New synthesis of 3′-deoxypurine nucleosides using samarium(III) iodide complex

Article abstract of DOI:10.1016/j.tetlet.2003.09.001

Regio- and stereoselective iodinative cleavage of 2′,3′ -anhydropurine nucleosides was achieved with samarium diiodide and ethyl bromoacetate to produce the corresponding 3′-iodopurine nucleosides, which were then converted to 3′-deoxypurine nucleosides including the natural product cordycepin.

Full text of DOI:10.1016/j.tetlet.2003.09.001

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7941–7943
New synthesis of 3%-deoxypurine nucleosides using samarium(III)
iodide complex
Doo Won Kwon,a Jae-Ho Jeon,b Changwon Kangb,* and Yong Hae Kima,*
aDepartment of Chemistry and Center for Molecular Design and Synthesis, Korea Advanced Institute of Science and Technology,
Daejeon 305-701, Republic of Korea
bDepartment of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
Received 5 July 2003; revised 28 August 2003; accepted 1 September 2003
Abstract—Regio- and stereoselective iodinative cleavage of 2%,3%-anhydropurine nucleosides was achieved with samarium diiodide
and ethyl bromoacetate to produce the corresponding 3%-iodopurine nucleosides, which were then converted to 3%-deoxypurine
nucleosides including the natural product cordycepin.
© 2003 Elsevier Ltd. All rights reserved.
The anti-proliferation activity of nucleosides containing
3%-deoxyribose moiety has been noted in several bacte-
rial and carcinoma cell lines.1 The wide spectrum of
inhibitory activity is likely due to the lack of 3%-
hydroxyl group on the ribose sugar. Incorporation of
the 3%-deoxyribonucleotides of natural bases by RNA
polymerases terminates RNA synthesis.2 Also, 2%,5%-
linked 3%-deoxyoligonucleotides have been utilized as
probes for structure and mechanism elucidation.3
Recent studies have revealed that they selectively bind
to complementary RNA (not DNA) and are stable
against common cellular nucleases that hydrolyze natu-
ral DNA, making them potential candidates for both
diagnostic and therapeutic antisense applications.4
cleosides, which are difficult to separate. Still other
methods involved reductive elimination of the halo-
genated carbohydrate ring8 but also resulted in a mix-
ture of 2%- and 3%-deoxy isomers.
Recently we have reported a new method for regio- and
stereoselective synthesis of a- and b-hydroxy iodohy-
drins from a- and b-hydroxy epoxides, respectively with
SmI2 in the presence of ethyl bromoacetate.9 However,
the reaction with d-hydroxy epoxide produced two
regioisomers, and the lack of regioselectivity was proba-
bly due to that the hydroxyl group is located too far
away from the epoxide ring to form an intermediate
important for the regioselectivity.9
As a result, the synthesis of 3%-deoxynucleosides has
been investigated in many laboratories. Procedures
have usually involved either (i) superhydride- or LAH-
reduction for ring opening of the anhydronucleoside,5
(ii) Bu3SnH/AIBN-mediated deoxygenation for ring
opening of the cyclic thiocarbonate6 or 3%-O-thiocar-
bonate, or (iii) a modified Moffatt reaction followed by
Bu3SnH/AIBN reductive elimination.7 However, reduc-
tive cleavage of the cyclic thiocarbonate proceeds in
low yield to afford a mixture of 2%- and 3%-deoxynu-
It led us to expand the utility and scope of the method
towards the regio- and stereoselective synthesis of 3%-
iodopurine nucleosides. In this paper, we describe a
facile method for the synthesis of 3%-deoxypurine
nucleosides through the regio- and stereoselective iodi-
nation at the C-3% position of 2%,3%-anhydropurine
nucleosides.
The starting material 1a was readily prepared from
guanosine.5 A solution of 1a (370 mg, 0.85 mmol) and
ethyl bromoacetate (142 mg, 0.85 mmol) in dry THF (3
ml) was reacted with SmI2 (1.7 mmol) at −78°C for 1 h
and further stirred at room temperature for another 1 h
to yield 2a (387 mg, 81%). Only one diastereoisomer of
* Corresponding authors.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.001

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D. W. Kwon et al. / Tetrahedron Letters 44 (2003) 7941–7943
2%-hyroxyl-3%-iodo 2a† was producted. The coupling
constant of H%1 signal (J=5.4 Hz) at l 5.69 ppm showed
the trans-diaxial arrangement of the substituents at C-1%
and C-2%,10 and no signals other than H1%, H%2, and H3%
The assignment of H%2-up, H3%-down and H4%-down
configuration was established on the basis of NOE
difference spectroscopy (CDCl3, 25°C, 400 MHz)11
(Fig. 1). Saturation of H8 of adenosine ring system
results in enhancement of NOE’s of H%2 signal (2.55%),
while H3% and H%4 signals do not show any significant
intensity enhancement (<0.5%). The chemical shifts of
H2% (l 5.75) and H%3 (l 4.43) of 3%-bromo adenosine
nucleoside12 show also the similar correlations with 1b
(1b: H2%=l 4.97, H%3=l 4.49).
1
signals were observed in H NMR spectra between l
5.69 and 4.46 ppm. The same reaction of 2%,3%-anhy-
droadenosine (1b)5 from adenosine gave 2b† in 83%
yield and proceeded with complete regio- and stereose-
lectivity (Scheme 1).
The regio- and stereoselective iodinative cleavage can
be rationalized by formation of an intermediate I (Fig.
2). Coordination between epoxide ether and silyloxy
ether at b-position with samarium iodoenolate (SmI2L)9
may form I by a strong oxophilicity of Sm. The addi-
tive ethyl bromoacetate is essential for the regio- and
stereoselective iodinative cleavage of epoxides. When
other additives such as I2 (2 SmI2+I2“2 SmI3) or
i-PrOH (SmI2+i-PrOH“SmI(i-PrO)2) were used in the
reaction of 1b to 2b, neither chemical yield nor regiose-
lectivity was high. After 6 h reaction at 25°C the former
reaction gave only the 2%-hydroxyl-3%-iodo isomer of 2b
but in only ca. 10% yield, and the latter resulted in ca.
40% of yield but in a mixture of the 2%- and 3%-iodo
regioisomers in the ratio of 1:5.
Next, deiodination of 2a could be achieved by treat-
ment with Bu3SnH (3 equiv.) and AIBN (cat.) in reflux-
ing toluene for 5 h,6,7 which yielded the protected
Scheme 1.
Figure 1.
† All new compounds showed satisfactory 1H NMR, HR-FAB-MS,
mp and optical rotation data for 2a–c. 2a: (400 MHz, DMSO-d6) l
11.36 (s, 1H), 8.57 (s, 1H), 7.96 (s, 1H), 6.27 (d, J=5.8, 1H, OH),
5.69 (d, J=5.4, H%1), 4.90 (m, H2% ), 4.46 (m, H3% ), 4.03 (m, H%4), 3.90
(m, H5% ), 3.15 (s, 3H), 3.03 (s, 3H), 0.89 (s, 9H), 0.00 (s, 6H); HRMS
calcd for C19H31IN6O4Si (M+1) 563.1320, found 563.1300; mp
175–178°C; [h]2D1.5 +74.5 (c 0.5, MeOH). 2b: (400 MHz, CDCl3) l
8.67 (s, 1H), 8.58 (br, 1H), 8.27 (s, 1H), 5.90 (d, J=4.2 Hz, H%1),
4.98 (m, H2% ), 4.49 (m, H3% ), 4.30 (m, H4% ), 4.08 (dd, J=3.3, 11.3, H%5),
3.95 (dd, J=3.5, 11.3, H%5), 1.38 (s, 9H), 0.72 (s, 9H), 0.00 (s, 6H);
HRMS calcd for C21H34IN5O4Si (M+1) 576.1425, found 576.1501;
mp 65–68°C; [h]2D7.6 +10.2 (c 0.9, CHCl3). 2c: l 9.26 (br, 1H), 8.71
(s, 1H), 8.31 (s, 1H), 8.01 (m, 2H), 7.60–7.50 (m, 3H), 5.92 (d,
J=4.3, H1% ), 5.67 (br, 1H, OH), 5.01 (m, H2% ), 4.50 (m, H3% ), 4.30 (m,
H4% ), 4.10 (dd, J=3.0, 11.2, H5% ), 3.96 (dd, J=3.4, 11.3, H5% ), 0.71 (s,
9H), 0.00 (s, 6H); HRMS calcd for C23H30IN5O4Si (M+1) 596.1112,
found 596.1187; mp 95–98°C (dec.); [h]2D4 −15.1 (c 2.1, CHCl3).
Figure 2.

D. W. Kwon et al. / Tetrahedron Letters 44 (2003) 7941–7943
7943
bromoacetate and the subsequent deiodination under
mild conditions without hazardous chemicals. This
method could be generally used for the synthesis of
various analogues of 3%-deoxypurine nucleosides.
Acknowledgements
This work was supported by grants from National
Research Laboratory Program (M1-0104-00-0179), the
Korea Science and Engineering Foundation (R01-1999-
00111 and R02-2002-00097), 21C Frontier Functional
Human Genome Project (M1-01KB-01-0001) and Brain
Korea 21 Project.
References
1. (a) Cunnigham, K. G.; Hutchinson, S. A.; Manson, W.;
Spring, F. S. J. Chem. Soc. 1951, 2299; (b) Jagger, D. V.;
Kredich, N. M.; Guarino, A. J. Cancer Res. 1961, 21,
2156; (c) Kaczka, E. A.; Dulaney, E. L.; Gitterman, C.
O.; Woodruff, H. R.; Folkers, K. Biochem. Biophys. Res.
Commun. 1964, 14, 452.
2. Axelrod, V.; Kramer, F. Biochemistry 1985, 24, 5716.
3. (a) Hashimoto, H.; Switzer, C. J. J. Am. Chem. Soc.
1992, 114, 6255; (b) Jung, K. E.; Switzer, C. J. J. Am.
Chem. Soc. 1994, 116, 6059.
Scheme 2.
4. Sheppard, T. L.; Breslow, R. C. J. Am. Chem. Soc. 1996,
118, 9810.
3%-deoxyguanosine 3a in 89% yield. In order to avoid
the use of toxic Bu3SnH, an alternative method was
developed for the deiodination as shown in Scheme 1.
The 2a was readily deiodinated with catalytic Pd/C (10
mol%) catalyst and Et3N (2 equiv.) in methanol under
15 psi hydrogen pressure for 4 h to yield 3a (90%). No
anomerization occurred at C-1% in the deiodination
step. When KOH (2 equiv.) was used instead of Et3N,
anomerization (5%) occurred with 92% yield (H%1: l 5.82
and 5.77 ppm for the b- and a-anomers of 3a, respec-
5. (a) Hansske, F.; Robins, M. J. Tetrahedron Lett. 1985,
26, 4295; (b) Bazin, H.; Chattopadhyaya, J. Synthesis
1985, 1108; (c) Norbeck, D. W.; Kramer, J. B. J. Am.
Chem. Soc. 1988, 110, 7217; (d) Rizzo, C. J.; Dougherty,
J. P.; Breslow, R. Tetrahedron Lett. 1992, 33, 4129; (e)
He, G.-X.; Bischofberger, N. Tetrahedron Lett. 1995, 36,
6991.
6. (a) Barton, D. H. R.; Subramanian, R. J. Chem. Soc.,
Chem. Commun. 1976, 867; (b) Nair, V.; Buenger, G. S. J.
Am. Chem. Soc. 1989, 111, 8502.
1
tively in H NMR spectroscopy10).
7. (a) Russell, A. F.; Greenberg, S.; Moffatt, J. G. J. Am.
Chem. Soc. 1973, 95, 4025; (b) Jain, T. C.; Jenkins, I. D.;
Russel, A. F.; Verheyden, J. P. H.; Moffatt, J. G. J. Org.
Chem. 1974, 39, 30; (c) Engels, J. Tetrahedron Lett. 1980,
21, 4339; (d) Dorland, E.; Serafinowski, P. Synthesis
1992, 477.
8. Mengel, R.; Wiedner, H. Chem. Ber. 1976, 109, 1395.
9. (a) Kwon, D. W.; Cho, M. S.; Kim, Y. H. Synlett 2003,
59; (b) Kwon, D. W.; Park, H. S.; Kim, Y. H. Bull.
Korean Chem. Soc. 2002, 23, 1185.
10. (a) Okabe, M.; Sun, R.-C.; Tam, S. Y.-K.; Todaro, L. J.;
Coffen, D. L. J. Org. Chem. 1988, 53, 4780; (b) Chu, C.
K.; Ullas, G. V.; Jeong, L. S.; Ahn, S. K.; Doboszewski,
B.; Lin, Z. X.; Beach, J. W.; Schinazi, R. F. J. Med.
Chem. 1990, 33, 1553.
Thus, our new SmI2 mediated regio- and stereoselective
iodination of epoxide 1 is successfully applied to the
synthesis of 3%-deoxy adenosine 5, which was initially
isolated from the fungus Cordyceps militaris and named
cordycepin.1 When 3c was treated with NH3/MeOH,
debenzoylated product 4c was produced in good yield
(90%). Finally, deprotection of 5%-silyl group was
achieved smoothly and the desired compound 5 was
1
obtained, which showed all satisfactory H NMR, 2D
NMR (1H–1H COSY), 13C NMR, FAB-MS and [h]D
value; [h]2D4.6 −41.1 (c 0.55, H2O), lit.5 [h]2D0 −44.0 (c 0.5,
H2O) (Scheme 2).
In conclusion, a novel route to the synthesis of 3%-
deoxypurine nucleosides is developed by regio- and
stereoselective iodinative cleavage of 2%,3%-anhydro-
purine nucleosides with SmI2 in the presence of ethyl
11. Hong, J. H.; Shim, M. J.; Ro, B. O.; Ko, O. H. J. Org.
Chem. 2002, 67, 6837.
12. Cui, Z.; Zhang, L. Tetrahedron Lett. 2001, 42, 561.