Preparation of highly substituted 6-arylpurine ribonucleosides by Ni-catalyzed cyclotrimerization. Scope of the reaction

Article abstract of DOI:10.1021/jo061485y

Transition metal complex catalyzed cocyclotrimerization of protected alkynylpurine ribonucleosides 1 with various diynes 2 gave rise to a series of 6-arylpurine nucleosides 3 that were further deprotected to free nucleosides 4. Generally, the best yields

Full text of DOI:10.1021/jo061485y

ribonucleosides show significant cytostatic4 and anti-HCV5
effects. Also, 6-alkynylpurines are potent cytostatics6 and inhibit
15-lipoxygenase.7 In addition, unnatural 6-arylpurine nucleo-
bases were used in artificial base pairs8 and as covalent base-
pair analogues.9 Until recently, biological activity screening and
other applications (e.g., in chemical biology) have been limited
to easily accessible purines bearing simple aryl groups, while
highly substituted and/or functionalized ones still remain to be
explored. Since many bulky and hydrophobic aryl C-nucleosides
also have been used recently as potential nucleobase surrogates10
in extension of the genetic alphabet, the preparation of 6-arylpu-
rines bearing bulky hydrophobic substituents is of particular
interest. As for the synthetic methods, 6-arylpurines mostly have
been prepared by cross-coupling reactions11 of 6-halopurines
with various organometallics (arylboronic acids, stannanes, or
zinc halides); however, for highly functionalized aryl groups,
such organometallics would not be easily available or even stable
enough under the reaction conditions. Therefore, alternative
procedures of their synthesis are still of interest.
Preparation of Highly Substituted 6-Arylpurine
Ribonucleosides by Ni-Catalyzed
Cyclotrimerization. Scope of the Reaction
Pavel Turek,†,‡ Petr Nova´k,† Radek Pohl,‡
Michal Hocek,*,‡ and Martin Kotora*,†,‡
Department of Organic and Nuclear Chemistry, and the Centre
for New AntiVirals and Antineoplastics, Faculty of Science,
Charles UniVersity, HlaVoVa 8, 128 43 Praha 2, Czech
Republic, and Centre for New AntiVirals and Antineoplastics,
Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, FlemingoVo na´m. 2,
166 10 Praha 6, Czech Republic
kotora@natur.cuni.cz; hocek@uochb.cas.cz
ReceiVed July 18, 2006
In our previous reports, we have shown that cyclotrimerization
of 6-alkynylpurines with zirconacyclopentadienes12 or with R,ω-
diynes catalyzed by in situ generated Ni(0)-species from NiBr2-
(dppe)/Zn is a suitable method for the preparation of 9-Bn- or
9-THP protected 6-arylpurines.13 Herein, we wish to describe
an extension of the latter methodology to the synthesis of the
corresponding ribonucleosides. It is not a routine extension
because for nucleoside synthesis, the method must be compatible
with acyl protected sugar moieties and with rather labile
nucleosidic bonds, and also, the functionality must survive
(3) (a) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.; Nolsøe,
J. M. J. Bioorg. Med. Chem. Lett. 2000, 10, 1207-1210. (b) Andresen, G.;
Gundersen, L.-L.; Nissen-Meyer, J.; Rise, F.; Spilsberg, B. Bioorg. Med.
Chem. Lett. 2002, 12, 567-569. (c) Gundersen, L.-L.; Nissen-Meyer, J.;
Spilsberg, B. J. Med. Chem. 2002, 45, 1383-1386. (d) Bakkestuen, A. K.;
Gundersen, L.-L.; Utenova, B. T. J. Med. Chem. 2005, 48, 2710-2723.
(4) (a) Hocek, M.; Holy´, A.; Votruba, I.; Dvorˇa´kova´, H. J. Med. Chem.
2000, 43, 1817-1825. (b) Hocek, M.; Holy´, A.; Votruba, I.; Dvorˇa´kova´,
H. Collect. Czech. Chem. Commun. 2001, 66, 483-499.
Transition metal complex catalyzed cocyclotrimerization of
protected alkynylpurine ribonucleosides 1 with various diynes
2 gave rise to a series of 6-arylpurine nucleosides 3 that were
further deprotected to free nucleosides 4. Generally, the best
yields of cyclotrimerizations were obtained with a catalytic
system Ni(cod)2/2PPh3. On the other hand, CoBr(PPh3)3
proved to be a superior catalyst for cyclotrimerization of 1
with dipropargyl ether 2g. In addition, Ni catalysis is also
suitable for direct cyclotrimerization of unprotected alky-
nylpurine ribonucleosides 5 to the corresponding 6-arylpu-
rinylribosides 4.
(5) Hocek, M.; Nausˇ, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish,
P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869-5873.
(6) (a) Hocek, M.; Votruba, I. Bioorg. Med. Chem. Lett. 2002, 12, 1055-
1058. (b) Hocek, M.; Dvorˇa´kova´, H.; C´ısaˇrova´, I. Collect. Czech. Chem.
Commun. 2002, 67, 1560-1578. (c) Hocek, M.; Votruba, I.; Dvorˇa´kova´,
H.; Tetrahedron 2003, 59, 607-611. (d) Hocek, M.; Sˇteˇpnicˇka, P.; Ludv´ık,
J.; C´ısaˇrova´, I.; Votruba, I.; Rˇ eha, D.; Hobza, P. Chem.sEur. J. 2004, 10,
2058-2066. (e) Nausˇ, P.; Votruba, I.; Hocek, M. Collect. Czech. Chem. Com-
mun. 2004, 69, 1955-1970. (f) Brathe, A.; Gundersen, L.-L.; Nissen-Meyer,
J.; Rise, F.; Spilsberg, B. Bioorg. Med. Chem. Lett. 2003, 13, 877-880.
(7) Berg, T. C.; Gundersen, L.-L.; Eriksen, A. B.; Malterud, K. E. Eur.
J. Org. Chem. 2005, 4988-4994.
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T.; Nakayama, H.; Takio, K.; Yabuki, T.; Kigawa, T.; Kodama, K.;
Yokogawa, T.; Nishikawa, K.; Yokoyama, S. Nat. Biotechnol. 2002, 20,
177-182.
(9) Havelkova´, M.; Dvoˇra´k, D.; Hocek, M. Tetrahedron 2002, 58, 7431-
7435.
Purine bases and nucleosides bearing an aryl moiety in
position 6 display diverse types of biological activity: some
substituted 6-arylpurine bases are antagonists of corticotropin
releasing hormones1 or adenosine receptors2 or possess anti-
mycobacterial and antibacterial activity,3 while 6-arylpurine
(10) (a) Pathak, A. K.; Pathak, V.; Seitz, L. E.; Suling, W. J.; Reynolds,
R. C. J. Med. Chem. 2004, 47, 273-276. (b) Kool, E. T. Acc. Chem. Res.
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Chem., Int. Ed. 2000, 39, 990-1009.
(11) Review: Hocek, M. Eur. J. Org. Chem. 2003, 245-254.
(12) For Ni-mediated reaction of 6-alkynylpurines with zirconacyclo-
pentadienes, see: Turek, P.; Kotora, M.; Hocek, M.; Votruba, I. Collect.
Czech. Chem. Commun. 2005, 70, 339-349.
(13) (a) Turek, P.; Kotora, M.; Hocek, M.; C´ısaˇrova´, I. 2003, 44, 785-
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C´ısaˇrova´, I. J. Org. Chem. 2004, 69, 9224-9233.
* To whom correspondence should be addressed. (M.H.) Phone: +420
220182324; fax: +420 220183559. (M.K.) Phone: +420 221 951 334; fax:
+420 221 951 326.
† Charles University.
‡ Institute of Organic Chemistry and Biochemistry.
(1) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.; Gilligan,
P. Bioorg. Med. Chem. Lett. 1999, 9, 1063-1066.
(2) Chang, L. C. W.; Spanjersberg, R. F.; von Frijtag Drabbe Ku¨nzel, J.
K.; Mulder-Krieger, T.; Brussee, J.; Izerman, A. P. J. Med. Chem. 2006,
49, 2861-2867.
10.1021/jo061485y CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/11/2006
8978
J. Org. Chem. 2006, 71, 8978-8981

TABLE 1. Influence of the Solvent on the Course of the Reaction
of 1a with 2a
SCHEME 1. Cyclotrimerization of Alkynylpurine
Nucleosides 1 with Diynes 2
entry
catalyst (20 mol %)a
solvent
yield (%)b
1
2
3
4
5
6
Ni(cod)2/2PPh3
Ni(cod)2/2PPh3
Ni(cod)2/2PPh3
Ni(cod)2/2PPh3
Ni(cod)2/2PPh3
Ni(cod)2/2PPh3
toluene
CH2Cl2
THF
acetone
DMF
36
13
40
52
63
81
MeCN
a 20 °C, 24 h. b Isolated yield.
propargylamines 2e and 2f gave the corresponding products 3ae
and 3af in average yields of 48 and 36%, respectively (entries
5 and 6). In the case of 1,7-octadiyne, the yield of 3ai was low
(13%). On the other hand, the reaction of 1a catalyzed by NiBr2-
(dppe)/Zn provided the products in inferior yields (entries 1-4,
and 7). Suprisingly, this system proved to be more efficient in
the reaction with dipropargylamines 2e and 2f; the corresponding
products 3ae and 3af were obtained in 70 and 69% yields, respec-
tively (entries 5 and 6). The cyclotrimerization of 1a with 2a
was tested also in the presence of Ni(cod)2 and polymeric PPh3;
however, the corresponding product 3aa was obtained only in
very low yield (7%). An attempt to carry out the cyclotrimer-
ization with CpCo(CO)220 did not yield any product, thus confirm-
ing the previous results.17b As expected, the cyclotrimerization
of 1a with dipropargyl ether 2g was efficiently catalyzed by
CoBr(PPh3)13b,21 to furnish 3ag in 80% yield (entry 7). Interest-
ingly, the same catalyst was also able to cyclotrimerize
dipropargylphenylamine 2f to 3af in 30% yield (entry 6).
The cyclotrimerizations of 1b and 1c with diynes 2 were
carried out in a similar manner. Thus, reactions catalyzed by
Ni(cod)2/2PPh3 proceeded in good yields only with 2a (entries
10 and 14) giving 3ba and 3ca in 85 and 66%, respectively. In
other cases, the yields were rather low in the range of 15-39%
(entries 11, 12, 14, and 15). Again, the NiBr2(dppe)/Zn system
proved to be more efficient for the cyclotrimerization of
dipropargylamine 2e with 1c (entry 14); the corresponding
product 3ce was obtained in higher yield (41%). The cyclotri-
merizations of dipropargyl ether 2g proceeded well in the
presence of CoBr(PPh3)3 to give the corresponding products in
28 and 55% yield (entries 12 and 15).
deprotection. This paper then reports on an efficient and modular
synthesis of highly substituted 6-arylpurine ribonucleosides by
Ni catalyzed cyclotrimerizations of 6-ethynylpurines 1 with R,ω-
diynes 2 (Scheme 1). In addition, a comparison of two Ni
catalytic systems, NiBr2(dppe)/Zn and Ni(cod)2/2PPh3, and in
some cases also a Co catalyst, is given.
14-16
Since Ni(cod)2/2PPh3
and other Ni based systems17,18
are known to be efficient catalysts for the cyclotrimerization of
various alkynes, it was desirable to compare their reactivity with
the NiBr2(dppe)/Zn system.13,19 Our initial study was focused
on the reaction of 1a with 2a in different solvents to optimize
reaction conditions. The results presented in Table 1 show that
yields of the corresponding arylpurinylglycoside 3aa rose with
the increasing polarity of the solvent used. Thus, the best yield
of 3aa was obtained in MeCN (81%), which is in agreement
with previous observations.
With the optimized reaction conditions in hand, we examined
the cyclotrimerization of 6-phenylethynyl-1a, 6-butylethynyl-1b,
and 6-[(trimethylsilyl)ethynyl]purine riboside-1c with various
alkynes (Table 2). The reactions of 1a catalyzed by Ni(cod)2/
2PPh3 proceeded in good yield with 2a-2d, 2g, and 2h (71-
88%) (entries 1-4, 7, and 8). The cyclotrimerization with di-
In the next step, the obtained 3xy were deprotected to obtain
free 6-arylpurine ribonucleosides 4xy. The deprotection of the
triacetylriboside moiety was carried out with 20 mol % MeONa
in MeOH at 20 °C within 1 h (Scheme 2). Generally, the
deprotection proceeded in most cases to give expected nucleo-
sides 4xy, other ester or keto groups present in the starting
molecules were not affected. Only the deprotection of 3ad
afforded the product 4ad as methyl cyanoacetate (71%) instead
of ethyl cyanoacetate. Very good yields of 4ac and 4ag (82
and 85%) were obtained in the deprotection of [acetyl-
(carboxyethyl)indanyl]purine 3ac and (dihydroisobenzofuranyl)-
purine 3ag. The deprotection of [diethylcarboxy)indanyl]purine
3aa afforded the corresponding products 4aa in 76% yield. In
the case of tosylderivative 3ae, the deprotection resulted in a
moderate yield of 4ae (65%). The deprotection proceeded also
with n-butyl and trimethylsilyl substituted derivatives 3ba and
3ca to afford the corresponding products 4ba and 4ca in 88
and 81% yield, respectively.
(14) (a) Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994, 59, 6133-
6135. (b) Sato, Y.; Nishimata, T.; Mori, M. Heterocycles 1997, 44, 443-457.
(c) Sato, Y.; Ohashi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5231-5234.
(15) (a) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil, Sˇ.;
Sˇaman, D. Tetrahedron Lett. 1999, 40, 1993-1996. (b) Teply´, F.; Stara´, I.
G.; Stary´, I.; Kolla´rovicˇ, A.; Sˇaman, D.; Rul´ısˇek, L.; Fiedler, P. J. Am.
Chem. Soc. 2002, 124, 9175-9180. (c) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ,
A.; Teply´, F.; Sˇaman, D.; Fiedler, P. Collect. Czech. Chem. Commun. 2003,
68, 917-930. (d) Teply´, F.; Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Sˇaman,
D.; Fiedler, P.; Vyskocˇil, Sˇ. J. Org. Chem. 2003, 68, 5193-5197.
(16) (a) Hocek, M.; Stara´, I. G.; Stary´, I.; Dvorˇa´kova´, H. Tetrahedron
Lett. 2001, 42, 519-522. (b) Hocek, M.; Stara´, I. G.; Stary´, I.; Dvorˇa´kova´,
H. Collect. Czech. Chem. Commun. 2002, 67, 1223-1235.
(17) (a) Rosenthal, U.; Schultz, W. J. Organomet. Chem. 1987, 321,
103-117. (b) Rosenthal, U.; Schultz, W. J. Organomet. Chem. 1988, 348,
135-139.
(18) For nickel-mediated cyclotrimerizations, see: (a) Bhatarah, P.;
Smith, E. H. J. Chem. Soc., Perkin Trans 1 1990, 2603-2606. (b) Bhatarah,
P.; Smith, E. H. J. Chem. Soc., Chem. Commun. 1991, 277-278. (c) Bha-
tarah, P.; Smith, E. H. J. Chem. Soc., Perkin Trans 1 1992, 2163-2168.
(19) For application of the NiBr2(dppe)/Zn system in other alkyne cyclo-
trimerizations, see: (a) Jeevanandam, A.; Korivi, R. J.; Huang, I.; Cheng,
C.-H. Org. Lett. 2002, 4, 807-810. (b) Dufkova´, L.; C´ısaˇrova´, I.; Sˇteˇpnicˇka,
P.; Kotora, M. Eur. J. Org. Chem. 2003, 2882-2887. (c) Rodr´ıguez, J. G.;
de los Rios, C.; Lafuente, A. Tetrahedron 2005, 61, 9042-9051.
(20) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539-
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(21) Field, L. D.; Ward, A. J.; Turner, P. Aust. J. Chem. 1999, 52, 1085-
1092.
J. Org. Chem, Vol. 71, No. 23, 2006 8979

TABLE 2. Cyclotrimerization of Alkynylpurine Ribonucleosides 1 with Diynes 2
8980 J. Org. Chem., Vol. 71, No. 23, 2006

Table 2. (Continued)
a Reactions were carried out at 20 °C for 24 h unless otherwise noted. b AcRfPur ) 2,3,5-tri-O-acetyl-â-D-ribofuranosyl. c Isolated yield. d 140 °C. e 8 h.
f 48 h. g 1 h.
SCHEME 2. Deprotection of Peracetylated Nucleosides 3 to
Free Nucleosides 4
ribosides with a range of diynes. On the other hand, in some
cases (e.g., the cyclotrimerizations with dipropargylamines), the
use of the latter system was more effective. The origin of this
phenomenon is not yet clear and will be the object of a future
study. As for other catalysts, CoBr(PPh3)3 proved to be excellent
for cyclotrimerization of dipropargyl ether and also showed
reasonable catalytic activity for reactions with dipropargyl-
amines. The obtained results are in accord with those reported
for other 6-alkynylpurines and thus should be considered as
reliable guidelines for future cyclotrimerization of other alky-
nylpurinyl derivatives. In addition, the cyclotrimerization could
even be carried out with substrates bearing free hydroxyl groups
to give the desired product in reasonable yields avoiding the
protection-cyclotrimerization-deprotection reaction sequence.
SCHEME 3. Cyclotrimerization of Free Purine
Ribonucleoside 5 with 2
Experimental Section
General Procedure for Ni(cod)2/2PPh3 Catalyzed Cyclotri-
merization of 6-Alkynylpurines 1 with Diynes 2. Into a mixture
of Ni(cod)2 (0.04 mmol, 11 mg) and PPh3 (0.10 mmol, 26 mg)
was added a solution of 6-alkynylpurine 1 (0.20 mmol) and diyne
2 (0.22 mmol) in dry MeCN (4 mL). The reaction mixture was
initially stirred at 20 °C for 24 h or until the consumption of the
starting material (TLC). Then, the solvent was evaporated under
reduced pressure, and the residue was subjected to column
chromatography.
6-[6-Phenyl-2,2-di(carboxyethyl)indan-5-yl]-9-(2,3,5-tri-O-
acetyl-â-D-ribofuranosyl)-9H-purine (3aa). Column chromatog-
raphy on silica gel (diethyl ether) afforded 116 mg (81%) of a white
From a synthetic point of view, it is desirable to avoid
deprotection and to cyclotrimerize unprotected 6-alkynylpurine
ribonucleosides with diynes directly to 6-arylpurine nucleosides.
Since it has been shown that the presence of free hydroxyl
groups in a molecule of an alkyne did not inhibit the reac-
tion,17,18,22 the unprotected 6-(phenylethynyl)purine riboside 5
was cyclotrimerized with 2a and 2c by a catalytic amount of
Ni(cod)2/2PPh3 (Scheme 3). The reaction took place; however,
the desired unprotected arylpurine ribosides 4aa and 4ac were
obtained in rather mediocre yields of 31 and 45%, respectively.
Obviously, these results indicate that this route is not a superior
alternative to cyclotrimerization of protected nucleosides;
however, it could be of some use for derivatives with function-
alities incompatible with deprotection by sodium methoxide.
The cyclotrimerization approach to highly substituted 6-arylpu-
rines previously reported13 only for purine bases is applicable
also for an efficient synthesis of the corresponding nucleosides.
From general point of view, the comparison of catalytic
activity of the Ni(0)-species generated from Ni(cod)2/2PPh3 or
NiBr2(dppe)/Zn is clearly in favor of the former system, which
is suitable for cocyclotrimerization of various 6-alkynylpurine
1
foam: [R]D -22.8 (c 0.23, CHCl3); H NMR (500 MHz, CDCl3)
δ 1.28 (t, 6H, J ) 7.1 Hz), 2.09, 2.10, and 2.15 (3 × s, 3 × 3H),
3.70 and 3.72 (2 × s, 2 × 2H), 4.23 (q, 4H, J ) 7.1 Hz), 4.36 (dd,
1H, J ) 13.1, 5.3 Hz), 4.43-4.49 (m, 2H), 5.67 (t, 1H, J ) 5.3,
4.9 Hz), 5.90 (t, 1H, J ) 5.3, 5.0 Hz), 6.19 (d, 1H, J ) 5.0 Hz),
7.12 (m, 5H), 7.38 (s, 1H), 7.60 (s, 1H), 8.03 (s, 1H), 8.83 (s, 1H);
13C NMR (125.8 MHz, CDCl3) δ 14.0, 20.4, 20.5, 20.7, 40.2, 40.4,
60.6, 61.8, 62.9, 70.5, 73.15, 80.3, 86.4, 126.5, 126.7, 126.7, 127.8,
129.2, 132.8, 133.1, 139.4, 141.2, 141.2, 142.4, 142.5, 150.9, 152.4,
159.8, 169.3, 169.5, 170.3, 172.4; IR (CHCl3) ν 3031, 2986, 1750,
1732, 1588, 1369, 1248, 1097, 1069, 1052 cm-1; MS (FAB, m/z
(rel.%)) 715 (M+ + H, 5), 457 (15), 139 (76), 97 (100); HR-MS
(FAB) calcd for C37H38N4O11 [M+ + H] 715.2615, found 715.2632.
EA calcd for C37H38N4O11: C 62.18, H 5.36, N 7.84; found: C
61.88, H 5.34, N 7.58. Rf (1:4 hexane/EtOAc) ) 0.45.
Acknowledgment. This work is a part of the Research
Project Z40550506 and was supported by the Centre for New
Antivirals and Antineoplastics (1M0508) from the Ministry of
Education of the Czech Republic.
Supporting Information Available: Experimental procedures
and compound characterization data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(22) (a) Bicev, P.; Furlani, A.; Sartori, G. Gazz. Chim. Ital. 1973, 103,
849-858. (b) Bicev, P.; Furlani, A.; Russo, M. V. Gazz. Chim. Ital. 1980,
110, 25-29.
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