Novel pyrrole C-nucleosides by nitrogen extrusion from pyridazine C-nucleosides

Article abstract of DOI:10.1016/j.tetlet.2003.11.088

Pyridazine C-nucleosides have been synthesized by [4+2] cycloaddition of alkynyl C-nucleosides with substituted tetrazines. These pyridazines on extrusion of a nitrogen atom afforded novel pyrrole C-nucleosides with good yields. The results of electrochemical and chemical reduction are compared.

Full text of DOI:10.1016/j.tetlet.2003.11.088

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1031–1033
Novel pyrrole C-nucleosides by nitrogen extrusion from
pyridazine C-nucleosides
a
a
a
a
a
Uday Joshi, Solen Josse, Muriel Pipelier, Floris Chevallier, Jean-Paul Prad ꢀe re,
b
c
c
a,
*
Roland Hazard, St ꢁe phanie Legoupy, Franßcois Huet and Didier Dubreuil
a
Laboratoire de Synth ꢀe se Organique (UMR 6513), University of Nantes, 2 rue de la Houssini ꢀe re, BP 92208,
4322 Nantes Cedex, France
Laboratoire d’Electrochimie, URA CNRS no. 439, Campus de Beaulieu, 35042 Rennes Cedex, France
4
b
c
Laboratoire de Synth ꢀe se Organique (UMR 6011), Universit ꢁe du Maine, av. Olivier Messiaen, 72085 Le Mans Cedex 9, France
Received 30 September 2003; revised 13 November 2003; accepted 19 November 2003
Abstract—Pyridazine C-nucleosides have been synthesized by [4+2] cycloaddition of alkynyl C-nucleosides with substituted tetra-
zines. These pyridazines on extrusion of a nitrogen atom afforded novel pyrrole C-nucleosides with good yields. The results of
electrochemical and chemical reduction are compared.
Ó 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
It was thus obvious to attempt the same methodology
toward the synthesis of pyrrole C-nucleosides in order to
test their biological activity. Herein we wish to sum-
marize our results on the electrochemical as well as the
chemical transformation of pyridazine C-nucleosides to
the corresponding pyrrole C-nucleosides.
C-Nucleosides bearing five-membered nitrogen hetero-
cycles such as thiazofurin, pyrazomycin, showdomycin
etc. and their analogs are known to possess varied bio-
logical activities. C-Nucleosides bearing a nitropyrrole
are known for their biochemical and pharmacological
activities. Recently Burnham et al. reported that pyr-
role C-nucleosides also exhibit anticancer activity. Even
simple substituted pyrroles are known to exhibit anti-
1
2
3
4
neoplastic, antileukemic activities.
2. Preparation of pyridazine C-nucleosides 4
This led us toward the synthesis of novel functionalized
pyrrole C-nucleosides. In the last few years we have
successfully developed an electrochemical method for
In the first place the pyridazine C-nucleosides 4 were
prepared by the procedure described by Seitz and
7
co-worker.
D
-())-Ribose (1) was converted to furanose
5
the synthesis of substituted pyrroles from pyridazines.
2 by a conventional method. Treatment of intermediate
2 with appropriate alkynyl GrignardÕs reagents, pre-
pared in situ, and cyclization of the resulting open-chain
compound through selective tosylation of the propar-
gylic hydroxy group, afforded the corresponding alkynyl
sugars 3a–b, in 25% and 40% overall yields, respectively
(Scheme 1). The b-isomer was found to be the major
isomer in every case (b:a ¼ 8:2). Having alkynyl sugars
in hand, they were converted to pyridazine C-nucleo-
sides 4a–b by inverse demand hetero Diels–Alder reac-
In this process the latter undergo extrusion of a nitrogen
atom to afford the corresponding substituted pyrrole
derivatives by a controlled potential electroreduction.
This process appears complementary to that of BogerÕs
strategy using Zn/AcOH to achieve the ring contraction
6
of diazaheterocycles.
8
tions with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate
7
as described by Seitz and co-worker. By slight changes
Keywords: Pyridazine C-nucleosides; Ring contraction; Pyrrole C-
nucleosides.
in the reaction conditions, we were successful in signif-
icantly increasing the yields of the individual steps for
the synthesis of pyridazine C-nucleosides 4a–b. Thus the
*
Corresponding author. Tel.: +33-251125420; fax: +33-251125402;
e-mail: didier.dubreuil@chimie.univ-nantes.fr
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.088

1032
U. Joshi et al. / Tetrahedron Letters 45 (2004) 1031–1033
O
O
Table 1
Entry Pyridazine
OH
OH
OH
OBn
a
b
HO
BnO
R
Method
Yield of 5
(%)
6
9%
HO
O
BnO
1
2
1
2
3
4
5
6
4a
4b
4a
4b
4b
4b
Ph
Electrolysis
Electrolysis
74
18
63
34
N
N
MeO C
n-Bu
Ph
2
R
c
O
CO Me
2
Zn, AcOH, rt, 24 h
Zn, AcOH, rt, 24 h
BnO
BnO
n-Bu
n-Bu
n-Bu
R
BnO
OBn
Zn, AcOH, 60 °C, 24 h 53
Zn, AcOH, reflux, 15 h 63
BnO
OBn
3
(a: R=Ph, 25%; b: R=nBu, 40%)
4 (a: R=Ph, 56%; b: R=nBu, 65%)
Scheme 1. Reagents and conditions: (a) (i) MeOH, catalytic H
ii) NaH, THF/DMF, BnBr, rt, (iii) AcOH, 1 M H SO
, 100 °C; (b) (i)
R–CBC–MgBr, THF, 60 °C, (ii) TsCl, pyridine, 60 °C; (c) dimethyl
,2,4,5-tetrazine-3,6-dicarboxylate, toluene, reflux.
2 4
SO ,
(
2
4
been described and can be transposed to the pyridazine
10
1
C-nucleoside precursors. Thus in the case of 4a, the
yield of the reaction was very good (75%) but, surpris-
ingly, in the case of 4b, the corresponding pyrrole was
isolated in only low yield (18%) along with the undesired
side products. In the case of 4a, no formation of side
products was observed. The results are summarized in
Table 1.
yield of the [4+2] cycloaddition reaction was optimized
to 56% in the case of 4a and 65% in the case of 4b,
9
respectively.
3. Nitrogen extrusion by the electrochemical method
The next step was to convert these pyridazine C-nucleo-
sides 4a–b into the corresponding pyrrole derivatives.
In a typical electroreduction experiment, previously
4. Nitrogen extrusion by chemical methods
The low yield obtained in the case of 4b led us to carry
out the same transformation by chemical means. Thus,
treatment of 4a with zinc and acetic acid at room tem-
perature for 24 h followed by the work up procedure as
10
optimized in our laboratory, the electrolysis of a
solution of the pyridazine derivative in the electrolytic
system, comprised of ethanol and acidic buffer, was
carried out in the potential range of )0.8 to )1.2 E/(V vs
SCE). The potential range was determined on the basis
of the polarograms of the pyridazine derivatives, which
indicated two successive bielectronic steps [E1=2 ¼ ꢀ0:9
and )1.1 E/(V vs SCE)]. Cyclic voltametry was per-
6
described by Boger et al., and purification of the crude
product by column chromatography on silica gel affor-
ded the desired pyrrole derivative, as shown in Scheme
2. In this case, the yield was comparable (63%) to that of
the electrochemical method, whereas in the case of 4b,
the desired pyrrole derivative was isolated in only 34%
yield. However, improvement in the yield of 4b
was achieved (63%) when the reaction was carried out at
a higher temperature. The results are summarized in
Table 1.
ꢀ
1
formed at a sweep rate of 0.2 V s . The polarogram and
the cyclic voltamogram are shown in Figure 1. The
mechanism of the electrochemical transformation of
pyridazines to pyrrole rings, consisting of a stepwise
transfer of four electrons and four protons, has already
Figure 1. Cyclic voltamogram (A) and polarogram (B) of pyridazine C-nucleosides.
H
N
H
N
MeO C
N
MeO C
N
MeO C
2
2
2
CO Me
CO Me
2
2
a
b
O
CO
2
Me
O
O
BnO
85-90%
HO
BnO
R
R
R
BnO
OBn
HO
BnO
OBn
OH
4
(a: R=Ph, b: R=nBu)
5 (a: R=Ph, b: R=nBu)
6 (a: R=Ph, b: R=nBu)
2
Scheme 2. Reagents and conditions: (a) Zn, AcOH or electrolysis; (b) H /Pd–C, ethyl acetate, rt.

U. Joshi et al. / Tetrahedron Letters 45 (2004) 1031–1033
1033
In the last step, the benzyl protecting groups were
removed by conventional hydrogenolysis of 5a–b, as
shown in Scheme 2, to afford the novel pyrrole
N. L.; Armitt, D. J.; Banwell, M. G. Synthesis 2003, 1837–
843.
. Fernandez-Bolanos, J.; Mota, J. F.; Ramirez, I. R. An.
Quim., Ser. C: Quim. Org. Bioquim. 1984, 80, 123–126,
and references cited therein.
. Lam, K. S.; Glersaye, S.; Patel, K.; Najmi, S.; Burnham,
B. S. Abstracts of Papers, 225th ACS National Meeting,
New Orleans, LA, United States, March 23–27, 2003.
. Anderson, W. K.; Heider, A. R. J. Med. Chem. 1986, 29,
2392–2395.
1
2
3
4
11
C-nucleosides (6a–b) in excellent yields (>85%).
In summary, we have synthesized novel pyrrole C-
nucleosides by a nitrogen extrusion strategy. Some
exploratory work such as the synthesis of pyridazine
C-nucleosides with different substituents and their elec-
trolysis under basic conditions is being undertaken in
order to study the behavior of the pyridazine deriva-
tives. The biological evaluation of novel pyrrole
C-nucleosides for their anticancer activity, is currently in
progress.
5. Manh, G. T.; Hazard, R.; Prad ꢀe re, J. P.; Tallec, A.;
Raoult, E.; Dubreuil, D. Tetrahedron Lett. 2000, 41, 647–
6
50.
6
7
8
. Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D.
J. Org. Chem. 1984, 49, 4405–4409.
. Richter, M.; Seitz, G. Arch. Pharm. (Weinheim) 1994,
327, 365–370.
. Boger, D. L.; Coleman, R. S.; Panek, J. S.; Huber, F. X.;
Sauer, J. J. Org. Chem. 1985, 50, 5377–5379.
6
Acknowledgements
9. 45% for 4b as reported by Seitz. Even in the case of 4a the
yield was about 35% when SeitzÕs conditions were
followed.
This work was supported by the ÔMinist ꢀe re de lÕEduca-
tion Nationale de la Recherche et de la TechnologieÕ
with a doctoral fellowship to S.J. and a postdoctoral
fellowship to U.J. We also thank CNRS and the ÔConseil
R ꢁe gional des Pays de la LoireÕ.
1
0. Manh, G. T.; Hazard, R.; Tallec, A.; Prad ꢀe re, J. P.;
Dubreuil, D.; Thiam, M.; Toupet, L. Electrochim. Acta
2
002, 47, 2833–2841.
1
1. 2,5-Bis(methoxycarbonyl)-4-phenyl-3-(b-
D
-ribofuranosyl)-
1
H-pyrrole 6a: Mp 83–84 °C (as colorless needles from pet.
25
ether–dichloromethane). ½aꢁ )23° (c 1.0, CHCl
3
). IR
D
H NMR (300 MHz, CDCl
ꢀ
1
1
(
neat): 3434, 1708 cm
.
3
2
):
),
d 2.37 (s, 1H, OH
3.48 (dd, 1H, H , J
5
), 3.17 (s, 1H, OH
¼ 10:3, J
3
), 3.31 (s, 1H, OH
References and notes
¼ 2:6), 3.65 (dd, 1H,
5
a
5a–5b
5a–4
H
5b, J5b–5a ¼ 10:3, J5b–4 ¼ 1:7), 3.67 (s, 3H, CH
1H, H ), 3.92 (s, 3H, CH ), 4.05 (m, 1H, H ), 4.21 (m, 1H,
), 4.94 (d, 1H, H
, J1–2 ¼ 7:8), 7.29–7.38 (m, 5H, Ph),
3
), 3.78 (m,
1
. (a) Petrie, C. R.; Revankar, G. R.; Dalley, N. K.; George,
R. D.; McKernan, P. A.; Hamill, R. L.; Robins, R. K. J.
Med. Chem. 1986, 29, 268–278; (b) Hammerschmidt, F.;
Peric, B.; Ohler, E. Monatsh. Chem. 1997, 128, 183–190;
4
3
3
H
2
1
1
3
9.96 (s, 1H, NH); C NMR (75 MHz, CDCl ): d 51.9,
3
52.4, 62.5, 70.6, 75.6, 77.6, 85.5, 121.6, 122.0, 127.5, 127.7,
128.0, 130.5, 132.3, 133.5, 160.5. Anal. Calcd for
(c) Franchetti, P.; Marchetti, S.; Cappellacci, L.; Yalowitz,
J. A.; Jayaram, H. N.; Goldstein, B. M.; Grifantini, M.
C
19
H21NO
8
: C, 58.31; H, 5.41; N, 3.58. Found: C, 58.63;
Bioorg. Med. Chem. Lett. 2001, 11, 67–69; (d) Hungerford,
H, 5.32; N, 3.39.