The first radical method for the introduction of an ethynyl group using a silicon tether and its application to the synthesis of 2′-deoxy-2′-C-ethynylnucleosides

Article abstract of DOI:10.1021/jo0206667

A novel radical method for the stereoselective introduction of an ethynyl group has been developed. When a solution of ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS) ethers of trans-2-iodoindanol was treated with Et_3<

Full text of DOI:10.1021/jo0206667

Th e F ir st Ra d ica l Meth od for th e In tr od u ction of a n Eth yn yl
Gr ou p Usin g a Silicon Teth er a n d Its Ap p lica tion to th e Syn th esis
of 2′-Deoxy-2′-C-eth yn yln u cleosid es1
Makoto Sukeda, Satoshi Ichikawa, Akira Matsuda, and Satoshi Shuto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6,
Kita-ku, Sapporo 060-0812, J apan
shu@pharm.hokudai.ac.jp
Received October 22, 2002
A novel radical method for the stereoselective introduction of an ethynyl group has been developed.
When a solution of ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS)
ethers of trans-2-iodoindanol was treated with Et3B followed by tetrabutylammonium fluoride in
toluene, atom transfer 5-exo-cyclization and subsequent elimination occurred to give cis-2-
ethynylindanol in high yield. The method was shown to be useful in the introduction of an ethynyl
group in various five- and six-membered-ring iodohydrins. Furthermore, 2′-deoxy-2′-C-ethynyl-
uridine (6) and -cytidine (7), which were designed as novel antimetabolites, were readily synthesized
by using this method as the key step. This would be the first example in which a radical reaction
was used for introducing an ethynyl group.
In tr od u ction
duction of an ethynyl group into the natural nucleoside
structure sometimes produces potent anti-metabolites.
5-Ethynyl-4-carbamoylimidazole-1-â-D-riboside (EICAR,
1) has shown anti-RNA viral and antitumor effects due
to its inosine 5′-phosphate dehydrogenase inhibition.6
1-(3-C-Ethynyl-â-D-ribo-pentofuranosyl)cytosine (ECyd,
2) is a potent antitumor nucleoside that significantly
inhibits the growth of various human solid tumor cells
both in vitro and in vivo, probably due to the inhibition
of tumor RNA synthesis.7 2′-Deoxy-4′-C-ethynylthymi-
dine (3) was identified as a potent anti-HIV agent,8 which
is effective against multidrug-resistant HIV strains
isolated from patients.8c,d Furthermore, the adenosine
derivatives 49 and 510 having ethynyl groups were identi-
fied as potent purinoceptor ligands.
Ethynyl groups, which have characteristic electronic
and structural features due to sp hybridization, are
present in many biologically active compounds.2 For
examples, an anti-Parkinsonian selegiline,3a a synthetic
follicle hormone ethynylestradiol,3b and an anti-human
immunodeficiency virus (HIV) agent efavirenz,3c the
structures of which are shown in Figure 1, have proven
effective in clinical use. Accordingly, in the course of
structure-activity relationship studies for drug develop-
ment, the introduction of ethynyl groups into compounds
is often attempted. Effective methods for regio- and/or
stereoselective introduction of ethynyl groups should
therefore be very useful.4
We have been engaged in medicinal chemical studies
These encouraging results prompted us to synthesize
further ethynyl nucleosides, such as 2′-deoxy-2′-C-ethyn-
yluridine (6) and 2′-deoxy-2′-C-ethynylcytidine (7). How-
of nucleoside analogues5 and have found that the intro-
* To whom all correspondence and reprint requests should be
addressed. Phone: +81-11-706-3228. Fax: +81-11-706-4980.
(1) This publication constitutes Part 219 of the series Nucleosides
and Nucleotides: for Part 218 see: Ueno, Y.; Hoshika, S.; Shibata, A.;
J in, J .; Kitade, Y.; Matsuda, A. Bioorg. Med. Chem. Submitted for
publication.
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J . Org. Chem. 2000, 65, 8988-8996 and references therein.
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10.1021/jo0206667 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/09/2003
J . Org. Chem. 2003, 68, 3465-3475
3465

Sukeda et al.
Ethynyl groups are also very useful in synthetic
organic chemical studies, and accordingly, much effort
has been expended to develop efficient methods for
introducing ethynyl and/or substituted ethynyl groups
into compounds, which produce alkynes via C-C single
bond formation.4 These methods can be generally clas-
sified as Type A, reactions of an acetylide or its congeners
to electrophilic carbon centers, and Type B, reactions of
an alkyne having an attached leaving group to nucleo-
philic carbon centers, as shown in Scheme 1 paths a and
b.11 Type A includes reactions of alkynylmetals with
carbon electrophiles12 and transition metal-catalyzed
cross-coupling reactions with alkyne derivatives.13 Type
B is typified by reactions between an alkynyl halide and
a carbon nucleophile, which appear to proceed via an
addition-elimination mechanism.14 Although these reac-
tions are very effective, introduction of an ethynyl group
at aliphatic carbon centers is often troublesome, espe-
cially regio- and stereoselectively. In fact, the synthesis
of our target ethynyl nucleosides 6 and 7, having a cis-
ethynylalkanol structure, was likely to be rather difficult.
We thought that radical reactions15 with silicon-
containing tethers, which have been widely used for
forming C-C bonds,16 might be employed effectively for
introducing ethynyl groups, as shown in Scheme 1c.Re-
cently, we developed a regio- and stereoselective method
for introducing C2-units at the position â to a hydroxyl
(11) Alkynes are also prepared by functional group transformations
forming CtC bonds, for examples see: (a) Bottini, A. T.; King, B. J .;
Lucas, J . M. J . Org. Chem. 1962, 27, 3688-3690. (b) Okuhara, K. J .
Org. Chem. 1976, 41, 1487-1494. (c) Negishi, E.; King, A. O.; Klima,
W. L. J . Org. Chem. 1980, 45, 2526-2528. (d) Shibasaki, M.; Torisawa,
Y.; Ikegami, S. Tetrahedron Lett. 1982, 23, 4607-4610. (e) Tsuji, J .;
Kezuka, H.; Toshida, Y.; Takayanagi, H.; Yamamoto, K. Tetrahedron
1983, 39, 3279-3282. (f) Ochiai, M.; Sumi, K.; Nagao, Y.; Fujita, E.;
Arimoto, M.; Yamaguchi, H. J . Chem. Soc., Chem. Commun. 1985,
697-699. (g) Abidi, S. L. Tetrahedron Lett. 1986, 27, 267-270. (h)
Akiyama, S.; Nakatsuji, S.; Nomura, K.; Matsuda, K.; Nakashima, K.
J . Chem. Soc., Chem. Commun. 1991, 948-950. (i) Ireland, R. E.;
Highsmith, T. K.; Genas, L. D.; Gleason, J . L. J . Org. Chem. 1992, 57,
5071-5073.
(12) Reactions of acetylides, for examaples see: (a) Smith, W. N.;
Beumel, O. F., J r. Synthesis 1974, 441-442. (b) Imamoto, T.; Sugiura,
Y.; Takiyama, N. Tetrahedron Lett. 1984, 25, 4233-4236. (c) Brown,
H. C.; Molander, G. A.; Singh, S. M.; Racherla, U. S. J . Org. Chem.
1985, 50, 1577-1582. (d) Isobe, M.; Hirose, Y.; Shimokawa, K.;
Nishikawa, T.; Goto, T. Tetrahedron Lett. 1990, 31, 5499-5502. (e)
Meyers, A. I.; Bienz, S. J . Org. Chem. 1990, 55, 791-798.
(13) Cross-coupling reactions introducing ethynyl groups, for ex-
amples see: (a) Armitage, J . B.; J ones, E. R. H.; Whiting, M. C. J .
Chem. Soc. 1952, 2014-2018. (b) Gardner, J . N.; J ones, E. R. H.;
Leeming, P. R.; Stephenson, J . S. J . Chem. Soc. 1960, 691-697. (c)
Giacomelli, G.; Marcacci, F.; Caporusso, A. M.; Lardicci, L. Tetrahedron
Lett. 1979, 20, 3217-3220. (d) Okuhara, K. Bull. Chem. Soc. J pn. 1981,
54, 2045-2052. (e) Rudisill, D. E.; Stille, J . K. J . Org. Chem. 1989,
54, 5856-5866. (f) Tao, W.; Nesbitt, S.; Heck, R. F. J . Org. Chem. 1990,
55, 63-69.
(14) Reactions of alkynylhalides, for examples see: (a) Oliver, R.;
Walton, D. R. M. Tetrahedron Lett. 1972, 13, 5209-5212. (b) Normant,
J . F.; Commercon, A.; Villieras, J . Tetrahedron Lett. 1975, 16, 1465-
1468. (c) Kende, A. S.; Fludzinski, P.; Hill, J . H.; Swenson, W.; Clardy,
J . J . Am. Chem. Soc. 1984, 106, 3551-3562. (d) de Graaf, W.; Smits,
A.; Boersma, J .; van Koten, G. Tetrahedron 1988, 44, 6699-6704. (e)
Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30, 4799-4802.
(15) (a) Laird, E. E.; J orgensen, W. L. J . Org. Chem. 1990, 55, 9-27.
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1489. (c) J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991,
91, 1237-1286. (d) Curran, D. P. In Comprehensive Organic Synthesis;
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in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2001.
F IGURE 1. Biologically active compounds having an ethynyl
group and the target ethynylnucleosides 6 and 7.
ever, the regioselective introduction of an ethynyl group
into nucleosides, especially into the sugar moiety in a
stereoselective manner, is problematic, and the previous
syntheses of the ethynyl nucleosides 2 and 3 required
rather long reaction pathways.7,8
(8) (a) Sugimoto, I.; Shuto, S.; Mori, S.; Shigeta, S.; Matsuda, A.
Bioorg. Med. Chem. Lett. 1999, 9, 385-388. (b) Nomura, M.; Shuto,
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Sakata, S.; Kodama, E.; Yoshimura, K.; Matsuoka, M.; Shigeta, S.;
Mitsuya, H. J . Med. Chem. 2000, 43, 4516-4525. (d) Kodama, E. I.;
Kohgo, S.; Kitano, K.; Machida, H.; Gatanaga, H.; Shigeta, S.;
Matsuoka, M.; Ohrui, H.; Mitsuya, H. Antimicrob. Agents Chemother.
2001, 45, 1539-1546.
(9) (a) Abiru, T.; Yamaguchi, T.; Watanabe, Y.; Kogi, K.; Matsuda.
A. Eur. J . Pharmacol. 1991, 196, 69-76. (b) Matsuda, A.; Shinozaki,
M.; Yamaguchi, T.; Homma, H.; Nomoto, R.; Miyasaka, T.; Watanabe,
Y.; Abiru. T. J . Med. Chem. 1992, 35, 241-252. (c) Abiru, T.; Miyashita,
T.; Watanabe, Y.; Yamaguchi, T.; Matsuda, A. J . Med. Chem. 1992,
35, 2253-2260. (d) Homma, H.; Watanabe, Y.; Abiru, T.; Murayama,
T.; Nomura, Y.; Matsuda. A. J . Med. Chem. 1992, 35, 2881-2890.
(10) (a) Matsuda, A.; Kosaki, H.; Yoshimura, Y.; Shuto, S.; Ashida,
N.; Shigeta, S. Bioorg. Med. Chem. Lett. 1995, 5, 1685-1688. (b)
Matsuda, A.; Kosaki, H.; Saitoh, Y.; Yoshimura, Y.; Minakawa, N.;
Nakata, H. J . Med. Chem. 1998, 41, 2676-2678. (c) Yoshioka, K.;
Matsuda, A.; Nakata, H. Clin. Exp. Pharmcol. Physiol. 2001, 28, 278-
284. (d) Shinozuka, K.; Ishii-Nozawa, R.; Takeuchi, K.; Minakawa, N.;
Matsuda, A.; Nakata, H.; Kunitomo, M. Clin. Exp. Pharmacol. Physiol.
2001, 28, 312-314.
3466 J . Org. Chem., Vol. 68, No. 9, 2003

Ethynyl Introduction via a Radical Reaction
SCHEME 1
by treatment of the resulting atom-transfer 5-exo-cycliza-
tion product I with fluoride ion forms the vinyl product
J .17d These reactions have been successfully applied to
the synthesis of biologically important 4′-branched-chain
sugar nucleosides17b,c and C-glycosides.17e,h
We hoped to develop a new radical method for intro-
ducing an ethynyl group based on these previous results
with a temporary silicon connection. Such a radical
method, as shown in Scheme 1c, would be a new type of
method for the introduction of ethynyl groups, which is
clearly different from the previous ionic type A and type
B reactions.
In this report, we describe a new efficient method for
the regio- and stereoselective introduction of an ethynyl
group by adapting an atom-transfer radical cyclization
reaction18,19 with an ethynylsilyl group as the radical
acceptor tether.20 Application of the new method to the
synthesis of 2′-deoxy-2′-C-ethynyluridine (6) and 2′-
deoxy-2′-C-ethynylcytidine (7) is also described.
Resu lts a n d Discu ssion
Wor k in g Hyp oth esis. Our strategy, using ethynyl-
dimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimeth-
ylsilyl (TEDMS)21 ethers of iodohydrins or R-phenylse-
lenoalkanols (I) as the reaction substrates, is shown in
Scheme 3. Treatment of the substrate I with a radical
initiator would produce the radical II, which preferen-
tially 5-exo-cyclizes to produce the radical III. When the
radical reaction is performed under atom-transfer condi-
tions,22 i.e., in the absence of a hydrogen source, the
radical III would abstract the iodine atom23 or PhSe
group24 of another substrate I to reproduce the radical
II along with the atom-transfer cyclization product IV.
Turnover of this scheme would accumulate the desired
product IV. We anticipated that, if this indeed occurred,
subsequent treatment of the product IV with fluoride ion
would promote elimination25 to give the desired ethynyl
product V. Thus, using the reaction sequence, the regio-
and stereoselective introduction of an ethynyl group at
the position â-cis to a hydroxyl group in iodohydrins or
R-phenylselenoalkanols would be achieved.26
group in halohydrins or R-phenylselenoalkanols using a
radical cyclization reaction with a dimethyl- or diphen-
ylvinylsilyl group as a temporary connecting radical-accep-
tor tether (Scheme 2).17 Thus, the selective introduction
of both the 1-hydroxyethyl and the 2-hydroxyethyl groups
can be achieved, depending on the concentration of Bu3-
SnH in the reaction system, via a 5-exo-cyclization
intermediate E or a 6-endo-cyclization intermediate F ,
respectively, after ring-cleavage of the radical reaction
products by their oxidative treatment, as shown in
Scheme 2.17a,b The studies on the mechanism showed that
the kinetically favored 5-exo-cyclized radical C, formed
from radical B, was trapped when the concentration of
Bu3SnH was high enough to give E. At lower concentra-
tions of Bu3SnH and higher reaction temperatures,
radical C rearranged into the more stable ring-enlarged
4-oxa-3-silacyclohexyl radical D, which was then trapped
with Bu3SnH to give F . This ring-enlarging rearrange-
ment was proved to occur via a pentavalent-like silicon-
bridging transition state X.17g A vinyl group can also be
introduced when the radical reaction is carried out under
the atom-transfer conditions, i.e., in the absence of a
hydrogen source such as Bu3SnH: a photoreaction of the
vinylsilyl ether A in the presence of (Bu3Sn)2, followed
Rea ction w ith Mod el In d a n ol Su bstr a tes. We first
planned to investigate the reaction with TEDMS ethers
of the indanols, 10a and 11a , as model substrates. The
TEDMS tether was introduced into the hydroxyl of trans-
SCHEME 2
J . Org. Chem, Vol. 68, No. 9, 2003 3467

Sukeda et al.
SCHEME 3
SCHEME 4
IV in Scheme 3, was thought to be unstable, tetrabutyl-
ammonium fluoride (TBAF, 2.5 equiv) was added directly
to the reaction mixture after the starting material had
disappeared on TLC. The resulting product of the reac-
tion sequence was isolated as the corresponding 3,5-
dinitrobenzoate by treatment with 3,5-dinitrobenzoyl
(DNBz) chloride, Et3N, and DMAP in MeCN. The results
are summarized in Table 1.
2-iodoindanol (8) and trans-1-phenylseleno-2-indanol (9)
with TEDMS-NMe2 as shown in Scheme 4. Since the
expected atom-transfer radical cyclization product, i.e.,
27
(16) Radical reactions with silicon tethers, for examples see: (a)
Nishiyama, H.; Kitajima, T.; Matsumoto, M.; Itoh, K. J . Org. Chem.
1984, 49, 2298-2300. (b) Stork, G.; Kahn, M. J . Am. Chem. Soc. 1985,
107, 500-501. (c) Magnol, E.; Malacria, M. Tetrahedron Lett. 1986,
27, 2255-2256. (d) Koreeda, M.; George, I. A. J . Am. Chem. Soc. 1986,
108, 8098-8100. (e) Tamao, K.; Maeda, K.; Yamaguchi, T.; Ito, Y. J .
Am. Chem. Soc. 1989, 111, 4984-4985. (f) Walkup, R. D.; Kane, R. R.;
Obeyesekere, N. U. Tetrahedron Lett. 1990, 31, 1531-1534. (g)
Koreeda, M.; Hamann, L. G. J . Am. Chem. Soc. 1990, 112, 8175-8177.
(h) Myers, A. G.; Gin, D. Y.; Widdowson, K. L. J . Am. Chem. Soc. 1991,
113, 9661-9663. (i) Hutchinson, J . H.; Daynard, T. S.; Gillard, J . W.
Tetraheron Lett. 1991, 32, 573-576. (j) Koot, W.-J .; van Ginkel, R.;
Kranenburg, M.; Hiemstra, H.; Louwrier, S.; Moolenaar, M. J .;
Speckamp, W. N. Tetraherdon Lett. 1991, 32, 401-404. (k) Stork, G.;
Suh, H. S.; Kim, G. J . Am. Chem. Soc. 1991, 113, 7054-7056. (l) Xi,
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Chem. Rev. 1995, 95, 1253-1277. (o) Fensterbark, L.; Malacria, M.;
Sieburth, S. M. Synthesis 1997, 813-854. (p) Abe, H.; Shuto, S.;
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The iodoindanol substrate 10a was heated in the
presence of (Bu3Sn)2 (1.0 equiv) and AIBN (0.6 equiv) in
benzene to give the expected cis-2-ethynylindanol 12 and
28
its dinitrobenzoate 12′ in 40% yield (entry 1). When
the radical reaction was carried out by irradiating a
solution of 10a in benzene containing (Bu3Sn)2 (0.1 equiv)
with a high-pressure mercury lamp at room temperature,
the yield of 12′ increased to 71% (entry 2). Excellent
results were observed when Et3B (0.3 equiv) was used
as a radical initiator to produce the desired product 12′
in 84% yield (entry 3).29 On the other hand, none of the
ethynyl product 13′ was obtained in the reactions with
the 1-phenylselenoindanol substrate 11a (entries 5-7).
In these experiments, TLC analysis suggested that the
radical cyclization did not occur.
(17) Our studies on the radical reactions with a silicon tether: (a)
Shuto, S.; Kanazaki, M.; Ichikawa, S.; Matsuda, A. J . Org. Chem. 1997,
62, 5676-5677. (b) Shuto, S.; Kanazaki, M.; Ichikawa, S.; Minakawa,
N.; Matsuda, A. J . Org. Chem. 1998, 63, 746-754. (c) Ueno, Y.;
Nagasawa, Y.; Sugimoto, I.; Kojima, N.; Kanazaki, M.; Shuto, S.;
Matsuda, A. J . Org. Chem. 1998, 63, 1660-1667. (d) Sugimoto, I.;
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Shuto, S.; Matsuda, A. J . Am. Chem. Soc. 2000, 122, 2422-2432.
(18) Atom-transfer radical cyclization reaction was first reported by
Curran: Curran, D. P.; Cheng, M.-H.; Kim, D. J . Am. Chem. Soc. 1986,
108, 2489-2490.
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6740. (h) Byers, J . H.; Gleason, T. G.; Knight, K. S. J . Chem. Soc.,
Chem. Commun. 1991, 354-356. (i) Curran, D. P.; Tamine, J . J . Org.
Chem. 1991, 56, 2746-2750. (j) Belvisi, L.; Gennari, C.; Poli, G.;
Scolastico, C.; Salom, B.; Vassalo, M. Tetrahedron 1992, 48, 3945-
3960. (k) Curran, D. P.; Geib, S. J .; Lin, C. H. Tetrahedron: Assmetry
1994, 5, 199-202. (l) Martinez-Grau, A.; Curran, D. P. J . Org. Chem.
1996, 60, 8332-8333. (m) Robertson, J .; Pillai, J .; Lush, R. K. Chem.
Soc. Rev. 2001, 30, 94-103.
(20) A preliminary account of this study: Sukeda, M.; Ichikawa, S.;
Matsuda, A.; Shuto, S. Angew. Chem., Int. Ed. 2002, 41, 4748-4750.
(21) Radical cyclization reactions with a TEDMS group as a tether
have been reported: (a) Xi, Z.; Rong, J .; Chattopadhyaya, J . Tetrahe-
dron 1994, 50, 5255-5272. (b) Skrydstrup, T.; Maze´as, D.; Elmouchir,
M.; Doisneau, G.; Riche, C.; Chiaroni, A.; Beau, J .-M. Chem. Eur. J .
1997, 3, 1342-1356.
(22) Atom-transfer radical cyclization reactions to a CtC bond: (a)
Curran, D. P.; Chen, M. H.; Kim, D. J . Am. Chem. Soc. 1986, 108,
2489-2490. (b) Ichinose, Y.; Matsunaga, S.; Fugami, K.; Oshima, K.;
Utimoto, K. Tetrahedron Lett. 1989, 30, 3155-3158.
(23) Atom transfer radical reactions effectively occur via a homolytic
C-I bond cleavage, see: (a) Curran, D. P.; Kim, D. Tetrahedron Lett.
1986, 27, 5821-5824. (b) Curran, D. P.; Chang, C.-T. Tetrahedron Lett.
1987, 28, 2477-2480. (c) Curran, D. P.; Tamine, J . J . Org. Chem. 1991,
56, 2746-2750. (d) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.;
Oshima, K. J . Org. Chem. 1998, 63, 8604-8605.
(24) Radical atom transfer reactions occur via a homolytic C-Se
bond cleavage when a phenylseleno group is attached at a benzylic
position: ref 17d
(25) Fluoride ion promoted elimination of 2-halogenovinylsilines to
produce alkynes has been reported: (a) Yamaguchi, R.; Kawasaki, H.;
Yoshitome T.; Kawanishi H. Chem. Lett. 1982, 1485-1486. (b) Shakes-
peare, W. C.; J ohnson, R. P. J . Am. Chem. Soc. 1990, 112, 8578-8579.
(c) Schmitz, C.; Rouanet-Dreyfuss, A.-C.; Tueni, M.; Biellmann, J .-F.
J . Org. Chem. 1996, 61, 1817-1821. (d) Marshall, J . A.; Maxson, K. J .
Org. Chem. 2000, 65, 630-633.
(26) Formyl group-transfer or cyano group-transfer radical reactions
have been reported: (a) Cossy, J .; Poitevin, C.; Pardo, D. G.; Peglion,
J . L. Synthesis 1995, 1368-1370. (b) J ung, M. E.; Tina, C. S. W.
Tetrahedron Lett. 1993, 34, 6247-6250.
(27) Stork, G.; Keitz, P. F. Tetrahedron Lett. 1989, 30, 6981-6984.
3468 J . Org. Chem., Vol. 68, No. 9, 2003

Ethynyl Introduction via a Radical Reaction
TABLE 1. Atom -Tr a n sfer Ra d ica l Cycliza tion a n d
Su bsequ en t Elim in a tion Rea ction of In d a n ol Su bstr a tes,
10a , 11a , a n d 10ba
SCHEME 6
radical reaction conditions
entry substrate
reagentsb/temp/solvent
product yield, %
1
2
3
4
5
6
7
8
9
10
11
12
13
10a
10a
10a
10a
11a
11a
11a
10a
10a
10a
10a
10a
10b
A/80 °C/benzene
B/rt/benzene
C/rt/toluene
D/rt/toluene
A/80 °C/benzene
B/rt/benzene
C/rt/toluene
C/rt/benzene
C/rt/hexane
C/rt/MeCN
12′
12′
12′
12′
13′
13′
13′
12′
12′
12′
12′
12′
12′
40
71
84
7
0
0
0
83
75
40
33
9
C/rt/THF
C/rt/CH2Cl2
C/rt/toluene
88
a
The radical reaction mixture was directly treated with TBAF,
b
the product of which was isolated as a 3,5-dinitrobenzoate. A:
(Bu3Sn)2 (1.0 equiv), AIBN (0.6 equiv). B: (Bu3Sn)2 (0.1 equiv),
hν. C: Et3B (0.3 equiv). D: (Bu3Sn)2 (0.3 equiv), V70 (0.3 equiv).
SCHEME 5
In vestiga tion of th e Rea ction P a th w a y. The reac-
tion pathway was investigated with the iodoindanol
substrate 10a . In the above experiments, the substrate
10a was effectively converted into cis-2-ethynylindanol
12 (12′), which corresponded to the expected atom-
transfer radical cyclization and subsequent elimination
product shown in Scheme 3. When 10a was treated under
the best conditions noted above with Et3B but in the
presence of the radical scavenger 2,2,6,6-tetramethylpi-
peridin-1-oxyl (TEMPO), the radical reaction did not
proceed, and the starting material 10a was recovered in
88% yield (Scheme 6). Thus, it was confirmed that the
radical reaction process is involved in the reaction
pathway, as expected.
The effect of the solvent on the reaction was next
examined. As shown in entries 3 and 8-12, nonpolar
solvents, such as benzene, toluene, or hexane, were
suitable for the reaction, while the yield decreased when
a relatively polar solvent, MeCN, THF, or CH2Cl2, was
used.
We next tried to isolate the atom-transfer radical
cyclization product 14; however, it was too labile to be
isolated. Therefore, after the radical reaction of 10a with
Et3B, the crude product was derivatized. The reductive
treatment of the radical reaction mixture with Bu3SnH
afforded the stable (Z)-exo-methylene product 15,27 which
was isolated in 75% yield from 10a . On the other hand,
when TBAF (1 equiv) and AcOH (0.35 equiv) were added
to the radical reaction mixture, cis-2-(2-trimethylsilyl-
ethynyl)indanol (16) was isolated in 80% yield from 10a .
It is reasonable to assume that the two products 15 and
16 were formed from the expected atom-transfer product
14 by its radical reduction and elimination reaction,
respectively.
On the basis of these experiments, we confirmed that
the best procedure was that used in entry 3, namely,
treatment of an iodohydrin-derived substrate with 0.3
equiv of Et3B at room temperature in toluene under
argon.30
We next examined the reaction using the EDMS group
to compare it with the TEDMS group as the tether. The
EDMS ether 10b, which was prepared by treating 8 with
EDMS chloride (EDMS-Cl)31 and Et3N in THF, was
subjected to the reaction under the best reaction condi-
tions used in entry 3. The reaction afforded the desired
ethynyl product 12′ in 88% yield (entry 13). Thus, the
EDMS group was shown to be as effective as the TEDMS
group.
The reactivity of compounds 15 and 16 to fluoride ion
was next examined. Treatment with 2.5 equiv of TBAF
quantitatively converted 15 into cis-2-[(E)-2-trimethyl-
silylvinyl]indanol (17)32 and 16 into cis-2-ethynylindanol
(12), respectively. These results suggest that elimination
of the atom transfer product 14 forms 2-(2-trimethylsi-
lylethynyl)indanol (16), the trimethylsilyl group of which
was subsequently removed to furnish the cis-2-ethynylin-
danol (12).
(28) The cis-stereochemistry was determined by NOE experi-
ments: see Experimental Section.
(29) When 0.1-0.5 equiv of Et3B was used under argon, it effectively
promoted the atom-transfer radical cyclization reactions of 10a .
(30) When the reaction was carried out under oxygen or air, the
yield significantly decreased.
(31) Shinohara, N.; Arai, M.; Ichinohe, S. J P-52065226, 1977 (Chem.
Abstr. 1977, 87, P 135905r).
(32) The E-configuration was determined by the 1H NMR coupling
constant: see Experimental Section.
J . Org. Chem, Vol. 68, No. 9, 2003 3469

Sukeda et al.
TABLE 2. P r ep a r a tion of th e Rea ction Su bstr a tes
TABLE 3. Atom -Tr a n sfer Ra d ica l Cycliza tion a n d
Su bsequ en t Elim in a tion Rea ction of Va r iou s Su bstr a tesa
a
The substrate (0.10 mmol) was successively treated with Et3B
(0.30 equiv) and then with TBAF (2.5 equiv) in toluene at room
temperature, and the product was purified by silica gel column
b
chromatography. The product was isolated after its conversion
into the corresponding 3,5-dinitrobenzoate (entries 1-4) or acetate
(entry 11). c The radical reaction was carried out with 0.60 equiv
d
of Et3B. The radical reaction was carried out at 50 °C.
On the basis of these experiments, we concluded that
the reaction pathway is an atom-transfer radical cycliza-
tion and subsequent elimination via intermediates 14
(IV) and 16 (V), which is identical with what we
hypothesized above.
indanol substrate 10a . The reaction successfully pro-
ceeded to give the desired ethynyl product 34 in 83% yield
(entry 1). When the corresponding EDMS ether 19b was
used as the substrate, the product 34 was also obtained
in high yield (86%, entry 2).
Eth yn yl-In tr odu ction Reaction with Var iou s Su b-
str a tes. With the above encouraging results in mind, we
then examined the reaction using the TEDMS or EDMS
ethers of a variety of iodohydrins as reaction substrates.
The substrates were prepared according to the above
methods, as summarized in Table 2. The reactions were
carried out according to the best method confirmed by
the above experiments, i.e., the procedure identical with
that of entry 3 in Table 1. The products were isolated
after purification by silica gel column chromatography,
and the results are shown in Table 3.
Reactions with more simplified monocyclic substrates,
the TEDMS ethers 21a and 23a of 2-iodo-cyclopentanol
and 2-iodo-cyclohexanol, were next examined. Although
the TLC analysis suggested that both of the reactions
seemed to proceed effectively like those of the above
indanol and tetrahydronaphthol substrates, the 2-ethynyl
products 35 and 36 were obtained in only moderate yields
(entries 3 and 4). The comparatively low isolated yields
might be explained by the volatility of the ethynylcy-
cloalkanol products. Reactions with similar simplified
five- and six-membered-ring substrates, i.e., pyrrolidine
and piperidine derivatives 25a , 25b, 27a , and 27b,
however, afforded the corresponding ethynyl products in
relatively good yields (entries 5-8), lending more support
We first performed the reaction with the TEDMS ether
of trans-2-iodotetrahydronaphthol (19a ), which corre-
sponds to the ring-expanded derivative of the model
3470 J . Org. Chem., Vol. 68, No. 9, 2003

Ethynyl Introduction via a Radical Reaction
SCHEME 7
TEDMS derivative 43, the substrate for the key radical
reaction. When 43 was subjected to the best procedure
as in entry 3 in Table 1, the expected reaction sequence
produced the desired 2′-C-ethynylnucleoside. After re-
moval of the monomethoxytrityl (MMTr) group and
subsequent treatment with Ac2O in pyridine, 3′,5′-di-O-
acetyl-2′-deoxy-2′-C-ethynyluridine (44) was isolated in
67% yield from the substrate 43, as expected. Removal
of the acetyl groups with K2CO3/MeOH finally produced
the target 2′-deoxy-2′-C-ethynyluridine (6). Another tar-
get, the corresponding cytidine congener 7, was obtained
in 88% yield by treating 44 with 2,4,6-triisopropylben-
zenesulfonyl chloride (TPSCl), Et3N, and DMAP in MeCN
followed by NH4OH.
Con clu sion . We have developed an efficient method
for introducing an ethynyl group via an atom-transfer
radical cyclization reaction with an EDMS or a TEDMS
group as a temporary connecting tether followed by a
fluoride ion-promoted elimination reaction. The method
was shown to be applicable to the introduction of an
ethynyl group in various five- and six-membered-ring
iodohydrins. 2′-Deoxy-2′-C-ethynyluridine (6) and 2′-
deoxy-2′-C-ethynylcytidine (7), newly designed as poten-
tial antimetabolites, were effectively synthesized by using
this reaction as the key step. This would be the first
example in which a radical reaction was used for intro-
ducing an ethynyl group.
Exp er im en ta l Section
to this presumption. Thus, it appears that the expected
reaction sequence occurs in both five- and six-membered-
ring iodohydrin substrates.
Melting points are uncorrected. NMR spectra were recorded
at 270 and 400 MHz (1H) and at 100 MHz (13C), and are
reported in ppm downfield from Me4Si. Mass spectra were
obtained by electron ionization (EI) or the fast atom bombard-
ment (FAB) method. Thin-layer chromatography was per-
formed on Merck coated plate 60F254. Silica gel chromatogra-
phy was performed with Merck silica gel 5715 or 9385
(neutral). Reactions were carried out under an argon atmo-
sphere.
tr a n s-2-Iodo-1-[(tr im eth ylsilyl)eth yln yldim eth ylsiloxy]-
in d a n e (10a ). A solution of 8 (757 mg, 2.9 mmol) and dimeth-
yl[(trimethylsilylethynyl)dimethylsilyl]amine (TEDMS-NMe2,
805 µL, 3.2 mmol) in toluene (15 mL) was stirred at room
temperature for 3 h and then evaporated. The residue was
purified by column chromatography (neutral SiO2, 0-3% Et2O
in hexane) to give 10a (997 mg, 83%) as a colorless liquid: 1H
NMR (400 MHz, CDCl3) δ 7.54-7.20 (m, 4 H), 5.56 (d, 1 H, J
) 5.3 Hz), 4.30 (dt, 1 H, J ) 5.3, 7.0 Hz), 3.64 (dd, 1 H, J )
7.0, 16.4 Hz), 3.30 (dd, 1 H, J ) 7.0, 16.4 Hz), 0.43 (s, 3 H),
0.37 (s, 3 H), 0.22 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ
142.30, 140.77, 128.38, 127.02, 124.55, 124.08, 115.50, 110.83,
85.68, 42.80, 29.97, 1.34, 1.00, -0.04; LRMS (EI) m/z 399 (M+
- CH3). Anal. Calcd for C16H23IOSi2: C, 46.37; H, 5.59.
Found: C, 46.46; H, 5.66.
When the reaction was applied to the acyclic iodohy-
drin substrate 29a , the expected ethynyl product 39 was
also obtained. However, the radical reaction was rather
slow and the yield of the product 39 was low. It seems
that abstraction of the iodine atom of the substrate 29a
by the cyclized radical (III in Scheme 3) is unfavorable
because it results in producing the relatively unstable
primary radical in this case.
The reaction was finally applied to sugar derivatives.
Thus, treatment of the 3′-EDMS ether of the 2-deoxy-2-
iodo-D-mannoside 31b following the same procedure
furnished the expected 2-ethynyl product 40 in 85% yield.
The results demonstrate that cis-halohydrin can also be
the effective substrate in this reaction. However, a
similar reaction of 3-iodo-D-ribosyl substrate 33a having
the TEDMS group at the 5-hydroxyl gave the desired
product 41, the ethynyl group of which was introduced
at the γ-cis position to the 5′-hydroxyl, in only 31% yield.
This may be because the 6-exo radical cyclization did not
occur so readily.
As described, we have successfully developed an ef-
ficient radical method, using the TEDMS or EDMS ethers
of cyclic iodohydrines as substrates, for introducing an
ethynyl group at the â-cis position to the hydroxyl.
Syn th esis of 2′-Deoxy-2′-C-eth yn ylu r id in e a n d 2′-
Deoxy-2′-C-eth yn ylcytid in e. We tried to synthesize the
targets 2′-deoxy-2′-C-ethynyluridine (6) and 2′-deoxy-2′-
C-ethynylcytidine (7) using the developed reaction as the
key step (Scheme 7). The 2′-deoxy-2′-iodouridine deriva-
tive 42, readily prepared from uridine via 2,2′-anhydrou-
ridine,5 was treated as in the above-mentioned procedure
with TEDMS-NMe2 to give the corresponding 3′-O-
tr a n s-2-iod o-1-(eth yn yld im eth ylsiloxy)in d a n e (10b). A
solution of 8 (260 mg, 1.0 mmol), Et3N (307 µL, 2.2 mmol),
and ethynyldimethylchlorosilane (EDMS-Cl, 279 µL, 2.0
mmol) in toluene (10 mL) was stirred at room temperature
for 3 h, and then evaporated. The residue was partitioned
between AcOEt and aqueous saturated Na2S2O3, and the
organic layer was washed with brine, dried (Na2SO4), and
evaporated. The residue was purified by column chromatog-
raphy (neutral SiO2, 0-5% AcOEt in hexane) to give 10b (243
mg, 71%) as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ
7.47-7.19 (m, 4 H), 5.57 (d, 1 H, J ) 5.6 Hz), 4.28 (dt, 1 H, J
) 5.6, 7.2 Hz), 3.62 (dd, 1 H, J ) 7.2, 16.4 Hz), 3.30 (dd, 1 H,
J ) 7.2, 16.4 Hz), 2.56 (s, 1 H), 0.46 (s, 3 H), 0.40 (s, 3 H); 13
C
NMR (100 MHz, CDCl3) δ 141.99, 140.54, 128.25, 126.95,
124.09, 123.91, 94.19, 87.38, 85.68, 42.56, 29.53, 1.24, 0.75;
J . Org. Chem, Vol. 68, No. 9, 2003 3471

Sukeda et al.
LRMS (EI) m/z 342 (M+). Anal. Calcd for C13H15IOSi: C, 45.62;
H, 4.42. Found: C, 45.62; H, 4.52.
Hz), 3.38 (d, 1 H, J ) 11.2 Hz), 2.42 (s, 3 H), 0.20 (s, 9 H), 0.12
(s, 6 H); 13C NMR (100 MHz, CDCl3) δ 143.35, 133.73, 129.42,
127.51, 127.41, 116.33, 109.32, 79.30, 55.83, 53.32, 24.63,
21.65, 0.31, 0.17, -0.08; LRMS (FAB, positive) m/z 522 (MH+).
Anal. Calcd for C18H28INO3SSi2: C, 41.45; H, 5.41; N, 2.69.
Found: C, 41.39; H, 5.37; N, 2.61.
tr a n s-3-Eth yn yld im eth ylsiloxy-4-iod o-1-tosylp yr r oli-
d in e (25b). Compound 25b (92 mg, quant.) was obtained as
a white solid from 24 (73 mg, 0.20 mmol) as described above
for the synthesis of 10b, after usual water workup: mp 95-
96 °C (white crystals from hexane/AcOEt); 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, 2 H, J ) 8.3 Hz), 7.32 (d, 2 H, J ) 8.3 Hz),
4.50 (m, 1 H), 4.05-3.99 (m, 2 H), 3.87 (dd, 1 H, J ) 4.3, 11.1
Hz), 3.71 (dd, 1 H, J ) 5.5, 15.1 Hz), 3.36 (dd, 1 H, J ) 2.1,
11.1 Hz), 2.50 (s, 1 H), 2.43 (s, 3 H), 0.17 (s, 3 H), 0.16 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 143.36, 133.67, 129.42, 127.46,
94.70, 86.38, 79.30, 55.80, 53.22, 24.24, 21.62, 0.21; LRMS
(FAB, positive) m/z 450 (MH+). Anal. Calcd for C15H20INO3-
SSi: C, 40.09; H, 4.49; N, 3.12. Found: C, 40.14; H, 4.49; N,
3.12.
tr a n s-4-Iod o-1-tosyl-3-[(tr im eth ylsilyl)eth yn yld im eth -
ylsiloxy]p ip er id in e (27a ). Compound 27a (140 mg, 77%) was
obtained as a white solid from 26 (114 mg, 0.30 mmol) as
described above for the synthesis of 10a , after purification by
column chromatography (neutral SiO2, 4% AcOEt in hexane):
mp 110.5-112 °C (white needles from hexane/AcOEt); 1H NMR
(400 MHz, CDCl3) δ 7.64 (d, 2 H, J ) 8.3 Hz), 7.33 (d, 2 H, J
) 8.3 Hz), 4.01 (m, 1 H), 3.95 (ddd, 1 H, J ) 1.7, 4.4, 11.7 Hz),
3.80 (m, 1 H), 3.38 (ddd, 1 H, J ) 2.8, 4.1, 11.7 Hz), 2.53-2.45
(m, 2 H), 2.44 (s. 3H), 2.37 (ddd, 1 H, J ) 4.4, 7.5, 23.9 Hz),
2.18 (ddd, 1 H, J ) 4.1, 10.4, 23.9 Hz), 0.36 (s, 3 H), 0.29 (s, 3
H), 0.24 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 143.50, 133.32,
129.58, 127.41, 116.01, 109.86, 72.97, 50.95, 46.63, 35.05,
31.65, 21.68, 0.92, 0.80, -0.07; LRMS (FAB, positive) m/z 536
(MH+). Anal. Calcd for C19H30INO3SSi2: C, 42.61; H, 5.65; N,
2.62. Found: C, 42.55; H, 5.56; N, 2.50.
tr a n s-3-E t h yn yld im et h ylsiloxy-4-iod o-1-t osylp ip er i-
d in e (27b). Compound 27b (94 mg, quant.) was obtained as
a white solid from 26 (76 mg, 0.20 mmol) as described above
for the synthesis of 10b, after purification by the only parti-
tion: mp 104-105 °C (white needles from hexane/AcOEt); 1H
NMR (400 MHz, CDCl3) δ 7.65 (d, 2 H, J ) 8.4 Hz), 7.33 (d, 2
H, J ) 8.4 Hz), 4.01 (m, 1 H), 3.95 (ddd, 1 H, J ) 2.0, 4.2, 11.7
Hz), 3.78 (ddd, 1 H, J ) 4.4, 8.2, 10.7 Hz), 3.41 (m, 1 H), 2.56
(s, 1 H), 2.53-2.35 (m, 3 H), 2.44 (s, 3 H), 2.22 (ddd, 1 H, J )
4.2, 10.7, 24.5 Hz), 0.40 (s, 3 H), 0.33 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 143.40, 133.18, 129.44, 94.53, 86.76, 73.07,
50.90, 46.50, 35.15, 31.30, 21.50, 0.66, 0.58; LRMS (FAB,
positive) m/z 464 (MH+). Anal. Calcd for C16H22INO3SSi: C,
41.47; H, 4.79; N, 3.02. Found: C, 41.76; H, 4.88; N, 2.81.
tr a n s-1-P h en ylselen o-2-[(tr im eth ylsilyl)eth yn yldim eth -
ylsiloxy]in d a n e (11a ). Compound 11a (992 mg, 45%) was
obtained as a colorless liquid from 9 (1.45 g, 5.0 mmol) as
described above for the synthesis of 10a , after purification by
column chromatography (neutral SiO2, 0-2% AcOEt in hex-
ane): 1H NMR (270 MHz, CDCl3) δ 7.55-7.17 (m, 9 H), 4.76-
4.74 (m, 2 H), 3.22 (dd, 1H, J ) 5.9, 15.8 Hz), 2.88 (d, 1 H, J
) 15.8 Hz), 0.21 (s, 9 H), 0.14 (s, 3 H), 0.11 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 141.17, 140.83, 134.34, 129.48, 128.80,
127.59, 127.46, 126.62, 125.40, 124.83, 114.68, 111.22, 80.22,
54.04, 40.46, 0.47, -0.01; LRMS (EI) m/z 444 (M+). Anal. Calcd
for C22H28OSeSi2: C, 59.57; H, 6.36. Found: C, 59.63; H, 6.39.
1,2,3,4-Tetr a h yd r o-2-iod o-1-[(tr im eth ylsilyl)eth yn yld i-
m eth ylsiloxy]n a p h th a len e (19a ). Compound 19a (115 mg,
67%) was obtained as a colorless liquid from 18 (110 mg, 0.40
mmol) as described above for the synthesis of 10a , after
purification by column chromatography (neutral SiO2, 0-2%
AcOEt in hexane): 1H NMR (400 MHz, CDCl3) δ 7.36-7.13
(m, 4 H), 5.19 (d, 1 H, J ) 2.9 Hz), 4.72 (m, 1 H), 3.00 (m, 1
H), 2.85 (m, 1 H), 2.32 (m, 1 H), 2.06 (m, 1 H), 0.33 (s, 3 H),
0.32 (s, 3 H), 0.25 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ
135.07, 134.21, 130.38, 128.72, 127.97, 136.05, 115.72, 110.55,
74.75, 33.60, 27.61, 26.61, 1.07, 0.93; LRMS (EI) m/z 413 (M+
- CH3). Anal. Calcd for C17H25IOSi2: C, 47.66; H, 5.88.
Found: C, 47.87; H, 5.96.
1,2,3,4-Tet r a h yd r o-2-iod o-1-(et h yn yld im et h ylsiloxy)-
n a p h th a len e (19b). Compound 19b (149 mg, 70%) was
obtained as a colorless liquid from 18 (164 mg, 0.60 mmol) as
described above for the synthesis of 10b, after purification by
column chromatography (neutral SiO2, 0-5% AcOEt in hex-
ane): 1H NMR (400 MHz, CDCl3) δ 7.35-7.12 (m, 4 H), 5.20
(d, 1 H, J ) 3.3 Hz), 4.67 (m, 1 H), 2.99 (m, 1 H), 2.85 (m, 1
H), 2.60 (s, 1 H), 2.33 (m, 1 H), 2.08 (m, 1 H), 0.35 (s, 3 H),
0.34 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 134.06, 133.14,
129.20, 127.71, 127.02, 125.09, 93.41, 86.47, 74.05, 32.41,
26.65, 25.89, 0.00, -0.07; LRMS (EI) m/z 356 (M+). Anal. Calcd
for C14H17IOSi: C, 47.20; H, 4.81. Found: C, 47.16; H, 4.89.
tr a n s-2-Iod o-1-[(tr im eth ylsilyl)eth yn yld im eth ylsiloxy]-
cyclop en ta n e (21a ). Compound 21a (285 mg, 78%) was
obtained as a colorless liquid from 20 (212 mg, 1.0 mmol) as
described above for the synthesis of 10a , after purification by
column chromatography (neutral SiO2, 0-3% ether in hex-
ane): 1H NMR (400 MHz, CDCl3) δ 4.59 (m, 1 H), 4.19 (m, 1
H), 2.35 (m, 1 H), 2.18 (m, 1 H), 2.03 (m, 1 H), 1.83 (m, 2 H),
1.64 (m, 1 H), 0.27 (s, 3 H), 0.25 (s, 3 H), 0.21 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 114.88, 110.72, 83.01, 35.83, 34.59,
31.91, 0.67, 0.57, 0.01; LRMS (EI) m/z 366 (M+). Anal. Calcd
for C12H23OSi2: C, 39.34; H, 6.33. Found: C, 39.47; H, 6.34.
1-Ben zyloxy-3-iod o-2-[(tr im eth ylsilyl)eth yn yld im eth -
ylsiloxy]p r op a n e (29a ). Compound 29a (290 mg, 65%) was
obtained as a colorless liquid from 28 (292 mg, 1.0 mmol) as
described above for the synthesis of 10a with TEDMS-NMe2
(303 µL, 1.0 mmol) at 50 °C, after purification by column
chromatography (neutral SiO2, 0-4% Et2O in hexane): 1H
NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 5 H), 4.56 (s, 2 H),
3.95 (m, 1H), 3.62 (dd, 1 H, J ) 5.3, 9.9 Hz), 3.53 (dd, 1 H, J
) 5.3, 9.9 Hz), 3.43 (dd, 1 H, J ) 5.9, 10.6 Hz), 3.33 (dd, 1 H,
tr a n s-2-Iod o-1-[(tr im eth ylsilyl)eth yn yld im eth ylsiloxy]-
cycloh exa n e (23a ). Compound 23a (1.36 g, 90%) was ob-
tained as a colorless liquid from 22 (0.90 g, 4.0 mmol) as
described above for the synthesis of 10a , after purification by
column chromatography (neutral SiO2, 0-5% ether in hex-
ane): 1H NMR (400 MHz, CDCl3) δ 4.06 (ddd, 1 H, J ) 4.1,
8.7, 10.5 Hz), 3.89 (dt, 1 H, J ) 4.1, 12.6 Hz), 2.41 (m, 1 H),
2.22 (m, 1 H), 1.97 (m, 1 H), 1.80 (m, 1 H), 1.52 (m, 1 H), 1.45-
1.23 (m, 3 H), 0.35 (s, 3 H), 0.28 (s, 3 H), 0.19 (s, 9 H); 13C
NMR (100 MHz, CDCl3) δ 114.68, 111.64, 76.65, 39.82, 37.71,
34.37, 26.85, 23.48, 1.21, 0.91, -0.12; LRMS (EI) m/z 380 (M+).
Anal. Calcd for C13H25IOSi2: C, 41.04.; H, 6.62. Found: C,
41.15; H, 6.50.
tr a n s-4-Iod o-1-tosyl-3-[(tr im eth ylsilyl)eth yn yld im eth -
ylsiloxy]p yr r olid in e (25a ). Compound 25a (131 mg, 63%)
was obtained as a white solid from 24 (147 mg, 0.40 mmol) as
described above for the synthesis of 10a , after purification by
column chromatography (neutral SiO2, 6% AcOEt in hexane):
mp 77-78 °C (white crystals from hexane); 1H NMR (270 MHz,
CDCl3) δ 7.73 (d, 2 H, J ) 8.6 Hz), 7.31 (d, 2 H, J ) 8.6 Hz),
4.51 (m, 1 H), 4.09 (m, 1 H), 4.02 (dd, 1 H, J ) 5.9, 11.2 Hz),
3.87 (dd, 1 H, J ) 4.6, 11.2 Hz), 3.71 (dd, 1 H, J ) 2.0, 11.2
J ) 5.3, 10.6 Hz), 0.32 (s, 3 H), 0.27 (s, 3 H), 0.19 (s, 9 H); 13
C
NMR (100 MHz, CDCl3) δ 137.83, 128.22, 127.54, 115.10,
110.47, 73.43, 72.79, 71.50, 10.08, 0.87, 0.83, -0.05; LRMS
(ESI) m/z 469 (MNa+). Anal. Calcd for C17H27IO2Si2: C, 45.73;
H, 6.10. Found: C, 45.78; H, 6.03.
Meth yl 2-Deoxy-2-iod o-3-O-eth yn yld im eth ylsilyl-4,6-O-
ben zylid en e-R-D-m a n n op yr a n osid e (31b). Compound 31b
(107 mg, 90%) was obtained as a white syrup from 30 (98 mg,
0.25 mmol) as described above for the synthesis of 10b with
EDMS-Cl (88 µL, 0.63 mmol), pyridine (57 µL, 0.70 mmol)
instead of Et3N, and THF (2.5 mL) as a solvent, after
purification by the only partition: 1H NMR (400 MHz, CDCl3)
δ 7.50-7.34 (m, 5 H), 5.59 (s, 1 H), 5.13 (s, 1 H), 4.53 (d, 1 H,
3472 J . Org. Chem., Vol. 68, No. 9, 2003

Ethynyl Introduction via a Radical Reaction
J ) 4.5 Hz), 4.25 (dd, 1 H, J ) 3.4, 9.3 Hz), 3.99-3.84 (m, 3
H), 3.55 (dd, 1 H, J ) 4.5, 8.8 Hz), 3.38 (s, 3 H), 2.54 (s, 1 H),
0.32 (s, 3 H), 0.28 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
136.98, 128.53, 127.74, 125.81, 103.57, 101.44, 93.50, 87.25,
80.33, 68.46, 67.30, 64.30, 54.98, 37.23, 0.71, 0.47; LRMS (EI)
m/z 474 (M+). Anal. Calcd for C18H23IO5Si: C, 45.58; H, 4.89.
Found: C, 45.87; H, 5.06.
37.11, 0.28; LRMS (FAB, positive) m/z 253 (MNa+). Anal. Calcd
for C14H18OSi: C, 72.99; H, 7.88. Found: C, 72.69; H, 7.91.
cis-2-Eth yn yl-1-in d a n ol (12). A mixture of 16 (23 mg, 0.10
mmol) and TBAF (1.0 M solution in THF, 120 µL, 0.12 mmol)
in THF (1 mL) was stirred at room temperature for 1 h. The
mixture was evaporated, and the residue was purified by
column chromatography (SiO2, 5-10% AcOEt in hexane) to
give 12 (15 mg, 95%) as a white solid: mp 80-81 °C (white
needles from hexane); 1H NMR (270 MHz, CDCl3) δ 7.46-7.22
(m, 4 H), 5.11 (m, 1 H), 3.39 (m, 1 H), 3.20 (dd, 1 H, J ) 5.9,
15.8 Hz), 3.14 (dd, 1 H, J ) 7.9, 15.8 Hz), 2.39 (br s, 1H), 2.23
(d, 1 H, J ) 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 142.44,
141.06, 128.69, 127.04, 124.94, 124.73, 82.75, 75.66, 72.40,
38.16, 36.84; LRMS (FAB, positive) m/z 158 (M+). Anal. Calcd
for C11H10O: C, 83.51; H, 6.37. Found: C, 83.43; H, 6.52.
Gen er a l P r oced u r e for Ra d ica l Atom -Tr a n sfer Rea c-
tion w ith Et3B (Ta bles 1 a n d 3). To a solution of a substrate
(0.10 mmol) in toluene (1 mL) was added dropwise Et3B (1.0
M solution in hexane, 30 µL, 0.030 mmol) under argon
atmosphere, and the mixture was stirred at room temperature
for 2 h. After addition of TBAF (1.0 M solution in THF, 250
µL, 0.25 mmol), the resulting mixture was stirred at room
temperature for an additional 2 h and then the solvent was
evaporated. To the residue was added AcOEt, and the insoluble
material was filtered off. The filtrate was evaporated, and the
residue was treated according to the procedure as described
below.
cis-1-(3,5-Din itr oben zoyloxy)-2-eth yn ylin d a n e (12′). Af-
ter the treatment of 10a (41 mg, 0.10 mmol) or 10b (34 mg,
0.10 mmol) according to the above general procedure, a
mixture of the resulting residue, DNBzCl (35 mg, 0.15 mmol),
Et3N (28 µL, 0.2 mmol), and DMAP (2 mg, 0.02 mmol) in
MeCN (1 mL) was stirred at room temperature for 3 h, and
then evaporated. The residue was partitioned between AcOEt
and H2O, and the organic layer was washed with brine, dried
(Na2SO4), and evaporated. The residue was purified by column
chromatography (SiO2, 3-6% AcOEt in hexane) to give 12′ (30
mg, 84% from 10a , or 31 mg, 88% from 10b) as a white solid:
mp 154-155 °C (colorless crystals from AcOEt/hexane); 1H
NMR (270 MHz, CDCl3) δ 9.21-9.18 (m, 3 H, DNBz), 7.57-
7.26 (m, 4 H, Ar), 6.50 (d, 1 H, H-1, J ) 5.9 Hz), 3.60 (m, 1 H,
H-2), 3.39 (m, 2 H, H-3a,3b), 2.18 (d, 1 H, -CtCH, J ) 2.6
Hz); NOE (400 MHz, CDCl3), irradiated H-2, observed H-1
(10.9%), and irradiated -CtCH, observed DNBz (1.3%); 13C
NMR (100 MHz, CDCl3) δ 161.92, 148.40, 142.83, 137.98,
133.98, 130.12, 129.48, 127.39, 126.36, 124.83, 122.24, 81.45,
79.49, 71.93, 37.95, 35.65; LRMS (EI) m/z 140 (M+ - DNB-
zOH). Anal. Calcd for C18H12N2O6: C, 61.37; H, 3.43; N, 7.95.
Found: C, 61.33; H, 3.51; N, 7.87.
1,2,3,4-Tetr a h yd r o-1-(3,5-d in itr oben zoyloxy)-2-eth yn -
yln a p h th a len e (34). After the treatment of 19a (43 mg, 0.10
mmol) or 19b (36 mg, 0.10 mmol) according to the above
general procedure, the product was converted into the corre-
sponding dinitrobenzoate as described above for the synthesis
of 12′. The purification was carried out by column chromatog-
raphy (SiO2, 2-5% AcOEt in hexane) to give 34 (30 mg, 83%
from 19a , or 32 mg, 86% from 19b) as a white solid: mp 170-
171 °C (white crystals from hexane/AcOEt); 1H NMR (400
MHz, CDCl3) δ 9.22-9.17 (m, 3 H), 7.42-7.20 (m, 4 H), 6.50
(d, 1 H, J ) 3.8 Hz), 3.18-3.10 (m, 2 H), 2.91 (m, 1 H), 2.34
(m, 1 H), 2.22 (m, 1 H), 2.06 (d, 1 H, J ) 2.4 Hz); 13C NMR
(100 MHz, CDCl3) δ 161.94, 148.40, 136.51, 133.90, 131.77,
129.86, 129.49, 129.13, 126.48, 122.26, 82.77, 72.53, 71.22,
31.89, 27.88, 24.92; LRMS (EI) m/z 366 (M+). Anal. Calcd for
3-Deoxy-5-O-eth yn yldim eth ylsilyl-3-iodo-1,2-O-(1-m eth -
yleth ylid en e)-R-D-r ibofu r a n ose (33a ). Compound 33a (116
mg, quant.) was obtained as a colorless viscous oil from 32
(90 mg, 0.3 mmol) as described above for the synthesis of 10a ,
after purification by column chromatography (neutral SiO2,
5-15% AcOEt in hexane): 1H NMR (400 MHz, CDCl3) δ 5.87
(d, 1 H, J ) 3.6 Hz), 4.63 (dd, 1 H, J ) 3.6, 4.3 Hz), 4.17 (dt,
1 H, J ) 2.3, 10.4 Hz), 4.09 (dd, 1 H, J ) 2.3, 12.2 Hz), 4.00
(m, 1 H), 3.96 (dd, 1 H, J ) 2.3, 12.2 Hz), 2.47 (s, 1 H), 1.56 (s,
3 H), 1.38 (s, 3 H), 0.32 (s, 3 H), 0.31 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 111.22, 103.26, 93.45, 87.19, 83.00, 80.70, 59.82,
26.52, 26.43, 19.92, 0.02, -0.23; HRMS (FAB, positive) calcd
for C12H20IO4Si 383.0176, found 383.0171 (MH+).
Bu 3Sn H-Red u ction P r od u ct 15. To a solution of 10a (124
mg, 0.3 mmol) in toluene (3 mL) was added dropwise Et3B (1.0
M solution in hexane, 90 µL, 0.090 mmol) under argon
atmosphere, and the mixture was stirred at room temperature
for 2 h. After addition of Bu3SnH (97 µL, 0.36 mmol), the
resulting mixture was stirred at room temperature for an
additional 2 h. The resulting mixture was evaporated, and the
residue was purified by column chromatography (SiO2, 0-3%
AcOEt in hexane) to give 15 (65 mg, 75%) as a colorless liquid:
1H NMR (270 MHz, CDCl3) δ 7.50-7.20 (m, 4 H, Ar), 6.67 (d,
1 H, -CdCH, J ) 2.0 Hz), 5.48 (d, 1 H, H-1, J ) 5.9 Hz), 3.41
(m, 1 H, H-2), 3.24 (dd, 1 H, H-3a, J ) 9.2, 16.5 Hz), 2.93 (dd,
1 H, H-3b, J ) 5.9, 16.5 Hz), 0.41 (s, 3 H, Si-CH3), 0.19 (s, 3
H, Si-CH3), 0.14 (s, 9 H, TMS); NOE (400 MHz, CDCl3),
irradiated H-2, observed H-1 (9.5%), H-3a (4.9%), and irradi-
ated -CdCHTMS, observed H-2 (5.6%), H-3b (2.8%); 13C NMR
(100 MHz, CDCl3) δ 163.52, 143.95, 142.47, 128.29, 126.64,
125.06, 124.54, 83.16, 55.19, 39.17, 1.73, 1.31, 0.12; LRMS (EI)
m/z 288 (M+). Anal. Calcd for C16H24OSi2: C, 66.60; H, 8.38.
Found: C, 66.77; H, 8.54.
cis-2-[E-2-(Tr im eth ylsilyl)vin yl]-1-in d a n ol (17). A mix-
ture of 15 (65 mg, 0.225 mmol) and TBAF (1.0 M solution in
THF, 563 µL, 0.56 mmol) in THF (2 mL) was stirred at room
temperature for 1 h and then evaporated. The residue was
purified by column chromatography (SiO2, 3-8% AcOEt in
hexane) to give 17 (52 mg, 99%) as a white solid: mp 56-58
1
°C (white crystals from hexane/AcOEt); H NMR (400 MHz,
CDCl3) δ 7.43-7.22 (m, 4 H, Ar), 6.14 (dd, 1 H, -CHdC, J )
7.0, 18.8 Hz), 5.94 (dd, 1 H, -CdCH, J ) 0.9, 18.8 Hz), 5.09
(dd, 1 H, H-1, J ) 5.6, 5.9 Hz), 3.17 (m, 1 H, H-2), 3.01 (m, 2
H, H-3a,3b), 1.65 (d, 1 H, OH-1, J ) 5.6 Hz), 0.09 (s, 9 H, TMS);
13C NMR (100 MHz, CDCl3) δ 144.06, 142.39, 134.46, 128.33,
126.63, 124.82, 124.66, 76.88, 51.93, 35.28, -0.96; LRMS (EI)
m/z 214 (M+ - H2O). Anal. Calcd for C14H20OSi: C, 72.36; H,
8.67. Found: C, 72.40; H, 8.83.
cis-2-(Tr im eth ylsilyl)eth yn yl-1-in d a n ol (16). To a solu-
tion of substrate 8a (41 mg, 0.10 mmol) in toluene (1 mL) was
added dropwise Et3B (1.0 M solution in hexane, 30 µL, 0.03
mmol) under argon atmosphere, and the mixture was stirred
at room temperature for 2 h. After addition of a mixture of
TBAF (1.0 M solution in THF, 100 µL, 0.10 mmol) and AcOH
(2 µL, 0.035 mmol), the resulting mixture was stirred at room
temperature for an additional 1 h, and then evaporated. The
residue was purified by column chromatography (SiO2, 0-5%
AcOEt in hexane) to give 16 (19 mg, 80%) as a white solid:
mp 98-100 °C (white needles from hexane); 1H NMR (270
MHz, CDCl3) δ 7.47-7.23 (m, 4 H), 5.07 (dd, 1 H, J ) 6.1, 5.6
Hz), 3.41 (m, 1 H), 3.14 (m, 2 H), 2.47 (d, 1 H, J ) 5.6 Hz),
0.17 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 142.37, 141.37,
128.61, 126.89, 125.16, 124.65, 104.53, 89.48, 75.25, 39.14,
C
19H14N2O6: C, 62.30; H, 3.85; N, 7.65. Found: C, 62.25; H,
4.02; N, 7.53.
cis-1-(3,5-Din it r ob en zoyloxy)-2-et h yn ylcyclop en t a n e
(35). After the treatment of 21a (37 mg, 0.10 mmol) according
to the above general procedure, the product was converted to
the corresponding dinitrobenzoate as described above for the
synthesis of 12′. Purification was carried out by column
chromatography (SiO2, 0-8% AcOEt) to give 35 (10 mg, 33%)
J . Org. Chem, Vol. 68, No. 9, 2003 3473

Sukeda et al.
as a pale brown solid: mp 117-118 °C (pale brown crystals
from hexane/AcOEt); 1H NMR (400 MHz, CDCl3) δ 9.24-9.19
(m, 3 H), 5.55 (m, 1 H), 3.00 (m, 1 H), 2.20 (m, 2 H), 2.09 (d,
1 H, J ) 2.6 Hz), 2.07-1.96 (m, 3 H), 1.73 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ 161.74, 148.41, 134.11, 129.34, 122.17,
82.31, 78.74, 71.33, 35.81, 31.53, 31.50, 22.46; LRMS (EI) m/z
304 (M+). Anal. Calcd for C14H12N2O6: C, 55.27; H, 3.98; N,
9.21. Found: C, 55.10; H, 4.11; N, 9.01.
128.13, 127.52, 127.41, 79.96, 73.26, 72.55, 70.43, 68.55, 23.41;
HRMS (EI) calcd for C12H23O2 189.0915, found 189.0919 (M+
- H).
Met h yl 2-Deoxy-2-C-et h yn yl-4,6-O-b en zylid en e-R-D-
m a n n op yr a n osid e (40). After the treatment of 29b (47 mg,
0.10 mmol) according to the general procedure, the resulting
residue was purified by column chromatography (SiO2, 20%
AcOEt in hexane) to give 40 (25 mg, 85%) as a white solid:
1H NMR (270 MHz, CDCl3) δ 7.52-7.36 (m, 5 H), 5.61 (s, 1
H), 4.88 (s, 1 H), 4.28 (dd, 1 H, J ) 2.6, 8.6 Hz), 4.20 (m, 1 H),
3.97-3.81 (m, 3 H), 3.38 (s, 3 H), 3.31 (m, 1 H), 2.37 (d, 1 H,
J ) 5.3 Hz), 2.30 (d, 1 H, J ) 2.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 136.80, 128.89, 128.00, 125.90, 101.91, 100.82, 80.11,
79.49, 73.20, 68.60, 66.27, 63.35, 54.97, 40.09; HRMS (EI) calcd
for 290.1154, found 290.1160 (M+).
5-O-Ace t yl-3-d e oxy-3-C-e t h yn yl-1,2-O-(1-m e t h yle t h -
ylid en e)-R-D-xylofu r a n ose (41). To a solution of 33a (38 mg,
0.10 mmol) in toluene (1 mL) was added dropwise Et3B (1.0
M solution in hexane, 30 µL, 0.030 mmol) under argon
atmosphere, and the mixture was stirred at room temperature
for 3 h and then at 60 °C for 15 h. After 3 h, the mixture was
warmed to 60 °C and stirred for an additional 15 h. The
reaction mixture was treated with TBAF according to the
above general procedure. The resulting residue was purified
by column chromatography (SiO2, 15-30% AcOEt in hexane)
to give a mixture of the desired 3-C-ethynylated product and
32 (27 mg, the ratio was 2:1) as a white solid. A solution of
the obtained mixture of the ethynylated product and 32 (27
mg), Ac2O (28 µL, 0.3 mmol), Et3N (42 µL, 0.3 mmol), and
DMAP (5 mg, 0.04 mmol) in MeCN (2 mL) was stirred at room
temperature for 3 h. The solvent was evaporated, and the
residue was purified by column chromatography (SiO2, 15%
AcOEt in hexane) to give 41 (8 mg, 31%) as a colorless liquid:
1H NMR (400 MHz, CDCl3) δ 5.96 (d, 1 H, J ) 3.6 Hz), 4.75
(d, 1 H, J ) 3.6 Hz), 4.43-4.30 (m, 3 H), 3.13 (dd, 1 H, J )
2.6, 4.1 Hz), 2.22 (d, 1 H, J ) 2.6 Hz), 2.10 (s, 3 H), 1.52 (s, 3
H), 1.33 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.27, 111.82,
105.01, 84.71, 77.50, 75.94, 73.96, 63.88, 39.72, 26.53, 26.16,
20.81; LRMS (EI) m/z 241 (MH+). Anal. Calcd for C12H16O5:
C, 59.99; H, 6.71. Found: C, 60.22; H, 6.91.
cis-1-(3,5-Din it r ob en zoyloxy)-2-et h yn ylcycloh exa n e
(36). After the treatment of 23a (38 mg, 0.10 mmol) according
to the above general procedure, the product, dinitrobenzoate,
was converted to the corresponding dinitrobenzoate as de-
scribed above for the synthesis of 12′. The purification was
carried out by column chromatography (SiO2, 0-8% AcOEt in
hexane) to give 36 (12 mg, 36%) as a yellow solid: mp 116-
118 °C (yellow crystals from hexane/AcOEt); 1H NMR (400
MHz, CDCl3) δ 9.24-9.18 (m, 3 H), 5.17 (m, 1 H), 3.11 (m, 1
H), 2.15 (d, 1 H, J ) 2.4 Hz), 2.10-1.95 (m, 2 H), 1.86-1.69
(m, 4 H), 1.56-1.43 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ
161.39, 148.27, 133.97, 129.20, 122.02, 82.72, 74.87, 71.23,
32.46, 29.19, 27.77, 22.98, 21.51; LRMS (EI) m/z 318 (M+).
Anal. Calcd for C15H14N2O6: C, 56.60; H, 4.43; N, 8.80.
Found: C, 56.35; H, 4.60; N, 8.89.
cis-4-Eth yn yl-3-h yd r oxy-1-tosylp yr r olid in e (37). After
the treatment of 25a (52 mg, 0.10 mmol) or 25b (45 mg, 0.10
mmol) according to the above general procedure, the resulting
residue was purified by column chromatography (SiO2, 15-
35% AcOEt in hexane) to give 37 (21 mg, 80% from 25a , or 21
mg, 80% from 25b) as a white solid: mp 120-121 °C (white
needles from hexane/AcOEt); 1H NMR (400 MHz, CDCl3) δ
7.72 (d, 2 H, J ) 8.3 Hz), 7.33 (d, 2 H, J ) 8.3 Hz), 4.28 (m, 1
H), 3.71 (dd, 1 H, J ) 7.5, 9.8 Hz), 3.55 (ddd, 1 H, J ) 1.1, 4.7,
11.5 Hz), 3.31 (dd, 1 H, J ) 1.7, 11.5 Hz), 3.22 (dd, 1 H, J )
9.8, 10.0 Hz), 2.89 (m, 1 H), 2.43 (s, 3 H), 2.22 (d, 1 H, J ) 2.3
Hz), 2.00 (dd, 1 H, J ) 1.1, 2.8 Hz); 13C NMR (100 MHz, CDCl3)
δ 143.35, 133.27, 129.40, 127.22, 78.20, 73.97, 71.00, 54.20,
50.03, 36.99, 21.52; LRMS (EI) m/z 265 (M+). Anal. Calcd for
C
13H15NO3S: C, 58.85; H, 5.70; N, 5.28. Found: C, 58.77; H,
5.79; N, 5.30.
cis-4-Eth yn yl-3-h yd r oxy-1-tosylp ip er id in e (38). After
the treatment of 27a (54 mg, 0.10 mmol) or 27b (46 mg, 0.10
mmol) according to above general procedure, the resulting
residue was purified by column chromatography (SiO2, 15-
25% AcOEt in hexane) to give 38 (15 mg, 55% from 27a , or 19
mg, 68% from 27b) as a white solid: mp 114-115 °C (white
crystals from hexane/AcOEt); 1H NMR (400 MHz, CDCl3) δ
7.66 (d, 2 H, J ) 8.3 Hz), 7.33 (d, 2 H, J ) 8.3 Hz), 3.85 (m, 1
H), 3.32 (dd, 1 H, J ) 3.6, 11.7 Hz), 3.18 (m, 1 H), 2.98 (m, 1
H), 2.91 (dd, 1 H, J ) 8.3, 11.7 Hz), 2.84 (m, 1 H), 2.44 (s, 3
H), 2.14 (d, 1 H, J ) 2.6 Hz), 2.11 (d, 1 H, J ) 8.5 Hz), 1.96
(m, 1 H), 1.83 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 143.36,
133.08, 129.42, 127.25, 81.25, 73.26, 66.27, 48.84, 42.63, 33.13,
27.55, 21.52; LRMS (FAB, positive) m/z 280 (MH+). Anal. Calcd
for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01. Found: C, 60.19;
H, 6.19; N, 5.01.
1-[5-O-(4-Meth oxytr ityl)-2-d eoxy-2-iod o-3-O-(tr im eth -
ylsilyl)eth yn yld im eth ylsilyl-â-D-r ibo-p en tofu r a n osyl]u r -
a cil (43). Compound 37 (285 mg, 78%) was obtained as a pale
yellow foam from 42 (251 mg, 0.40 mmol) as described above
for the synthesis of 10a , after purification by column chroma-
tography (SiO2, 25-50% AcOEt in hexane): 1H NMR (400
MHz, CDCl3) δ 8.10 (br s, 1 H), 7.83 (d, 1 H, J ) 7.9 Hz), 7.39-
6.85 (m, 14 H), 6.39 (d, 1 H, J ) 5.9 Hz), 5.31 (d, 1 H, J ) 7.9
Hz), 4.50 (m, 1 H), 4.26 (m, 1 H), 4.10 (m, 1 H), 3.81 (s, 3 H),
3.55 (dd, 1 H, J ) 2.6, 11.2 Hz), 3.48 (dd, 1 H, J ) 2.0, 11.2
Hz), 0.36 (s, 3 H), 0.23 (s, 3 H), 0.09 (s, 9 H); 13C NMR (100
MHz, CDCl3) δ 162.56, 158.76, 149.96, 143.55, 143.26, 139.33,
134.28, 130.39, 128.30, 128.05, 127.36, 127.34, 116.39, 113.32,
109.63, 102.52, 90.96, 87.63, 84.38, 71.89, 61.99, 55.28, 31.79,
0.59, 0.46, -0.32; LRMS (FAB, positive) m/z 781 (MH+). Anal.
Calcd for C36H41IN2O6Si2: C, 55.38; H, 5.29; N, 3.59. Found:
C, 55.37; H, 5.32; N, 3.44.
1-(3,5-O-Dia cetyl-2-d eoxy-2-C-eth yn yl-â-D-r ibo-p en to-
fu r a n osyl)u r a cil (44). To a solution of 43 (78 mg, 0.10 mmol)
in toluene (1.0 mL) was added dropwise Et3B (1.0 M solution
in hexane, 30 µL, 0.03 mmol) under argon atmosphere, and
the mixture was stirred at room temperature for 5 h. After
addition of TBAF (1.0 M solution in THF, 300 µL, 0.30 mmol),
the resulting mixture was stirred for an additional 2 h, and
the solvent was evaporated. The residue was purified by
column chromatography (SiO2, 5-10% MeOH in CHCl3) to give
crude 4 including some impurities. A mixture of the solid and
Ac2O (84 µL, 0.90 mmol) in pyridine (1 mL) was stirred at room
temperature for 24 h, and then evaporated. The residue was
partitioned between AcOEt and H2O, and the organic layer
was washed with brine, dried (Na2SO4), evaporated. The
residue was purified by column chromatography (SiO2, 0-4%
1-O-Ben zyl-4-p en tyn -1,2-d iol (39). To a solution of 29a
(44 mg, 0.10 mmol) in toluene (1 mL) was added dropwise Et3B
(1.0 M solution in hexane, 30 µL, 0.030 mmol) under argon
atmosphere at room temperature, and the mixture was stirred
at room temperature. After 12 h, additional Et3B (1.0 M
solution in hexane, 30 µL, 0.030 mmol), was added, and the
mixture was stirred for an additional 60 h. The reaction
mixture was treated with TBAF according to the above general
procedure. The resulting residue was purified by column
chromatography (SiO2, 15-20% AcOEt in hexane), and then
by HPLC (YMC Pack ODS-AM-120-S50, 30 × 300 mm; MeOH,
10 mL/min; room temperature; 254 nm) to give 39 (7 mg, 18%)
as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 7.38-7.29
(m, 5 H), 4.58 (s, 2 H), 3.99 (m, 1 H), 3.62 (dd, 1 H, J ) 4.1,
9.7 Hz), 3.52 (dd, 1 H, J ) 6.8, 9.7 Hz), 2.47-2.45 (m, 3 H),
2.03 (t, 1 H, J ) 2.6 Hz); 13C NMR (100 MHz, CDCl3) δ 137.38,
3474 J . Org. Chem., Vol. 68, No. 9, 2003

Ethynyl Introduction via a Radical Reaction
MeOH in CHCl3) to give 44 (23 mg, 67%) as a white foam: 1H
NMR (400 MHz, CDCl3) δ 9.17 (br s, 1 H), 7.37 (d, 1 H, J )
8.2 Hz), 6.26 (d, 1 H, J ) 8.2 Hz), 5.83 (dd, 1 H, J ) 2.1, 8.2
Hz), 5.33 (dd, 1 H, J ) 2.3, 6.2 Hz), 4.38-4.28 (m, 3 H), 3.32
(m, 1 H), 2.29 (d, 1 H, J ) 2.3 Hz), 2.19 (s, 3 H), 2.15 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 169.65, 169.48, 162.17, 149.78,
138.37, 103.40, 87.65, 80.91, 75.11, 74.19, 72.87, 63.30, 39.91,
20.79, 20.72; HRMS (FAB, positive) calcd for C15H17N2O7
337.1036, found 337.1035 (MH+).
reversed phase column chromatography (1.5 × 10 cm, 50%
MeOH in H2O) to give 7 (73 mg, 88%) as a white solid: mp
230 °C (decomposed, colorless crystals from MeOH); 1H NMR
(400 MHz, DMSO-d6) δ 7.73 (d, 1 H, J ) 7.5 Hz), 7.25 (br s, 1
H), 7.22 (br s, 1 H), 6.13 (d, 1 H, J ) 8.5 Hz), 5.73 (d, 1 H, J
) 5.3 Hz), 5.61 (d, 1 H, J ) 7.5 Hz), 5.04 (t, 1 H, J ) 5.3 Hz),
4.15 (m, 1 H), 3.82 (m, 1 H), 3.51 (m, 2 H), 3.14 (m, 1 H), 3.01
(d, 1 H, J ) 2.3 Hz); 13C NMR (100 MHz, DMSO-d6) δ 165.31,
155.13, 141.04, 94.72, 87.10, 86.43, 78.79, 75.71, 71.92, 61.46,
41.20; LRMS (FAB, positive) m/z 252 (MH+). Anal. Calcd for
1-(2-Deoxy-2-C-et h yn yl-â-D-r ibo-p en t ofu r a n osyl)u r -
a cil (6). A mixture of 44 (50 mg, 0.15 mmol) and K2CO3 (4
mg, 0.03 mmol) in MeOH (1.5 mL) was stirred at room
temperature for 15 h, and then evaporated. The residue was
purified by column chromatography (SiO2, 2-10% MeOH in
CHCl3) to give 6 (37 mg, 98%) as a white solid: 1H NMR (400
MHz, DMSO-d6) δ 11.26 (br s, 1 H), 7.81 (d, 1 H, J ) 8.1 Hz),
6.09 (d, 1 H, J ) 8.8 Hz), 5.71 (d, 1 H, J ) 5.7 Hz), 5.70 (d, 1
H, J ) 8.1 Hz), 5.10 (t, 1 H, J ) 5.1 Hz), 4.18 (m, 1 H), 3.86
(m, 1 H), 3.53 (m, 2 H), 3.22 (m, 1 H), 3.08 (d, 1 H, J ) 2.3
Hz); 13C NMR (100 MHz, DMSO-d6) δ 162.78, 150.56, 140.09,
102.51, 86.97, 86.19, 78.15, 76.10, 72.04, 61.38, 41.01; HRMS
(EI) calcd for C11H12N2O5 252.0746, found 252.0766 (M+).
1-(2-De oxy-2-C-e t h yn yl-â-D-r ibo-p e n t ofu r a n osyl)cy-
tosin e (7). A mixture of 44 (111 mg, 0.33 mmol), TPSCl (200
mg, 0.66 mmol), DMAP (81 mg, 0.66 mmol), and Et3N (92 µL,
0.66 mmol) in MeCN (3.3 mL) was stirred at room temperature
for 15 h. After addition of queous NH4OH (25%, 3.3 mL), the
resulting mixture was stirred at the room temperature for 10
h, and then evaporated. The residue was purified by silica gel
column chromatography (0-4% MeOH in CHCl3) then by C18
C
11H13N3O4: C, 52.59; H, 5.22; N, 16.72. Found: C, 52.40; H,
5.18; N, 16.66.
Ack n ow led gm en t . This investigation was sup-
ported by a Grant-in-Aid for Creative Scientific Re-
search (13NP0401) and a Grant-in-Aid for Scientific
Research (S.S.) from the J apan Society for Promotion
of Science. We are also grateful to Ms. H. Matsumoto,
A. Maeda, and S. Oka (Center for Instrumental Analy-
sis, Hokkaido University) for technical assistance with
NMR, MS, and elemental analyses.
Su p p or tin g In for m a tion Ava ila ble: Experimentally de-
tails for the synthesis of TEDMS-NMe2, EDMS-Cl, 18, 24,
26, 28, 30, and 32, and 1H NMR charts of 6, 18, 30, 33a , 39,
40, 44, and S12. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O0206667
J . Org. Chem, Vol. 68, No. 9, 2003 3475