Novel heterocyclic Tro?ger's base derivatives containing N-methylpyrrole units

Article abstract of DOI:10.1016/S0040-4039(03)00177-1

Novel analogues of Tr?ger's base were prepared regioselectively from 4-amino-N-methylpyrrole carboxylates in good yield. Catalytic hydrogenation of dibenzyl-4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo- [3,2-b:3′,2′-f][1,5]diazocin-2,7-dicarboxylate 2b led to 4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b: 3′,2′-f][1,5]diazocin-2,7-dicarboxylic acid 3 which was used for the preparation of Tr?ger's base derivatives of natural antibiotics via an amide protocol. The novel heterocyclic Tr?ger's bases were characterized by a variety of spectroscopic techniques and compound 2b by X-ray crystallography. Incorporation of guanidine as the terminal group in the N-methylpyrrole Tr?ger's base skeleton opens the possibility for preparation of water soluble derivatives.

Full text of DOI:10.1016/S0040-4039(03)00177-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2083–2086
Novel heterocyclic Tro¨ger’s base derivatives containing
N-methylpyrrole units
Martin Val´ık,a Bohumil Dolensky,a Hana Petrˇ´ıcˇkova´,b Petr Vasˇeka and Vladim´ır Kra´la,*
aDepartment of Analytical Chemistry, Institute of Chemical Technology Prague, Technicka´ 5, Praha 6, 166 28, Czech Republic
bDepartment of Solid State Chemistry, Institute of Chemical Technology Prague, Technicka´ 5, Praha 6, 166 28, Czech Republic
Received 25 November 2002; revised 13 January 2003; accepted 17 January 2003
Abstract—Novel analogues of Tro¨ger’s base were prepared regioselectively from 4-amino-N-methylpyrrole carboxylates in good
yield. Catalytic hydrogenation of dibenzyl-4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:3%,2%-f ][1,5]-
diazocin-2,7-dicarboxylate 2b led to 4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:3%,2%-f ][1,5]diazocin-
2,7-dicarboxylic acid 3 which was used for the preparation of Tro¨ger’s base derivatives of natural antibiotics via an amide
protocol. The novel heterocyclic Tro¨ger’s bases were characterized by a variety of spectroscopic techniques and compound 2b by
X-ray crystallography. Incorporation of guanidine as the terminal group in the N-methylpyrrole Tro¨ger’s base skeleton opens the
possibility for preparation of water soluble derivatives. © 2003 Elsevier Science Ltd. All rights reserved.
Although the original Tro¨ger’s base1 (TB) was prepared
more than a century ago, only recently has its V-shape
motif with a concave cavity attracted the attention of
scientists involved in the design of novel selective
molecular receptors.2 The synthesis of TB derivatives
was initially aimed at using aminobenzenes. Our contri-
butions to this area have involved compounds contain-
ing two and three Tro¨ger’s base units.3 Recently
heterocycle substituted anilines,4 amino heterocycles5
and aminophenanthroline6 and acridine7,8 derivatives
have been used for the construction of novel TB’s. The
latest reports on new TB derivatives have established
their specific interaction with DNA.8,9 However, TB
analogues bearing heterocyclic rings with functional
groups, allowing the construction of more advanced
and selective systems, have not been prepared to date.
oligo N-methylpyrrole derivatives interconnecting with
the methandiazocin scaffold.
The synthetic strategy was based on the preparation of
TB analogues from esters of 4-amino-1-methylpyrrole/
imidazole 1, which are amenable to further functionali-
zation of the periphery. Theoretically, two TB regioiso-
mers can arise from esters of 4-amino-1-methyl-2-car-
boxypyrrole 1a and 1b (cyclization can take place at
two different positions, a or b) during their treatment
with formaldehyde in ethanolic solutions in conc.
HCl.11 However, in both cases we isolated the regioiso-
mers 2 only. The lower reactivity of the b-pyrrole
position determines the exclusive formation of isomer 2.
While 1a and 1b afforded TB analogues 2a and 2b (Ref.
12), ethyl 4-amino-1-methylimidazole-2-carboxylate 1c,
which can only form isomer of type 2, did not give the
corresponding TB analogue under the same reaction
conditions.
Here, we describe the synthesis of novel substituted
heterocyclic TB derivatives extended by well known
selective receptor systems. We chose amino-N-
methylpyrroles and amino-N-methylimidazoles as
attractive starting materials for the construction of the
novel TB’s, because they constitute building blocks of
the natural antibiotics, e.g. distamycin and netropsin,
compounds recognized for their binding in the minor
groove of DNA with high affinity and specificity.10 We
thought that interesting properties could be achieved by
The key compound, TB derivative 3, with two car-
boxylic groups could be generated either by the hydroly-
sis of the methyl ester groups of 2a or by catalytic
reduction of the benzyl ester groups of 2b. The hydroly-
sis was performed with 1 M aqueous NaOH. However,
the subsequent acidification of the disodium salt solu-
tion of 3 led to partial degradation of the free dicar-
boxylic acid 3. On the other hand, the mild reaction
conditions of catalytic hydrogenation yielded the
desired dicarboxylic TB derivative 3 in 88% yield (see
Scheme 1).
Keywords: Tro¨ger’s base; N-methylpyrrole; regioselectivity;
guanidine.
* Corresponding author. E-mail: kralv@vscht.cz
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00177-1

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M. Val´ık et al. / Tetrahedron Letters 44 (2003) 2083–2086
Scheme 1. Preparation of starting TB derivatives. (i) CH2O, HCl, EtOH, 24 h, rt (Ref. 12); (ii) H2, Pd/C, DMF.
Scheme 2. Modifications of TB dicarboxylic acid 3. (i) DCC, HOBT, DMF, CH2Cl2, 50°C; (ii) corresponding amino compound,
2 days; (iii) H2, Pd/C, DMF; (iv) TFA, CH2Cl2; (v) HCl (g), MeOH.

M. Val´ık et al. / Tetrahedron Letters 44 (2003) 2083–2086
2085
Compound 3 was subsequently used for the preparation
of the hexa-N-methylpyrrole TB derivatives 5a and 5b
through the active ester13 4 generated in the reaction
mixture (Scheme 2). In addition, the intermediate 5c
was obtained as a by-product in preparation of 5b in
26% yield. The products 5 were separated from the
reaction mixtures by column chromatography (methyl-
ene dichloride with 5% of methanol) and purified by
precipitation with petroleum ether. All attempts to
prepare 5a and 5b directly from the corresponding
amino-functionalized tri-N-methylpyrrolopeptides were
unsuccessful, because degradation predominated. The
preparation of an acid chloride from the dicarboxylic
acid 3 failed as well. The derivative 5b was converted to
the dicarboxylic acid 6 by catalytic hydrogenation of
benzyl ester groups (Scheme 2).
Suitable amino derivative 8 could have been generated
from its protected form 7, which was obtained in 26%
yield. Unfortunately, acidic deprotection of 7 was
accompanied by degradation of the product. Conse-
quently, an alternative procedure was used involving
the reaction of aminoethylhexahydropyrimidin-2-yl-
amine 11 (Ref. 15) with the TB active ester 4 to give the
bis-cyclic guanidine derivative 9.
Recently the reported conversion of a methyl ester into
an acylguanidine moiety16 was used as another method
for the introduction of the guanidinium moiety. Reflux
of 2a for 2 days with an excess of guanidine in 2 M
sodium methoxide solution gave the bis-acylguanidine
derivative 12 (Scheme 3). Product 12 was separated in
only 43% yield, although the conversion was almost
quantitative (monitored by TLC).
Many TB receptors have been described,2 but their
recognition properties were mostly studied in organic
solvents. With the intention of studying medicinal
applications, we introduced hydrophilic guanidinium
units into the compounds. This modification led not
only to an improvement of their water solubility, but
also to the derivatives 9, with terminal cyclic guanidine
groups, and 12 with acylguanidine terminal groups,
with suitable binding properties for dianionic species.
Reaction of the primary amines with 2-methylsulfanyl-
1,4,5,6-tetrahydropyrimidine hydriodide 10 (Ref. 14) is
an alternative way to prepare guanidinium derivatives.
All new compounds were characterized by NMR, MS,
in some cases by elemental analysis and the spatial
structure of 2b was unambiguously determined by X-
ray crystallography (Fig. 1). The dihedral angle charac-
terizing the TB core for 2b is 104.17° (program Parst17
Scheme 3. Preparation of water soluble TB derivative 12. (i) CH3OH, CH3ONa, 2 days, reflux.
Figure 1. ORTEP19 drawing of receptor 2b (for selected data see Ref. 12)

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M. Val´ık et al. / Tetrahedron Letters 44 (2003) 2083–2086
was used for its calculation). This angle is very similar
to those found in other TB structures.18
ular Chemistry; Pergamon Press: Oxford, 1996; p. 81; (b)
Dervan, P. B. Bioorg. Med. Chem. 2001, 9, 2215–2235; (c)
Reddy, B. S.; Sharma, S. K.; Lown, J. W. Curr. Med. Chem.
2001, 8, 475–508.
In conclusion, we have introduced
a
new N-
methylpyrrole TB scaffold as the central unit for novel
distamycin analogues and new receptors. Synthetic mod-
ifications of 3 afforded the hexapyrrole derivatives 5a and
5b. Water solubility was provided by the incorporation
of the guanidinium moiety to compounds 2a and 3,
respectively. Our preliminary data show that the bis
guanidine derivative 9 and the bis-acylguanidinium 12
exhibit binding affinity to DNA. A detailed study includ-
ing DNA foot-printing experiments is in progress.
11. Miller, T. R.; Wagner, E. C. J. Am. Chem. Soc. 1941, 63,
832–836.
12. Selected data for dibenzyl-4,9-methano-1,6-dimethyl-
4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:3%,2%-f ][1,5]-
diazocin-2,7-dicarboxylate 2b. Compound 1b, obtained
from 4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-
2-carboxylic acid benzyl ester (5 g; 15.15 mmol) by
treatment with trifluoroacetic acid, was dissolved in a
mixture of ethanol (50 ml), formaldehyde (7.5 ml) and
aqueous concentrated HCl (7.5 ml). The reaction mixture
was stirred for 24 h at rt, then concentrated to one half of
the original volume and finally made alkaline with ammonia
to pH 14. The mixture was extracted with methylene
chloride (5×40 ml) and the combined organic layers were
washed with water (80 ml), dried over MgSO4 and evapo-
rated. Crystallization from methylene dichloride–diethyl
ether mixture gave 2.36 g (63%) of 2b. 1H NMR (300 MHz,
CDCl3) l 3.64 (s, 6H); 3.92 (d, J=15.9 Hz, 2H); 4.09 (s,
2H); 4.36 (d, J=16.5 Hz, 2H); 5.24 (s, 4H); 6.77 (s, 2H);
7.36 (m, 10H); 13C NMR (75 MHz, CDCl3) l 32.56, 52.21,
65.31, 68.90, 110.29, 119.76, 127.18, 127.86, 127.97, 128.46,
131.24, 136.50, 160.90; IR (KBr, cm−1): 3060, 3034, 2946,
1698, 1550, 1497, 1457, 1234, 1085 cm−1. MS(CI) 495
((M−H)+). For C29H28N4O4 calcd: C, 70.15 ; H, 5.68; N,
11.28%. Determined: C, 70.45; H, 5.97; N, 11.20%. X-Ray
data for C29N4O4H28 (2b), triclinic system, space group P-1,
Acknowledgements
Financial support from the Ministry of Education of the
Czech Republic Grant No. MSM 223400008, the Grant
EU QLRT-2000-02360 and Grant Agency of the Czech
Republic No. 309/02/1193 is gratefully acknowledged.
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