Stereoselective synthesis of alkynyl C-2-deoxy-β-D-ribofuranosides via intramolecular Nicholas reaction: A versatile building block for nonnatural C-nucleosides

Article abstract of DOI:10.1021/ol027210w

Figure presented The reaction of 3,5-di-O-benzyl-2-deoxy-D-ribofuranose with various alkynyllithium reagents afforded diastereomeric mixtures of the corresponding ring-opened alkynyldiols. The resulting diastereomeric mixtures were successively treated wi

Full text of DOI:10.1021/ol027210w

ORGANIC
LETTERS
2003
Vol. 5, No. 5
625-628
Stereoselective Synthesis of Alkynyl
C-2-Deoxy-â-D-ribofuranosides via
Intramolecular Nicholas Reaction: A
Versatile Building Block for Nonnatural
C-Nucleosides
,‡,§
Masayoshi Takase,† Tomoyuki Morikawa,‡ Hajime Abe,‡ and Masahiko Inouye*
PRESTO, Japan Science and Technology Corporation (JST), Faculty of
Pharmaceutical Sciences, Toyama Medical and Pharmaceutical UniVersity,
Toyama 930-0194, Japan, and Department of Chemistry, Graduate School of Science,
Kyoto UniVersity, Kyoto 606-8502, Japan
inouye@ms.toyama-mpu.ac.jp
Received October 31, 2002
ABSTRACT
The reaction of 3,5-di-O-benzyl-2-deoxy-D-ribofuranose with various alkynyllithium reagents afforded diastereomeric mixtures of the corresponding
ring-opened alkynyldiols. The resulting diastereomeric mixtures were successively treated with Co2(CO)8, a catalytic amount of TfOH, Et3N,
and iodine in one pot to give alkynyl C-3,5-di-O-benzyl-2-deoxy-â-D-ribofuranosides with high â-selectivities. The cobalt-mediated cyclization
(intramolecular Nicholas reaction) is reversible; thus, thermodynamically more stable â-anomers were obtained preferentially. The alkynyl
C-deoxyribofuranosides were converted to a variety of C-deoxyribofuranoside derivatives.
The significant and diverse pharmaceutical value of various
C-glycosides has inspired investigations into developing new
synthetic methods for their practical preparation.1 Among
the C-glycosides, alkynyl C-glycosides are attracting much
attention because of the synthetic flexibility of the acetylenic
function.2 To the best of our knowledge, however, only one
example of the synthesis of alkynyl C-2-deoxy-D-ribofura-
nosides has been reported, in which the weakly selective
formation of the less important R-anomer was attained.3 In
our continuous studies on the development of synthetic
receptors for nucleobases and its application to nonnatural
oligonucleotides, we were confronted with difficulties in the
preparation of alkynyl C-2-deoxy-â-D-ribofuranosides. Thus,
we report herein a new approach for the stereoselective
synthesis of the alkynyl C-deoxyribofuranosides.4
In the initial attempt for the synthesis of the furano-
sides, we examined the Mitsunobu cyclization of the alky-
nylated diol 2a, which was prepared from 3,5-di-O-benzyl-
† Kyoto University.
‡ Toyama Medical and Pharmaceutical University.
§ PRESTO, JST.
(1) Recent books and reviews: (a) Simons, C. Nucleoside Mimetics:
Their Chemistry and Biological Properties; Gordon and Breach: Amster-
dam, 2001. (b) Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett 1998,
700-717. (c) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Pergamon: Oxford, 1995. (d) Postema, M. H. D. C-Glycoside Synthesis;
CRC: Boca Raton, FL, 1995. (e) Jaramillo, C.; Knapp, S. Synthesis 1994,
1-20. (f) Postema, M. H. D. Tetrahedron 1992, 48, 8545-8599.
(2) Recent reviews: (a) Isobe, M.; Nishizawa, R.; Hosokawa, S.;
Nishikawa, T. Chem. Commun. 1998, 2665-2676. (b) Isobe, M. J. Synth.
Org. Chem., Jpn. 1994, 52, 968-979. Some examples were also seen in
ref 1.
(3) Wamhoff, H.; Warnecke, H. ARKIVOC (online computer file) 2001,
2, 1085-1090.
10.1021/ol027210w CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/05/2003

Unfortunately, Tsunoda modification10 of the Mitsunobu
reaction revealed no improvement of the product yield. Thus,
the two-step reaction from 1 gave 3a(â) in only 23% yield
accompanied with troublesome separation of the diastereo-
isomers.
Scheme 1
We thought that the useless diol 2a(R) could be trans-
formed to the desired 3a(â) via an intramolecular Nicholas
reaction.11 Complexation of the alkynyl group of 2a(R) with
dicobalt octacarbonyl (Co2(CO)8) would afford 5a(R). In this
complex, the Co2(CO)6-alkyne functionality stabilizes the
adjacent sp2-hybridized carbocation formed by treatment with
acid, bringing about the loss of configuration at C1. The
following nucleophilic attack of the C4-OH on the stablized
carbocation may at least partly afford 6a(â). Treatment of
2a(R) with 1.2 equiv of Co2(CO)8 in CH2Cl2 gave rise to
the corresponding 5a(R) in a quantitative yield. Cyclization
of 5a(R) to 6a smoothly proceeded in the presence of 0.1
equiv of trifluoromethanesulfonic acid (TfOH) at 25 °C in
CH2Cl2 (Scheme 2). Surprisingly, only one cyclized product
Scheme 2
2-deoxy-D-ribofuranose (1)5 with (trimethylsilyl)ethynyllith-
ium (Scheme 1). The diol 2a was a mixture of two epimers
(32 and 58%), and the ratio of the epimers was scarcely
influenced by changing the reaction conditions. After treat-
ment with standard Mitsunobu reagents (Ph3P, DEAD),6 2a-
(S) gave one cyclized product 3a(â) and the other epimer
2a(R) gave two cyclized products 3a(r) and 4a(â).7 The
stereochemistry of the resulting furanosides was determined
by NOE experiments8 and derivatization of 3a(â) to the
known compound reported by Woerpel et al.,5,8 while the
C1 configurations of the starting diols 2a were assigned on
the basis of the stereochemistry of 3a and 4a, considering
Mitsunobu inversion. The diol 2a(S) was converted to the
desired â-anomer 3a(â) in 65% yield; on the other hand,
R-anomer 3a(r) and C4-inverted diastereomer 4a(â)9 were
obtained from 2a(R) in 38 and 12% yields, respectively.
6a(â) was obtained, which was determined to be the desired
anomer after decomplexation with iodine to 3a(â) in 93%
overall yield. The reaction was also successful when the
diastereomeric mixture of 2a was used, and the reaction
sequence of the complexation, cyclization, and decomplex-
ation could be conducted in one pot. Indeed, a mixture of
2a(S) and 2a(R) was treated with Co2(CO)8, TfOH, Et3N
(for neutralization of TfOH), and iodine to yield 3a(â) in
90% yield. In the conventional cyclization method utilizing
TsCl and pyridine,4a 2a(S) gave 3a(â) and 4a(r) in 51 and
8% yields, respectively, and 2a(R) gave 3a(r) and 4a(â) in
59 and 7% yields, respectively.
This reaction sequence is applicable to a wide variety of
alkynes. Thus, (trimethylsilyl)ethynyl, ethynyl, alkylethynyl,
arylethynyl, heteroarylethynyl, and (allyloxymethyl)ethynyl-
lithium or magnesium reagents could be used for the
alkynylation. The complexation and following reactions
afforded the corresponding alkynyl C-2-deoxy-D-ribofura-
nosides in high yields with high â-selectivities (Table 1).
Next, we tried to elucidate this high â-selectivity. The
isolated 6a(r) was subjected to the reaction conditions for
(4) On the other hand, various methods have been reported for the
synthesis of alkynyl C-â-D-ribofuranosides: (a) Buchanan, J. G.; Edgar,
A. R.; Power, M. J. J. Chem. Soc., Perkin Trans. 1 1974, 1943-1949.
Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. J. Chem. Soc., Perkin Trans.
1 1975, 1191-1200. (b) Arakawa, K.; Miyasaka, T.; Hamamichi, N. Chem.
Lett. 1976, 1119-1122. Hamamichi, N.; Miyasaka, T.; Arakawa, K. Chem.
Pharm. Bull. 1978, 26, 898-907. (c) De Las Heras, F. G.; Tam, S. Y.-K.;
Klein, R. S.; Fox, J. J. J. Org. Chem. 1976, 41, 84-90. Tam, S. Y.-K.;
Klein, R. S.; De Las Heras, F. G.; Fox, J. J. J. Org. Chem. 1979, 44, 4854-
4862. (d) Alonso, G.; Garcia-Lopez, M. T.; Garcia-Mun˜oz, G.; Madron˜ero,
R. An. Quim. 1976, 72, 987-990. (e) Gupta, C. M.; Jones, G. H.; Moffatt,
J. G. J. Org. Chem. 1976, 41, 3000-3009. (f) Zhai, D.; Zhai, W.; Williams,
R. M. J. Am. Chem. Soc. 1988, 110, 2501-2505. (g) Rycroft, A. D.; Singh,
G.; Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1995, 2667-2668.
(h) Maqbool, Z.; Hasan, M.; Pott, K. T.; Malik, A.; Nizami, T. A.; Voelter,
W. Z. Naturforsch 1997, 52b, 1383-1392.
(5) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208-12209. See Supporting Information of this
paper.
(6) Reviews for Mitsunobu reaction: Mitsunobu, O. Synthesis 1981,
1-28. Hughes, D. L. In Organic Reaction; Paquette, L. A., Ed.; John
Wiley: New York, 1992; Vol. 42, pp 335-656.
(7) Weizman, H.; Tor, Y. J. Am. Chem. Soc. 2001, 123, 3375-3376.
(8) See Supporting Information.
(10) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Itoˆ, S. Chem. Lett. 1994,
539-542. Itoˆ, S.; Tsunoda, T. Pure Appl. Chem. 1994, 66, 2071-2074.
(11) Reviews for Nicholas reaction: (a) Nicholas, K. M. Acc. Chem.
Res. 1987, 20, 207-214. (b) Smith, W. A.; Caple, R.; Smoliakova, I. P.
Chem. ReV. 1994, 94, 2359-2382.
(9) This type of C4 inversion was also seen in the preparation of C-aryl
ribofuranosides: Yokoyama, M.; Toyoshima, A.; Akiba, T.; Togo, H. Chem.
Lett. 1994, 265-268.
626
Org. Lett., Vol. 5, No. 5, 2003

Scheme 4
Table 1. Various Alkynylation and the Following
Intramolecular Nicholas Reaction
yield
(%)
epimer
ratioa
yield
(%)
R
2
3
R:âa
SiMe3
H (BrMgCtCH)
C4H9-n
Ph
2-pyrenyl
2-thienyl
2a
2b
2c
2d
2e
2f
90
83
84
90
90
97
89
36 (S):64 (R) 3a
90
62
62
99
97
78
75
1:99
32:68
8:92
12:88
13:87
10:90
4:96
34:66
46:54
34:66
34:66
37:63
39:61
3b
3c
3d
3e
3f
CH2OCH2CHdCH2 2g
3g
a Diastereomeric ratios were determined by isolated yields.
the cyclization (0.2 equiv of TfOH, 25 °C in CH2Cl2). The
epimerization from 6a(r) to 6a(â) occurred, and the final
ratio of 6a(r) to 6a(â) was found to be 1:7 (Scheme 3).12
This ratio was slightly different from the value obtained by
one-pot cyclization, indicating that further epimerization may
proceed under the subsequent conditions for neutralization
and decomplexation. This epimerization demonstrated that
the â-anomer of the complex is thermodynamically more
stable than the R-anomer, and both complexes were equili-
brated under the acidic conditions.13 The thermodynamic
difference between 6a(r) and 6a(â) is still unknown and
remains to be elucidated.
lar reduction and to C-carboxyl 2-deoxy-â-D-ribofuranoside
9 by oxidative cleavage of the acetylenic bond.15 The latter
product represents 2-deoxy-â-D-ribofuranoside with one
carbon at the anomeric position. The acetylenic group can
easily be transformed to various substituents with more than
two carbon atoms. Thus, the reaction sequences described
herein provide all kinds of building blocks covering most
of C-2-deoxy-D-ribofuranoside. Furthermore, the acetylenic
bond is a versatile precursor for the construction of various
heterocycles, which was demonstrated by 1,3-dipolar cy-
cloaddition16 of 3b(â) with nitrile N-oxide to afford C-
isoxazolyl deoxyribofuranoside 10. Alkynes possessing an
external alkene moiety exhibit another notable extension of
the reaction. The cobalt complex 11, the precursor of 3g(â),
was directly subjected to the conditions for Pauson-Khand
reaction17 to afford a novel bicyclic cyclopentenone-attached
C-2-deoxy-D-ribofuranoside 12. These types of C-nucleosides
may be attracting much attention from the viewpoint of
antiviral and antitumor drugs.1a
Scheme 3
The alkynyl C-deoxyfuranosides thus prepared have a wide
flexibility for the synthesis of various classes of C-deoxyri-
bofuranosides (Scheme 4). The (trimethysilyl)ethynyl moiety
of 3a(â) survived under the condition for the deprotection
of the benzyl groups with BCl3,14 leaving unprotected
(trimethylsilyl)ethynyl C-2-deoxyribofuranoside 7 in 93%
yield. A parent ethynyl C-deoxyribofuranoside 3b(â) was
converted to vinyl C-2-deoxy-â-D-ribofuranoside 8 by Lind-
In summary, we developed an effective method for the
synthesis of various alkynyl C-2-deoxy-D-ribofuranosides
with high â-selectivity. The reaction is applicable to a many
kinds of alkynes, and the complexation, cyclization, and
decomplexation steps can be conducted in one pot. We are
currently investigating the utilization of the C-nucleosides
(15) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938.
(12) Extra Co2(CO)8 (ca. 0.2 equiv) was added to preserve 6a from
decomposition.
(13) Isobe et al. reported similar phenomena in the cases of the cobalt
complexes of the alkynyl C-pyranose ring: see ref 2.
(14) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc.
1989, 111, 1923-1925.
(16) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Caramella, P.,
Grunanger, P., Eds.; Wiley & Sons: New York, 1984; Vol. 1, pp 322-
356.
(17) Krafft, M. E.; Scott, I. L.; Romero, R. H.; Feibelmann, S.; Van
Pelt, C. E. J. Am. Chem. Soc. 1993, 115, 7199-7205.
Org. Lett., Vol. 5, No. 5, 2003
627

as building blocks in oligonucleotides and their application
to the antisense DNA strategy.
NMR spectra of 5a(R), 5a(S), 6a(â), 6a(r), and 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds;
1
NOESY spectra of 3a(â), 4a(â), 3a(r), and 4a(r); and H
OL027210W
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Org. Lett., Vol. 5, No. 5, 2003