Novel stereoselective entry to 2′-β-carbon-substituted 2′-deoxy-4′-thionucleosides from 4-thiofuranoid glycals

Article abstract of DOI:10.1021/ol040035u

2β-β-Methyl- and 2′-β-hydroxymethyl-2′-deoxy- 4′-thionucleosides have been synthesized through PhSeCl-mediated electrophilic glycosidation using 4-thiofuranoid glycals having carbon substituents at the C2-position as a glycosyl donor. Preparation of these glycals were carried out by means of the C2 lithiation of 1-chloro-4- thiofuranoid glycal with LTMP followed by the Birch reduction of the chlorine atom.

Full text of DOI:10.1021/ol040035u

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2645-2648
Novel Stereoselective Entry to
2′-â-Carbon-Substituted
2′-Deoxy-4′-thionucleosides from
4-Thiofuranoid Glycals
Kazuhiro Haraguchi,* Noriaki Shiina, Yuichi Yoshimura, Hisashi Shimada,
Kyoko Hashimoto, and Hiromichi Tanaka
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan
harakazu@pharm.showa-u.ac.jp
Received April 29, 2004
ABSTRACT
2′-â-Methyl- and 2′-â-hydroxymethyl-2′-deoxy-4′-thionucleosides have been synthesized through PhSeCl-mediated electrophilic glycosidation
using 4-thiofuranoid glycals having carbon substituents at the C2-position as a glycosyl donor. Preparation of these glycals were carried out
by means of the C2 lithiation of 1-chloro-4-thiofuranoid glycal with LTMP followed by the Birch reduction of the chlorine atom.
1-â-D-Arabinofuranosylcytosine (ara-C, 1) is an antimetabo-
lite under clinical use for the treatment of leukemia.1 Despite
its effectiveness, it has been pointed out that rapid deami-
nation of 1 leads to inactive 1-â-D-arabinofuranosyluracil.2
To overcome this drawback, a number of 2′-substituted
arabinofuranosyl nucleosides, in which the 2′-hydroxyl group
is replaced with other functional groups, have been evaluated
for their effectiveness as antimetabolites. As a result of these
studies, potent antitumor activity was found in 2′-â-carbon-
substituted analogues such as SMDC (2), SFDC (3), and
CNDAC (4).3
thymidine (5) and 2′-deoxy-4′-thiocytidine (6),4 has stimu-
lated the synthesis of this class of nucleosides, especially
those modified at the sugar moiety. There has been, however,
only one report concerning the synthesis of 2′-â-carbon
substituted 2′-deoxy-4′-thionucleosides.5 As a part of our
ongoing efforts toward the synthesis of 4′-thionucleosides,6
we describe herein a novel stereoselective entry to 2′-â-
carbon substituted analogues using 4-thiofuranoid glycals
having a carbon substituent at the C2 position as a glycosyl
donor.
We previously reported6b that the reaction between 4-thio-
A recent discovery that the simple replacement of the
furanose ring-oxygen of nucleosides with sulfur atom leads
to promising antiviral and antitumor activities, e.g., 4′-thio-
furanoid glycal 7 and silylated nucleobase in the presence
(4) For a review, see: Yokoyama, M. Synthesis 2000, 1637-1655.
(5) 2′-â-Methyl-2′-deoxy-4′-thiouridine and -thymidine have been syn-
thesized by Vorbru¨ggen-type condensation. In this case, due to the steric
hindrance exerted by the 2′-â-methyl substituent, the undesired R-anomers
were obtained as the major products: Uenishi, J. J. Synth. Org. Chem. Jpn.
1997, 55, 186-195.
(6) (a) Haraguchi, K.; Nishikawa, A.; Sasakura, E.; Tanaka, H.; Naka-
mura, K. T.; Miyasaka, T. Tetrahedron Lett. 1998, 39, 3713-3716. (b)
Haraguchi, K.; Takahashi, H.; Shiina, N.; Horii, C.; Yoshimura, Y.;
Nishimura, A.; Sasakura, E.; Nakamura, K. T.; Tanaka, H. J. Org. Chem.
2002, 67, 5919-5927. (c) Haraguchi, K.; Takahashi, H.; Tanaka, H.
Tetrahedron Lett. 2002, 43, 5657-5660.
(1) Keating, M. J.; McCredie, K. B.; Bodey, G. P.; Smith, T. L.; Gehan,
E.; Freidreich, E. J. JAMA 1982, 248, 2481-2486.
(2) (a) Prince, H. N.; Grumgerg, E.; Buck, M.; Cleeland, R. A. Proc.
Soc. Exp. Biol. Med. 1969, 130, 1080-1086. (b) Ho, W. D. H. Cancer.
Res. 1973, 33, 2816-2820. (c) Plunkett, W.; Gandhi, V. Semin. Oncol.
1993, 20, 50-63.
(3) (a) Matsuda, A. In Nucleosides and Nucleotides as Antitumor and
AntiViral Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York,
1993; pp 1-22. (b) Yoshimura, Y.; Saitoh, K.; Ashida, N.; Sakata, S.;
Matsuda, A. Bioorg. Med. Chem. Lett. 1994, 4, 721-724.
10.1021/ol040035u CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004

We considered that generation of a C2-anion would be a
suitable approach to construct C-C bonds, and thus, it was
necessary to protect the more acidic H-1 in IV. For the
protection of the C1-position, LDA lithiation (2.0 equiv, -70
°C, 15 min, in THF) of 3,5-O-(tetraisopropyldisiloxane-1,3-
diyl) (TIPDS)-4-thiofuranoid glycal (10) was carried out by
using electrophiles (2.0 equiv) such as Me3SiCl, Bu3SnCl,
iodine, and PhSO2Cl. Reflecting the fact that sulfur is the
best R-activator through d-σ overlap, the C1-protected
products 11-14 were obtained uniformly in good yields
(Table 1).7
Table 1. Preparation of C1-Protected 4-Thiofuranoid Glycals
(11-14)
of phenylselenenyl chloride (PhSeCl) gave the â-anomer of
4′-thionucleosides 8 as shown in Scheme 1. Radical-mediated
removal of the phenylseleno group in 8 allows ready access
Scheme 1
entry
electrophile
product (isolated yield, %)
1
2
3
4
Me3SiCl
Bu3SnCl
I2
11 (82)
12 (70)
13 (84)
14 (86)
PhSO2Cl
Generation of the C2-anion of 11-14 was next examined
with the more basic lithiating agent LTMP followed by
quenching the lithiated species 15 with MeI (Scheme 3).
to 2′-deoxy-4′-thionucleosides (9). This method led us to
propose the present synthetic plan shown in Scheme 2. Since
Scheme 3
Scheme 2
When 11 or 12 was used as a substrate, no reaction took
place, presumably due to bulkiness of the C1-protecting
group. In the case of 13, exclusive halogen-lithium exchange
reaction occurred to give the 1-methylglycal 16 (67%). In
contrast to these results, the 1-chloroglycal 14 appeared to
be a suitable substrate. Thus, LTMP lithiation (5 equiv, -70
the target molecules I can be prepared simply by removing
the phenylseleno group from the glycosylated product (II),
and since II would be prepared from appropriate C2-
substituted 4-thioglycals (III) through PhSeCl-mediated
electrophilic glycosidation, the major challenge was to
construct the C-C bond at the C2-position of the starting
material (IV).
(7) We expected that the use of 3,5-O-(di-tert-butylsilylene)-protected
4-thiofuranoid glycal 7 would give better stereoselectivity in the glycosi-
dation step. However, the C1-chlorinated product derived from 7 was found
to be unstable.
2646
Org. Lett., Vol. 6, No. 16, 2004

°C, 30 min, in THF) of 14 and successive methylation (10
equiv of MeI, -70 °C, 30 min) led to the isolation of the
desired C2-methylated product (17) in 71% yield. When 15
was reacted with DMF and then treated with NaBH4 in a
one-pot manner, the 2-hydroxymethyl derivative 18 was
isolated in 85% yield.
Alkali metal reduction was employed to remove the C1-
chloro atom of 17 and 18, and the results are summarized in
Table 2. Upon reaction of 17 with lithium wire in THF, the
silylated thymine in the presence of PhSeCl at 0 °C, a mixture
of two diastereomers was obtained in 87% yield with a
diastereomeric ratio of 27:1. A NOE experiment of the
mixture confirmed overwhelmingly preferential formation of
the desired â-anomer 21. Under the same reaction conditions,
the 2′-acetoxymethyl derivative 22 was prepared in 92% from
20 as a mixture (â/R ) 21:1). Treatment of 21 with Bu3-
SnH in the presence of Et3B in toluene at -70 °C gave the
4′-thiothymidine derivative 23 in quantitative yield. Similarly,
24 was obtained from 22 in almost quantitative yield.
Synthesis of the corresponding 2′-deoxycytidine analogues
is also feasible. Reactions of 19 and 20 with silylated
N-acetylcytosine gave 25 (96%) and 26 (92%), respectively,
with high stereoselectivity (25, â/R ) 25/1; 26, â/R )
23/1). Subsequent radical reduction gave 4′-thio-SMDC (27)
and the 2′-â-acetoxymethyl-2′-deoxy-4′-thiocytidine deriva-
tive 28 in quantitative yields.
Table 2. Dechlorination of Glycals 17 and 18
products
(isolated
yields, %)
entry glycal
reaction conditions
1
2
3
4
17
17
17
18
Li wire/THF/-70 °C/34 h
Li dispersion/THF/-70 °C/ 3 h
Na/liq NH3-Et2O/-80 °C/0.5 h
(1) Na/liq NH3-Et2O/-80 °C/0.5 h 20 (70)
(2) Ac2O/i-Pr2NEt/DMAP/CH2Cl2
19 (6), 17 (51)
19 (36), 17 (13)
19 (81)
dechlorinated product 19 was isolated in only 6% yield (entry
1). Although more reactive lithium dispersion improved the
isolated yield of 19 to 36% yield, many unidentified
byproducts were formed, along with the recovered starting
material (entry 2). The Birch reduction of 17 was found to
give the best result (entry 3). The reaction also works well
for the 2-hydroxymethyl derivative 18. After acetylation of
the reaction mixture, 20 was isolated in 70% yield (entry
4).
Some chemical transformations of the 2′-â-hydroxymethyl
group were next explored starting from 24 (Scheme 5).
Scheme 5
In Scheme 4 is shown electrophilic glycosidation of the
above prepared glycals (19 and 20) and subsequent removal
of the phenylseleno group (only the major diastereomers are
depicted). When the 2-methylglycal 19 was reacted with
Scheme 4
Conventional NH3/MeOH treatment of 24 did not effect
deacetylation, probably due to encumbered accommodation
of the acetyl group, while the use of NaOMe resulted in
partial removal of the 3′,5′-O-(tetraisopropyldisiloxane-1,3-
diyl) group. Therefore, the 3′,5′-bis-O-TBDMS-protected 29
was prepared from 24, and it was converted to 30 by the
treatment with NaOMe. Dess-Martin oxidation of 30
provided the formyl derivative 31 (93%).
Org. Lett., Vol. 6, No. 16, 2004
2647

As the first step toward the synthesis of the 2′-â-ethynyl
derivative, reaction of 31 with 3.0 equiv of Ph3PdCHBr8
was carried out. Quite unexpectedly, this Wittig reagent gave
the epoxide 32 (60%) as the major product. Careful
examination of the reaction mixture revealed the presence
resulting triol was converted to the 3′,5′-(di-tert-butyl-
silylene)-protected 40 in good yield. Dess-Martin oxidation
of 40 gave the corresponding aldehyde, which was then
reacted with hydroxylamine to give the oxime 41. When the
oxime 41 was mesylated with methanesulfonyl chloride in
pyridine, spontaneous elimination took place to give the
nitrile 42 in 97% yield. Tin radical-mediated removal of the
phenylseleno group proceeded again stereoselectively to
furnish the desired 43 in 72% yield.
1
of a small amount of an additional product. Its H NMR
and MS spectra showed that it was not the expected product
but the dibromoolefin 33 (5%). When this reaction was
conducted by using 6.0 equiv of the reagent, the yield of 33
increased to 32% at the expense of a lowered yield of 32
(33%). Although we do not have satisfactory explanation
for the above two experimental results, it would be reason-
able to assume that the epoxide formation could be ac-
companied by generation of the new Wittig reagent Ph3Pd
CBr2 as depicted in Scheme 6. Treatment of 33 with BuLi
Scheme 6
(4.0 equiv) in THF at -30 °C gave the 2′-â-ethynyl-4′-
thiothymidine derivative 34 in 56% yield.
Attempted fluorination of 30 by direct treatment with
diethylaminosulfur trifluoride (DAST) gave the cyclonucleo-
side 35 as the sole product in 92% yield. To avoid this
pathway, N3-benzyloxymethyl (BOM)-protected 37 was
prepared from 29 via 36 in a two step-sequence. Although
no reaction was observed with DAST alone, addition of
Na2CO3 accelerated the fluorination to give fluoromethylated
38 in 63% yield. Removal of the BOM group was carried
out by hydrogenolysis with Pd-black to provide 39 in 69%
yield.
Finally, synthesis of 2′-â-cyano-4′-thiothymidine 43 was
explored. To prevent anticipated glycosyl bond cleavage
caused by dissociation of the acidic 2′-hydrogen, the 2′-
phenylseleno derivative 22 was used as the starting material.
After deprotection of TIPDS and acetyl group in 22, the
In conclusion, we have developed a novel approach to the
synthesis of 2′-â-carbon substituted 2′-deoxy-4′-thionucleo-
sides. Biological evaluation of the corresponding parent
nucleosides is under investigation.
Acknowledgment. Financial support from Japan Society
for the Promotion of Science (KAKENHI No. 15590100 to
K.H. and No. 15590020 to H.T.) and the Research Founda-
tion of Pharmaceutical Sciences (to K.H.) is gratefully
acknowledged.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 11-14 and
17-43. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1980, 21, 4021-4024.
OL040035U
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Org. Lett., Vol. 6, No. 16, 2004