q, 148.2, 142.4, 140.3, 137.2, 136.5, 136.2, 135.7, 133.6, 132.5, 132.4
J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 2.42 [s, 6 H, N(CH3)2], 2.75 (PyϪC), 133.2, 132.1, 129.6, 129.4 (ArϪC), 121.4, 118.9 (PyϪC),
(t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N), 3.22 (t, J ϭ 7.0 Hz, 2 H, 118.8 (CN), 51.4, 50.4, 50.3 (NϪCH3), 31.6 (NCH2CH2CN), 22.6
CH2CH2CH2N), 3.92 (s, 3 H, NϪCH3), 4.00 (s, 3 H, NϪCH3), (CH2CH2CN). Ϫ HRMS: calcd. for C29H29N8O6 585.220; found
2100
Eur. J. Org. Chem. 2000, 2095Ϫ2103

Geometrically Constrained Bis(polyamides) Related to the Antiviral Distamycin
FULL PAPER
585.223 (Mϩ ϩ H, 100%); calcd. C 59.57, H 4.83, N 19.18; found
C 58.98, H 4.64, N 19.01.
J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 8.48 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2CH2N), 9.68 (s, 1 H, CONH), 9.76 (s, 1 H,
CONH), 9.80 (s, 1 H, CONH), 9.90 (s, 1 H, CONH), 10.00 (s, 1 H,
CONH), 11.06 (s, 1 H, CONH). Ϫ HRMS: calcd. for C47H62N19O8
1020.502; found 1020.501 (Mϩ ϩ H, 100%).
Pyridinecarboxamide 23: 75% yield, as a yellow solid, m.p. 245Ϫ247
°C. Ϫ 1H NMR ([D6]DMSO): δ ϭ 2.06 (q, J ϭ 7.0 Hz, 2 H,
CH2CH2CH2N), 2.73 [s, 6 H, N(CH3)2], 3.20 [t, J ϭ 7.0 Hz, 2 H,
CH2CH2CH2N(CH3)2], 3.48 (t, J ϭ 7.0 Hz, 2 H, CH2CH2CH2N),
3.96 (s, 3 H, NϪCH3), 4.02 (s, 3 H, NϪCH3), 4.05 (s, 3 H,
NϪCH3), 4.15Ϫ5.00 (s, 1 H, ArCOOH), 7.26 (s, 1 H, Im 5-H),
7.48 (s, 1 H, Im 5-H), 7.48 (s, 1 H, Im 5-H), 8.31 (d, J ϭ 7.0 Hz,
1 H, pyridyl 3-H), 8.39 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N),
8.76 (dd, 7.0 Hz and J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.34 (d, J ϭ
2.0 Hz, 1 H, pyridyl 6-H), 9.68 (s, 1 H, CONH), 9.72 (s, 1 H,
CONH), 11.14 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ
165.6, 164.3, 158.4, 155.5, 155.2 (CϭO), 144.6, 137.0, 135.2, 134.8,
134.7, 133.2 (ImϪC), 151.4, 150.1, 138.6, 129.1, 124.4 ( pyridyl C),
127.3, 116.3, 113.2 (ImϪC), 56.2 (NCH2CH2CH2N), 45.3
[N(CH3)2], 37.2 (CH2CH2CH2N), 36.2, 35.4, 35.2 (NϪCH3), 26.3
[CH2N(CH3)2]. Ϫ HRMS: calcd. for C27H33N12O6 621.263; found
621.265 (Mϩ ϩ H, 100%); calcd. C 52.24, H 5.20, N 27.09; found
C 51.97, H 4.99, N 28.89.
The following compounds were prepared by this procedure.
Benzene Derivative 26: 47% yield, as a yellow powder, mp. 205Ϫ207
°C. Ϫ1H NMR ([D6]DMSO): δ ϭ 1.67 (q, J ϭ 7.0 Hz, 4 H, 2 ϫ
CH2CH2ϪCH2N), 2.20 [s, 12 H, 2 ϫ N(CH3)2], 2.24 (t, J ϭ 7.0 Hz,
4 H, 2 ϫ CH2CH2CH2N), 3.25 (dt, J ϭ 6.0 Hz, J ϭ 7.0 Hz, 4 H,
2 ϫ CH2CH2CH2N), 3.85 (s, 3 H, NϪCH3), 3.85 (s, 3 H, NϪCH3),
3.90 (s, 3 H, NϪCH3), 3.93 (s, 3 H, NϪCH3), 3.95 (s, 3 H,
NϪCH3), 4.10 (s, 3 H, NϪCH3), 6.85 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
6.95 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.08 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.25 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.28 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.39 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.52 (s, 1 H, Im 5-H), 7.72 (s,
1 H, Im 5-H), 7.76 (s, 1 H, Im 5-H), 8.10 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2CH2N), 8.15 (dd, J ϭ 10 Hz, 4 H, phenylic), 8.40
(t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 9.73 (s, 1 H, CONH),
9.76 (s, 1 H, CONH), 9.89 (s, 1 H, CONH), 9.90 (s, 1 H, CONH),
10.15 (s, 1 H, CONH), 11.06 (s, 1 H, CONH). Ϫ HRMS: calcd.
for C51H64N19O8 1070.517; found 1070.515 (Mϩ ϩ H, 100%).
Pyridinecarboxamide 24: 73% yield, as a light brown solid, m.p. Ͼ
1
300 °C. Ϫ H NMR ([D6]DMSO): δ ϭ 2.73 (t, J ϭ 6.0 Hz, 2 H,
CH2CH2CN), 3.43 (q, 2 H, NHCH2CH2CN), 3.79 (s, 3 H,
NϪCH3), 3.95 (s, 3 H, NϪCH3), 4.03 (s, 3 H, NϪCH3), 4.50 (s, 1
H, ArCOOH), 6.94 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.09 (d, J ϭ
2.0 Hz, 1 H, PyϪH), 7.20 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.31 (d,
J ϭ 2.0 Hz, 1 H, PyϪH), 7.58 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.26
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 8.29 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2CN), 8.30 (d, J ϭ 7.0 Hz, 1 H, pyridyl 3-H), 8.72
(dd, 7.0 Hz and J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.32 (d, J ϭ 2.0 Hz,
1 H, pyridyl 6-H), 9.97 (s, 1 H, CONH), 10.21 (s, 1 H, CONH),
11.04 (s, 1 H, CONH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 164.7, 165.6,
164.3, 158.3, 155.4 (CϭO), 151.3, 150.5, 137.3, 129.2, 124.6 (pyri-
dyl C), 148.0, 142.2, 140.5, 137.2, 136.5, 136.4, 135.4, 133.6, 132.9,
132.6, 121.8, 119.6 (PyϪC), 119.8 (CN), 51.7, 50.2, 50.2 (NϪCH3),
31.9 (NCH2CH2CN), 22.7 (CH2CH2CN). Ϫ HRMS: calcd. for
C28H28N8O6 571.212; found 572.210 (Mϩ ϩ H, 100%); calcd. C
58.82, H 4.76, N 19.61; found C 57.98, H 4.39, N 19.23.
Pyridine Derivative 27: 40% yield, as a light yellow fluffy solid, m.p.
227Ϫ230 °C. Ϫ H NMR ([D6]DMSO): δ ϭ 1.70 (q, J ϭ 7.0 Hz,
1
4 H, 2 ϫ CH2ϪCH2CH2N), 2.25 [s, 12 H, 2 ϫ N(CH3)2], 2.38 (t,
J ϭ 7.0 Hz, 4 H, 2 ϫ CH2CH2CH2N), 3.21 (dt, J ϭ 6.0 Hz, J ϭ
7.0 Hz, 4 H, 2 ϫ CH2CH2CH2N), 3.88 (s, 3 H, NϪCH3), 3.91 (s,
3 H, NϪCH3), 3.95 (s, 3 H, NϪCH3), 3.94 (s, 3 H, NϪCH3), 3.95
(s, 3 H, NϪCH3), 4.10 (s, 3 H, NϪCH3), 6.67 (d, J ϭ 2.0 Hz, 1 H,
PyϪH), 6.90 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.05 (d, J ϭ 2.0 Hz, 1
H, PyϪH), 7.21 (d, 1 H, J ϭ 2.0 Hz, PyϪH), 7.23 (d, J ϭ 2.0 Hz,
1 H, PyϪH), 7.40 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.48 (s, 1 H, Im 5-
H), 7.73 (s, 1 H, Im 5-H), 7.79 (s, 1 H, Im 5-H), 8.15 (t, J ϭ 6.0 Hz,
1 H, CONHCH2CH2CH2N), 8.35 (d, J ϭ 7.0 Hz, 1 H, pyridyl 3-
H), 8.39 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CH2N), 8.75 (dd,
7.0 Hz and J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.34 (d, J ϭ 2.0 Hz, 1
H, pyridyl 6-H), 9.83 (s, 1 H, CONH), 9.86 (s, 1 H, CONH), 9.89
(s, 1 H, CONH), 9.95 (s, 1 H, CONH), 10.17 (s, 1 H, CONH),
11.14 (s, 1 H, CONH). Ϫ HRMS: calcd. for C50H63N20O8
1071.512; found 1071.514 (Mϩ ϩ H, 100%).
Dicarboxamide 25. ؊ General Procedure: Compound 7 (55 mg,
0.11 mmol) was dissolved in DMF/methanol (1:1, v/v, 5 mL) and
hydrogenated in the presence of Pd/C (10%, 25 mg). The catalyst
was removed by filtration, washed with methanol and dried in high
vacuum in order to remove traces of methanol. The dried amino
compound was mixed with compound 19 (63 mg, 0.11 mmol) and
1-hydroxybenzotriazole (21 mg, 0.15 mmol) in DMF (15 mL). This
procedure was followed by the addition of a solution of 1,3-dicyclo-
hexylcarbodiimide (31 mg, 0.15 mmol) in DMF (1 mL). The stir-
ring was continued at room temperature for 18 h under argon. TLC
examination after 18 h confirmed formation of the product. The
solvent was removed in vacuo and the crude product was purified
on a silica gel column using CH2Cl2/MeOH/NH4OH (8.0:2.0:0.2)
as eluent to afford pure 25; 44% yield, as a yellow powder, m.p.
Fumaroyl Derivative 28: 48% yield, as a light brown solid, m.p.
1
232Ϫ235 °C. Ϫ H NMR ([D6]DMSO): δ ϭ 2.78 (t, J ϭ 6.0 Hz,
4 H, 2 ϫ CH2CH2CN), 3.49 (q, 4 H, 2 ϫ NHCH2CH2CN), 3.82
(s, 3 H, NϪCH3), 3.87 (s, 3 H, NϪCH3), 3.89 (s, 3 H, NϪCH3),
3.91 (s, 3 H, NϪCH3), 4.00 (s, 3 H, NϪCH3), 4.02 (s, 3 H,
NϪCH3), 6.87 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 6.95 (d, J ϭ 2.0 Hz, 1
H, PyϪH), 7.05 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.20 (m, 3 H, 1 H
PyϪH and 2 H CHϭCH), 7.29 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.41
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.50 (s, 1 H, Im 5-H), 7.63 (s, 1 H,
Im 5-H), 7.80 (s, 1 H, Im 5-H), 8.08 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2CN),
8.42
(t,
J
ϭ
6.0 Hz,
1
H,
CONHCH2CH2CN), 9.50 (s, 1 H, CONH), 9.79 (s, 1 H, CONH),
9.90 (s, 1 H, CONH), 9.98 (s, 1 H, CONH), 10.13 (s, 1 H, CONH),
11.21 (s, 1 H, CONH). Ϫ HRMS: calcd. for C43H46N19O8 956.377;
found 956.376 (Mϩ ϩ H, 100%).
1
195Ϫ198 °C. Ϫ H NMR ([D6]DMSO): δ ϭ 1.64 (q, J ϭ 7.0 Hz,
4 H, 2 ϫ CH2CH2ϪCH2N), 2.12 [s, 12 H, 2 ϫ N(CH3)2], 2.24 (t,
J ϭ 7.0 Hz, 4 H, 2 ϫ CH2CH2CH2N), 3.20 (dt, J ϭ 6.0 Hz, J ϭ
7.0 Hz, 4 H, 2 ϫ CH2CH2CH2N), 3.82 (s, 3 H, NϪCH3), 3.85 (s,
3 H, NϪCH3), 3.87 (s, 3 H, NϪCH3), 3.91 (s, 3 H, NϪCH3), 3.95 Benzene Derivative 29: 47% yield, as a brown solid, m.p. Ͼ 300
(s, 3 H, NϪCH3), 4.02 (s, 3 H, NϪCH3), 6.82 (d, J ϭ 2.0 Hz, 1 H, °C. Ϫ1H NMR ([D6]DMSO): δ ϭ 2.85 (t, J ϭ 6.0 Hz, 4 H, 2 ϫ
PyϪH), 6.95 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.05 (d, J ϭ 2.0 Hz, 1
CH2ϪCH2CN), 3.65 (q, 4 H, 2 ϫ NHCH2CH2CN), 3.85 (s, 3 H,
H, PyϪH), 7.20 (m, 3 H, 1 H, PyϪH and 2 H, CHϭCH), 7.28 (d, NCH3), 3.87 (s, 3 H, NϪCH3), 3.90 (s, 3 H, NϪCH3), 3.94 (s, 3
J ϭ 2.0 Hz, H, PyϪH), 7.36 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.52 (s,
1 H, Im 5-H), 7.66 (s, 1 H, Im 5-H), 7.76 (s, 1 H, Im 5-H), 8.08 (t,
H, NϪCH3), 4.00 (s, 3 H, NϪCH3), 4.05 (s, 3 H, NϪCH3), 6.85
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 6.95 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
Eur. J. Org. Chem. 2000, 2095Ϫ2103
2101

S. K. Sharma, M. Tandon, J. W. Lown
FULL PAPER
7.12 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.24 (m, J ϭ 2.0 Hz, 1 H, PyϪH), 6.0 Hz, 1 H, CONHCH2CH2), 8.65 [s, 8 H, 2 ϫ C(NH2)2], 9.05 [s,
7.32 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.43 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 8 H, 2 ϫ C(NH2)2], 9.10 (s, 1 H, CONH), 9.40 (s, 1 H, CONH),
7.60 (s, 1 H, Im 5-H), 7.65 (s, 1 H, Im 5-H), 7.83 (s, 1 H, Im 5-H), 9.70 (s, 1 H, CONH), 9.78 (s, 1 H, CONH), 9.99 (s, 1 H, CONH),
8.10 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN), 8.28 (dd, J ϭ 10 Hz,
10.14 (s, 1 H, CONH), 10.78 (s, 1 H, CONH). Ϫ HRMS: calcd.
4 H, phenylic), 8.40 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN), 9.80 for C47H54N21O8 1040.446; found 1040.446 (Mϩ ϩ H, 100%).
(s, 1 H, CONH), 9.85 (s, 1 H, CONH), 9.93 (s, 1 H, CONH), 9.98
(s, 1 H, CONH), 10.09 (s, 1 H, CONH), 11.14 (s, 1 H, CONH). Ϫ
Pyridine Derivative 33: 65% yield, m.p. Ͼ 300 °C. Ϫ 1H NMR
HRMS: calcd. for C47H48N19O8 1006.393; found 1006.393 (Mϩ
H, 100%).
ϩ
([D6]DMSO): δ ϭ 2.73 [t, J ϭ 6.0 Hz, 4 H, 2 ϫ CH2CH2C(NH2)2],
3.58 (t, J ϭ 6.0 Hz, 4 H, 2 ϫ CONHCH2CH2), 3.84 (s, 3 H,
NϪCH3), 3.88 (s, 3 H, NϪCH3), 3.92 (s, 3 H, NϪCH3), 4.00 (s, 3
H, NϪCH3), 4.10 (s, 3 H, NϪCH3), 4.17 (s, 3 H, NϪCH3), 6.97
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.00 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.15 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.52 (s, 1 H, Im 5-H), 7.57 (s, 1
H, Im 5-H), 7.84 (s, 1 H, Im 5-H), 8.32 (d, J ϭ 7.0 Hz, 1 H, pyridyl
3-H), 8.40 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2), 8.53 (t, J ϭ
6.0 Hz, 1 H, CONHCH2CH2), 8.69 [s, 8 H, 2 ϫ C(NH2)2], 8.83
(dd, J ϭ 7.0 Hz, J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.52 (d, J ϭ 2.0 Hz,
1 H, pyridyl 6-H), 9.10 [s, 8 H, 2 ϫ C(NH2)2], 9.15 (s, 1 H, CONH),
9.44 (s, 1 H, CONH), 9.79 (s, 1 H, CONH), 9.89 (s, 1 H, CONH),
10.01 (s, 1 H, CONH), 10.14 (s, 1 H, CONH), 10.78 (s, 1 H,
CONH). Ϫ HRMS: calcd. for C46H53N22O8 1041.441; found
1041.443 (Mϩ ϩ H, 100%).
Pyridine Derivative 30: 37% yield, as a brown powder, m.p. 300
1
°C. Ϫ H NMR ([D6]DMSO): δ ϭ 2.67 (t, J ϭ 6.0 Hz, 4 H, 2 ϫ
CH2CH2CN), 3.63 (q, 4 H, 2 ϫ NHCH2CH2CN), 3.80 (s, 3 H,
NϪCH3), 3.83 (s, 3 H, NϪCH3), 3.90 (s, 3 H, NϪCH3), 3.98 (s, 3
H, NϪCH3), 4.02 (s, 3 H, NϪCH3), 4.10 (s, 3 H, NϪCH3), 6.87
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 6.95 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.20 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.24 (m, J ϭ 2.0 Hz, 1 H, PyϪH),
7.38 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.43 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.58 (s, 1 H, Im 5-H), 7.63 (s, 1 H, Im 5-H), 7.79 (s, 1 H, Im 5-H),
8.05 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN), 8.29 (d, J ϭ 7.0 Hz,
1 H, pyridyl 3-H), 8.48 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2CN),
8.79 (dd, J ϭ7.0 Hz, J ϭ 2.0 Hz, 1 H, pyridyl 4-H), 9.48 (d, J ϭ
2.0 Hz, 1 H, pyridyl 6-H), 9.89 (s, 1 H, CONH), 10.01 (s, 1 H,
CONH), 10.08 (s, 1 H, CONH), 10.19 (s, 1 H, CONH), 10.29 (s, 1
H, CONH), 11.31 (s, 1 H, CONH). Ϫ HRMS: calcd. for
C46H47N20O8 1007.388; found 1007.388 ( Mϩ ϩ H, 100%).
Acknowledgments
Fumaroyl Derivative 31. ؊ General Procedure: Compound 28
(500 mg. 0.523 mmol) in 25 mL of anhydrous ethanol was saturated
with dry HCl with cooling. After 2 h at room temperature, the solv-
ent was evaporated to dryness, and the residue was washed with
dry diethyl ether (2 ϫ 50 mL) and then dried. The residue was
again dissolved in dry ethanol followed by treatment with NH3
condensed (4.5 mL) into the reaction vessel. The reaction mixture
was stirred at room temperature for 18 h. The solvent was then
removed, the residue was dissolved in a large amount (100 mL)
of methanol, and the impurities were collected. The solution was
concentrated to a small volume (10 mL) and the pure compound
31 was collected as a dihydrochloride salt, 65% yield, m.p. Ͼ 300
°C. Ϫ 1H NMR ([D6]DMSO): δ ϭ 2.63 [t, J ϭ 6.00 Hz, 4 H, 2 ϫ
We are grateful for a research grant (to J. W. L.) from the Natural
Sciences and Engineering Research Council of Canada.
[1]
R. W. Sidwell, J. T. Witkowsky, ‘‘Antiviral Agents’’, in Burger’s
Medicinal Chemistry (Ed.: M. E. Wolff), 4th ed., Wiley-Inter-
science, New York, 1979, pp. 543Ϫ593.
[2]
[2a] K. E. Rao, R. G. Shea, B. Yadagiri, J. W. Lown, Anticancer
[2b]
Drug Des. 1990, 5, 3Ϫ20. Ϫ
L. H. Hurley, C. S. Lee, J. P.
McGouren, M. A. Mitchell, M. A. Warpchoski, R. C. Kelly,
[2c]
P. A. Aristoff, Biochemistry 1988, 27, 3886Ϫ3892. Ϫ
M. D.
Lee, T. S. Dunne, C. C. Chang, G. A. Ellestad, M. M. Siegel,
G. O. Morton, W. J. McGahren, D. B. Borders, J. Am. Chem.
[2d]
CH2CH2C(NH2)2], 3.50 (t,
J
ϭ
6.00 Hz,
4
H,
2
ϫ
Soc. 1987, 109, 3466Ϫ3468. Ϫ
J. Stubbe, J. W. Kozarich,
Chem. Rev. 1987, 87, 1107Ϫ1136.
CONHCH2CH2), 3.80 (s, 3 H, NϪCH3), 3.83 (s, 3 H, NϪCH3),
3.84 (s, 3 H, NϪCH3), 3.95 (s, 3 H, NϪCH3), 4.11 (s, 3 H,
NϪCH3), 4.15 (s, 3 H, NϪCH3), 6.89 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
6.94 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.05 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.20 (d, 2 H, CHϭCH), 7.46 (s, 1 H, Im 5-H), 7.50 (s, 1 H, Im 5-
[3]
[4]
[5]
[6]
[7]
M. Julia, N. C. R. Preau-Joseph, Acad. Sci. 1963, 257,
1115Ϫ1122.
F. Arcamone, P. G. Orezzi, W. Barbieri, V. Nicolella, S. Penco,
Gazz. Chim. Ital. 1967, 97, 1097Ϫ1109.
M. W. Van Dyke, P. B. Dervan, Nucleic Acids Res. 1983, 11,
5555Ϫ5567.
K. L. Kissinger, J. C. Dabrowiak, J. W. Lown, Chem. Res.
Toxicol. 1990, 3, 162Ϫ168.
R. S. Youngquist, P. B. Dervan, J. Am. Chem. Soc. 1985, 107,
5528Ϫ5529.
W. Wang, J. W. Lown, J. Med. Chem. 1992, 35, 2890Ϫ2897.
N. Neamati, A. Mazumder, S. Sunder, J. M. Owen, M. Tandon,
J. W. Lown, Y. Pommier, Mol. Pharmacol. 1998, 54, 280Ϫ290.
W. H. Gmeiner, W. Cui, D. E. Konerding, P. Keifer, S. K.
Sharma, A. M. Soto, L. A. Marky, J. W. Lown, J. Biomol.
Struct. Dyn. 1999, 17, 507Ϫ518.
H), 7.86 (s,
1 H, Im 5-H), 8.34 (t, J ϭ 6.0 Hz, 1 H,
CONHCH2CH2), 8.42 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2), 8.65
[s, 8 H, 2 ϫ C(NH2)2], 9.01 [s, 8 H, 2 ϫ C(NH2)2], 9.01 (s, 1 H,
CONH), 9.40 (s, 1 H, CONH), 9.64 (s, 1 H, CONH), 9.78 (s, 1 H,
CONH), 9.95 (s, 1 H, CONH), 10.03 (s, 1 H, CONH), 10.57 (s, 1
H, CONH). Ϫ HRMS: calcd. for C43H52N21O8 990.430; found
990.430 (Mϩ ϩ H, 100%).
[8]
[9]
[10]
[11]
The following compounds were prepared by this procedure.
Benzene Derivative 32: 64% yield, m.p. Ͼ 300 °C. Ϫ 1H NMR
([D6]DMSO): δ ϭ 2.71 [t, J ϭ 6.0 Hz, 4 H, 2 ϫ CH2CH2C(NH2)2],
3.53 (t, J ϭ 6.0 Hz, 4 H, 2 ϫ CONHCH2CH2), 3.83 (s, 3 H,
NϪCH3), 3.85 (s, 3 H, NϪCH3), 3.87 (s, 3 H, NϪCH3), 3.98 (s, 3
H, NϪCH3), 4.14 (s, 3 H, NϪCH3), 4.17 (s, 3 H, NϪCH3), 6.93
(d, J ϭ 2.0 Hz, 1 H, PyϪH), 6.96 (d, J ϭ 2.0 Hz, 1 H, PyϪH),
7.15 (d, J ϭ 2.0 Hz, 1 H, PyϪH), 7.49 (s, 1 H, Im 5-H), 7.54 (s, 1
H, Im 5-H), 7.86 (s, 1 H, Im 5-H), 8.32 (dd, J ϭ 10 Hz, 4 H,
phenylic), 8.38 (t, J ϭ 6.0 Hz, 1 H, CONHCH2CH2), 8.49 (t, J ϭ
K. E. Rao, J. W. Lown, Trends Org. Chem. 1992, 3, 141Ϫ171
and references cited therein.
[12] [12a]
N. H. Al-Said, J. W. Lown, Synth. Commun. 1995, 25,
[12b]
1059Ϫ1070. Ϫ
E. Nishiwaki, S. Tanaka, H. Lee, M. Shib-
uya, Heterocycles 1988, 27, 1945Ϫ1952.
[13a] T. A. Bryson, J. C. Wisowaty, R. B. Dunlap, R. R. Fisher, P.
[13b]
D. Ellis, J. Org. Chem. 1974, 39, 1158Ϫ1160. Ϫ
Hotten, Ind. Eng. Chem. 1957, 49, 1691Ϫ1694. Ϫ
Russell, E. G. Janzen, H. D. Becker, F. Y. Smentowski, J. Am.
B. W.
G. A.
[13c]
2102
Eur. J. Org. Chem. 2000, 2095Ϫ2103

Geometrically Constrained Bis(polyamides) Related to the Antiviral Distamycin
FULL PAPER
K. Krowicki, J. W. Lown,
[13d]
[14d]
Chem. Soc. 1962, 84, 2652Ϫ2653. Ϫ
H. B. Hass, M. L.
Khim. 1952, 22, 2201Ϫ2029. Ϫ
J. Org. Chem. 1987, 52, 3493Ϫ3501.
Bender, J. Am. Chem. Soc. 1949, 71, 1767Ϫ1769.
[14] [14a] E. Fromm, Justus Liebigs Ann. Chem. 1925, 442, 130Ϫ149.
Received November 2, 1999
[O99614]
[14b]
Ϫ
A. Pinner, F. Klein, Ber. Dtsch. Chem. Ges. 1877, 10,
1889Ϫ1897. Ϫ [14c] A. N. Baksheev, N. I. Gavrilov, Zh. Obshch.
Eur. J. Org. Chem. 2000, 2095Ϫ2103
2103