Synthesis of C-aryldeoxyribosides by [2 + 2 + 2]-cyclotrimerization catalyzed by Rh, Ni, Co, and Ru complexes

Article abstract of DOI:10.1021/ol060454m

A novel approach to the synthesis of functionalized C-nucleosides was developed. Cyclotrimerization of C-alkynyldeoxyriboside with a variety of substituted 1,6-heptadiynes to the corresponding C-aryldeoxyribosides was catalyzed by various transition metal

Full text of DOI:10.1021/ol060454m

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2051-2054
Synthesis of C-Aryldeoxyribosides by
[2 2]-Cyclotrimerization
Catalyzed by Rh, Ni, Co, and Ru
Complexes
+
2 +
Petr Nova´k,† Radek Pohl,‡ Martin Kotora,*,†,‡ and Michal Hocek*,‡
Department of Organic and Nuclear Chemistry and Centre for New AntiVirals &
Antineoplastics, Faculty of Science, Charles UniVersity, HlaVoVa 8, 128 43 Prague 2,
Czech Republic, and Institute of Organic Chemistry and Biochemistry,
FlemingoVo na´m. 2, 160 11 Prague 6, Czech Republic
kotora@natur.cuni.cz
Received February 21, 2006
ABSTRACT
A novel approach to the synthesis of functionalized C-nucleosides was developed. Cyclotrimerization of C-alkynyldeoxyriboside with a variety
of substituted 1,6-heptadiynes to the corresponding C-aryldeoxyribosides was catalyzed by various transition metal complexes (Rh, Ir, Co, Ru,
and Ni). The most general catalyst proved to be RhCl(PPh3)3, which could catalyze most of the cyclotrimerizations in high yields (52−95%).
C-Nucleosides are an important class of compounds char-
acterized by replacement of a labile nucleosidic C-N bond
by a stable C-C bond. Many of them possess antiviral or
antineoplastic activities.1 Quite recently, C-nucleosides bear-
ing hydrophobic aryl groups as nucleobase surrogates at-
tracted great attention due to their use in the extension of
the genetic alphabet.2 Duplexes containing self-pairs of
hydrophobic nucleobases are stable due to increased stacking
and favorable desolvation energy as compared to canonical
nucleobases.3 Triphosphates of some of the C-nucleosides
are efficiently incorporated to DNA by DNA polymerase.4
There are a number of synthetic approaches to C-nucleo-
sides.5 The most general methods are (i) additions of
organometallics to ribono- or 2-deoxyribonolactones,4,6 (ii)
(3) (a) Ogawa, A. K.; Abou-Zied, O. K.; Tsui, V.; Jimenez, R.; Case,
D. A.; Romesberg, F. E. J. Am. Chem. Soc. 2000, 122, 9917-9920. (b)
Wu, Y. Q.; Ogawa, A. K.; Berger, M.; Mcminn, D. L.; Schultz, P. G.;
Romesberg, F. E. J. Am. Chem. Soc. 2000, 122, 7621-7632. (c) Guckian,
K. M.; Krugh, T. R.; Kool, E. T. J. Am. Chem. Soc. 2000, 122, 6841-
6847. (d) Parsch, J.; Engels, J. W. J. Am. Chem. Soc. 2002, 124, 5664-
5672. (e) Lai, J. S.; Qu, J.; Kool, E. T. Angew. Chem., Int. Ed. 2003, 42,
5973-5977. (f) Lai, J. S.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 3040-
3041.
(4) Henry, A. A.; Olsen, A. G.; Matsuda, S.; Yu, C.; Geierstanger, B.
H.; Romesberg, F. E. J. Am. Chem. Soc. 2004, 126, 6923-6931. (b) Henry,
A. A.; Yu, C. Z.; Romesberg, F. E. J. Am. Chem. Soc. 2003, 125, 9638-
9646.
† Charles University.
‡ Institute of Organic Chemistry and Biochemistry.
(1) Examples: (a) Franchetti, P.; Cappellacci, L.; Griffantini, M.; Barzi,
A.; Nocentini, G.; Yang, H. Y.; O’Connor, A.; Jayaram, H. N.; Carrell, C.;
Goldstein, B. M. J. Med. Chem. 1995, 38, 3829-3837. (b) Walker, J. A.;
Liu, W.; Wise, D. S.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998,
41, 1236-1241.
(2) Reviews: (a) Wang, L.; Schultz, P. G. Chem. Commun. 2002, 1-11.
(b) Henry, A. A.; Romesberg, F. E. Curr. Opin. Chem. Biol. 2003, 7, 727-
733. (c) Kool, E. T.; Morales, J. C.; Guckian, K. M. Angew. Chem., Int.
Ed. 2000, 39, 990-1009. (d) Kool, E. T. Acc. Chem. Res. 2002, 35, 936-
943.
(5) Wu, Q. P.; Simons, C. Synthesis 2004, 1533-1553.
(6) (a) Matsuda, S.; Romesberg, F. E. J. Am. Chem. Soc. 2004, 126,
14419-14427. (b) Mathis, G.; Hunziker, J. Angew. Chem., Int. Ed. 2002,
41, 3203-3205. (c) Brotschi, C.; Ha¨berli, A.; Leumann, C. J. Angew. Chem.,
Int. Ed. 2001, 40, 3012-3014. (d) Brotschi, C.; Mathis, G.; Leumann, C.
J. Chem.sEur. J. 2005, 11, 1911-1923. (e) Zahn, A.; Brotschi, C.;
Leumann, C. J. Chem.sEur. J. 2005, 11, 2125-2129.
10.1021/ol060454m CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/18/2006

coupling of a halogenose with organometallics,7 or (iii)
electrophilic substitutions of electron-rich aromatics with
sugars under Lewis acid catalysis.8 All these approaches
suffer from insufficient anomeric selectivity and the necessity
to optimize reaction and separation conditions for each
particular C-nucleoside. Very recently, we have developed9
a modular approach consisting of the preparation of bromo-
phenyl C-nucleosides as versatile intermediates suitable for
further derivatization, giving rise to a series of diverse target
C-nucleosides. Here we report on another modular approach
consisting of construction of an aromatic ring on deoxyribose
by cyclotrimerization of 1-ethynyl-2-deoxyribose with R,ω-
diynes.
Catalytic cyclotrimerization of alkynes to benzene deriva-
tives is a nice example of an efficient and clean reaction
during which three new C-C bonds are formed in one step.
As such, it fulfills all standards to define it as an atom
economical procedure.10 Therefore, it is not surprising that
it has been used as a key step for the synthesis of a plethora
of natural and biologically active compounds and their
derivatives.11 Out of many possible synthetic approaches to
C-arylglycosides, the one based on a catalytic [2 + 2 +
2]-cyclotrimerization of R,ω-diynes with C-alkynylglycosides
is promising because it can furnish the desired compounds
under mild reaction conditions. Moreover, the reaction of
pure R- and â-alkynylsaccharides should furnish the corre-
sponding anomers, thus overcoming stereochemistry prob-
lems. As far as the application of cyclotrimerization methods
in the synthesis of C-arylglycosides is concerned, it has been
carried out with various alkynylpyranoses,12-14 whereas its
application for the synthesis of deoxyribose or ribose
derivatives has been rather neglected. Our goal was to fill
this gap and to test the cyclotrimerization strategy for the
preparation of a series of variously substituted C-aryldeoxy-
ribosides, as well as to assess the suitability of various
commonly used transition metal catalysts for this reaction.
Our initial goal was to prepare pure 1â-ethynyl-1,2-dideoxy-
3,5-di-O-(4-toluoyl)-D-ribofuranose 1â according to the
reported procedure.15 Although we followed the protocol
precisely, only a 2:1 anomeric mixture of 1R- and 1â-
ethynyl-1,2-dideoxy-3,5-di-O-(4-toluoyl)-D-ribofuranose, 1r
and 1â, was obtained each time.
Scheme 1. Catalytic Cyclotrimerization of 1 with 2a
the reactants were stirred in a 3 mL glass vial under
protective atmosphere of argon for an appropriate amount
of time. The obtained results are presented in Table 1. At
Table 1. Catalytic Cyclotrimerization of an Anomeric Mixture
1 with Diynes 2a
entry diyne 2
catalyst
product 3 yield (%)b
1
2a
Rh(PPh3)3Cl
[Ir(COD)Cl]2/dppec
NiBr2(dppe)/Znc
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
3a
86
42
44
57
57
52
17
52
2
3
4
5
6
2b
2c
2d
2e
2f
3b
3c
3d
3e
3f
a The reaction was carried out at 20 °C. b Isolated yields. c The reaction
was carried out at 80 °C.
the ambient temperature (20 °C), only Rh(PPh3)3Cl was
catalytically active.16 The use of [Ir(COD)Cl]2/dppe17 and
NiBr2(dppe)/Zn18,19 required the use of a temperature of 80
°C to promote the reaction (entry 1). The isolated yields of
the C-aryldeoxyriboside 3a were 86, 42, and 44%, respec-
(10) For a discussion on atom economy, see: (a) Trost, B. M. Science
1991, 254, 1471-1477. (b) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34,
259-281.
(11) (a) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1977, 99,
5853-5854. (b) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980,
102, 5253-5261. (c) Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J.
Am. Chem. Soc. 1986, 108, 856-858. (d) Neeson, S. J.; Stevenson, P. J.
Tetrahedron 1989, 45, 6239-6248. (e) Saa´, C.; Crotts, D. D.; Hsu, G.;
Vollhardt, K. P. C. Synlett 1994, 487-489. (f) Witulski, B.; Zimmermann,
A.; Gowans, N. D. Chem. Commun 2002, 2984-2985. (g) Moser, M.; Sun,
X.; Hudlicky´, T. Org. Lett. 2005, 7, 5669-5672.
Since the separation of anomeric mixtures required the
use of HPLC, we decided to check the catalytic activity of
various transition metals complexes for [2 + 2 + 2]-cyclo-
trimerization with the anomeric mixture 1. As the second
reaction partner, dipropargylmalonate 2a was chosen. To
keep the experimental conditions as simple as possible, all
(12) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem.
Soc. 1995, 117, 6605-6606.
(13) Yamamoto, Y.; Saigoku, T.; Nishiyama, H.; Ohgai, T.; Itoh, K.
Chem. Commun. 2004, 2702-2703.
(7) (a) Chaudhuri, N. C.; Kool, E. T. Tetrahedron Lett. 1995, 36, 1795-
1798. (b) Ren, R. X.-F.; Chaudhuri, N. C.; Paris, P. L.; Rumney, S., IV;
Kool, E. T. J. Am. Chem. Soc. 1996, 118, 7671-7678. (c) Strassler, C.;
Davis, N. E.; Kool, E. T. HelV. Chim. Acta 1999, 82, 2160-2171. (d)
Griesang, N.; Richert, C. Tetrahedron Lett. 2002, 43, 8755-8758. (e)
Aketani, S.; Tanaka, K.; Yamamoto, K.; Ishihama, A.; Cao, H.; Tengeiji,
A.; Hiraoka, S.; Shiro, M.; Shinoya, M. J. Med. Chem. 2002, 45, 5594-
5603.
(8) (a) Yokoyama, M.; Nomura, M.; Togo, H.; Seki, H. J. Chem. Soc.,
Perkin Trans. 1 1996, 2145-2149. (b) He, W.; Togo, H.; Yokoyama, M.
Tetrahedron Lett. 1997, 38, 5541-5544. (c) Hainke, S.; Arndt, S.; Seitz,
O. Org. Biomol. Chem. 2005, 3, 4233-4238.
(9) Hocek, M.; Pohl, R.; Klepeta´rˇova´, B. Eur. J. Org. Chem. 2005, 4525-
4528.
(14) Yamamoto, Y.; Saigoku, T.; Nishiyama, H.; Ohgai, T.; Itoh, K. Org.
Bioorg. Chem. 2005, 3, 1768-1775.
(15) Wamhoff, H.; Warnecke, H. ARKIVOC 2001, 95-100.
(16) For leading references on Rh-catalyzed cyclotrimerizations, see: (a)
Mu¨ller, E. Synthesis 1974, 761-774. (b) Grigg, R.; Scott, R.; Stevenson,
P. Tetrahedron Lett. 1982, 23, 2691-2692. (c) Magnus, P.; Witty, D.;
Stamford, A. Tetrahedron Lett. 1993, 34, 23-26. (d) Kotha, S.; Brahma-
chary, E. Tetrahedron Lett. 1997, 38, 3561-3564. (e) Witulski, B.; Stengel,
T. Angew. Chem., Int. Ed. 1999, 38, 2426-2430. (f) McDonald, F. E.;
Smolentsev, V. Org. Lett. 2002, 4, 745-748. (g) Kotha, S. Brahmachary,
E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741-4767.
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2991-2994.
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Org. Lett., Vol. 8, No. 10, 2006

tively. Since the best result was obtained with Wilkinson’s
catalyst, next we examined the generality of the cyclo-
trimerization of 1 with differently substituted R,ω-diynes
(Table 1, entries 2-6). The reactions with heptadiynes 2b-
2d afforded the corresponding C-aryldeoxyribosides 3b-
3d in good isolated yields (52-57%). Surprisingly, intro-
duction of nitrogen into the linker connecting the triple bonds,
the reaction with dipropargyltosylamide 2e, yielded the target
glycoside 3e only in low yield of 17%. On the other hand,
the reaction with dipropargyl ether 2f resulted in the
formation of 3f in reasonable yield (52%) (entry 6). In
contrast to the above-mentioned results, the cyclotrimeriza-
tion with 1,7-octadiyne gave only a complex reaction
mixture. This observation is not surprising since a similar
result has been observed before.16b
After the method was optimized with the anomeric mixture
1, we applied it to pure â-anomer 1â. The cyclotrimerizations
were carried out with various Ru, Rh, Co, and Ni complexes
as representatives of the most widely utilized catalysts to
assess their catalytic activity and selectivity (Table 2). Out
of them, as expected, Rh(PPh3)3Cl (Wilkinson’s catalyst)
emerged as the most active and general one. The corre-
sponding C-aryldeoxyribosides were obtained from reason-
able (entries 3 and 4) to excellent yields (entries 1 and 2).
Nonetheless, in cases where the heterocyclic ring was
formed, such as in 3âe and 3âf (entries 5 and 6), the yields
were rather low. Although it has recently been shown that
Co(PPh3)3Br was very active for cyclotrimerization of various
alkynes and especially dipropargyl ether,18b,20 the reaction
of 1â with 2a and 2f afforded the corresponding products
3âa and 3âf in only 23 and 25% yields (entry 5 and 6),
respectively.
Table 2. Cyclotrimerization of 1â with 2 to 3â Catalyzed by
Various Catalystsa
entry
1
diyne 2
catalyst
product 3â
3âc
yield (%)b
2a
Rh(PPh3)3Cl
Ni(cod)2/2PPh3
Cp*RuCl(cod)
Co(PPh3)3Br
Rh(PPh3)3Cl
Ni(cod)2/2PPh3
Cp*RuCl(cod)
Rh(PPh3)3Cl
Ni(cod)2/2PPh3
Cp*RuCl(cod)
Rh(PPh3)3Cl
Ni(cod)2/2PPh3
Cp*RuCl(cod)
Rh(PPh3)3Cl
Ni(cod)2/2PPh3
Cp*RuCl(cod)
Rh(PPh3)3Cl
Ni(cod)2/2PPh3
Cp*RuCl(cod)
Co(PPh3)3Br
95
74
95
23
81
76
40
62
50
39
52
42
33
12
45
41
32
30
30
25
2
3
4
5
6
2b
2c
2d
2e
2f
3âb
3âc
3âd
3âe
3âf
a The reaction was carried out at 20 °C. b Isolated yields.
3â (30-59%) were generally lower than those obtained with
the Rh catalyst. Only in the case of the reaction with
dipropargyltosylamide 2e (entry 5) was the use of Ni catalysis
advantageous: the yield of 3âe (45%) was 3-fold higher than
that obtained with the Rh catalyst (13%).
Interestingly, the use of Cp*RuCl(cod),13,14,22,23 which has
recently been used for a number of high-yielding cyclo-
trimerizations, did not meet our expectations. Generally, the
yields of cyclotrimerized products 3â (30-95%) were lowest
in comparison with other catalysts. The only exception was
the cyclotrimerization of 2a with 1â (entry 1), where the
yield matched the one obtained with Wilkinson’s catalyst.
At the moment, we are not able to offer any sensible
explanation as to why this otherwise highly active catalyst
known for its tolerance to a wide array of functional groups
gave these surprisingly inferior results.
Next, we decided to carry out Ni-catalyzed cyclotrimer-
izations. In contrast to the previously used catalytic system
(NiBr2(dppe)/Zn), in this instance, we chose to use Ni(0)-
phosphine complexes generated from Ni(cod)2 and tri-
phenylphosphine because of their known high catalytic
activity.21 However, the yields of cyclotrimerization products
(18) For the use of Ni(dppe)/Zn for cyclotrimerization of alkynylpurines
with diynes, see: (a) Turek, P.; Kotora, M.; Hocek, M.; C´ısarˇova´, I.
Tetrahedron Lett. 2003, 44, 785-788. (b) Turek, P.; Kotora, M.; Tisˇlerova´,
I.; Hocek, M.; Votruba, I.; C´ısaˇrova´, I. J. Org. Chem. 2004, 69, 9224-
9233.
(19) For the use Ni(dppe)Br2/Zn for cyclotrimerization of allenes with
diynes, see: Jeevanandam, A.; Korivi, R. J.; Huang, I.; Cheng, C.-H. Org.
Lett. 2002, 4, 807-810.
(20) For Co(PPh3)3Br-catalyzed cyclotrimerizations, see: (a) Field, L.
D.; Ward, A. J.; Turner, P. Aust. J. Chem. 1999, 52, 1085-1092. (b)
Dufkova´, L.; C´ısaˇrova´, I.; Sˇteˇpnicˇka, P.; Kotora, M. Eur. J. Org. Chem.
2003, 2882-2887. For CoI2/PPh3/Mn-catalyzed cyclotrimerizations, see:
(c) Slowinski, F.; Aubert, C.; Malacria, M. AdV. Synth. Catal. 2001, 343,
64-67.
(21) (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. (d) Stara´, I. G.; Stary´, I.; Kolla´rovicˇ, A.; Teply´, F.; Vyskocˇil, Sˇ.;
Sˇaman, D. Tetrahedron Lett. 1999, 40, 1993-1996. (e) Hocek, M.; Stara´,
I. G.; Stary´, I.; Dvorˇa´kova´, H. Tetrahedron Lett. 2001, 42, 519-522. (f)
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. (g) Hocek, M.; Stara´,
I. G.; Stary´, I.; Dvorˇa´kova´, H. Collect. Czech. Chem. Commun. 2002, 67,
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Vyskocˇil, Sˇ. J. Org. Chem. 2003, 68, 5193-5197.
In conclusion, we have shown that a transition metal
complex catalyzed [2 + 2 + 2]-cyclotrimerization of R,ω-
(22) (a) Yamamoto, Y.; Hattori, Y.; Ishii, J.; Nishiyama, H.; Itoh, K.
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Org. Lett., Vol. 8, No. 10, 2006
2053

diynes with C-ethynyldeoxyriboside under simple and mild
reaction conditions is an effective synthetic tool for prepara-
tion of anomerically pure C-aryldeoxyribosides. Although
all Rh, Ru, and Ni complexes proved to be effective for
catalyzing the reaction, the best results were obtained
with the stable and easy to handle Wilkinson’s catalysts
(Rh(PPh3)3Cl). From a synthetic point of view, the advantage
of this strategy is in the modular approach with regard to
structural variety of the R,ω-diynes, the functional group
compatibility of the transition metal catalysis with a wide
variety of functional groups in the reactants, and an easily
removable p-toluoyl protective group in the deoxyriboside.
This approach will be further used in the synthesis of a large
series of new C-nucleosides applicable in bioorganic and
medicinal chemistry.
Acknowledgment. This project was supported by Project
No. 1M0508 to the Centre for New Antivirals and Anti-
neoplastics from the Ministry of Education of the Czech
Republic and by Project No. 320/2005/B-CH/PrF from the
Grant Agency of Charles University.
Supporting Information Available: Experimental
procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060454M
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Org. Lett., Vol. 8, No. 10, 2006