Solid Phase Synthesis of Carbocyclic L-2′-Deoxynucleosides

Article abstract of DOI:10.1021/ol015783n

matrix presented Carbocyclic L-2'deoxynucleosides 17 were synthesized on solid phase in four steps from the appropriately protected intermedate 11. The Mitsunobu reaction was used as a condensation method between the carbocyclic moiety and heterocyclic ba

Full text of DOI:10.1021/ol015783n

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1471-1473
Solid Phase Synthesis of Carbocyclic
L-2′-Deoxynucleosides
Hyunah Choo, Youhoon Chong, and Chung K. Chu*
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy,
The UniVersity of Georgia, Athens, Georgia 30602-2352
dchu@mail.rx.uga.edu
Received March 2, 2001
ABSTRACT
Carbocyclic L-2’deoxynucleosides 17 were synthesized on solid phase in four steps from the appropriately protected intermedate 11. The
Mitsunobu reaction was used as a condensation method between the carbocyclic moiety and heterocyclic bases. The regioselectivity of the
carbocyclic nucleosides was compared between the solid and solution phase syntheses.
Nucleosides have been playing a major role in combating
tumor and virus, and a variety of modifications of natural
nucleosides have been made to discover novel antitumor and/
or antiviral agents.1 Among nucleosides, carbocyclic ana-
logues have been one of the interesting classes of compounds
due to the nonglycosidic nature of the bond between the
carbocyclic moiety and the heterocyclic base, which results
in metabolic stability to phosphorylases. Several methods2
of condensation between the carbocyclic moiety and het-
erocyclic bases have been reported: (1) a classical SN2 type
reaction with tosylate or mesylate, (2) an epoxide ring
opening method, (3) a palladium-catalyzed coupling reaction,
and (4) a Mitsunobu reaction.3 The Mitsunobu reaction has
been widely utilized for the synthesis of both purine and
pyrimidine derivatives. However, solution phase synthesis
needs to be improved. For example, the byproducts, reduced
DEAD and triphenylphosphine oxide, are very difficult to
separate from the products after reaction, and a regioisomeric
mixture of N1- and O2-alkylated pyrimidines is usually
produced. However, there has not been much effort to solve
this regioselectivity problem. Recently, Crimmins et al.
reported regioselective synthesis of purine nucleosides by
using the palladium-catalyzed coupling method in solid phase
synthesis.4 Herein we report a comparison of solid phase
synthesis with solution phase synthesis of carbocyclic
nucleosides by Mitsunobu reaction, in which we focused on
the regioselectivity of the condensation. Furthermore, this
method can be proposed as a general strategy for a library
of carbocylic nucleosides.
Previously, we reported the syntheses of several carbo-
cyclic L-nucleosides such as L-aristeromycin and L-carbovir5
from alcohol 1, which was synthesized by a known method6
in five steps from D-ribose. By using the alcohol 1, 2′-deoxy
carbocyclic moiety 11 was synthesized as shown in Scheme
1. Appropriately protected carbocyclic moiety 11 was
proposed as the key intermediate because the protecting
groups could be kept stable under the reaction conditions
on solid phase and removed at the time when the product is
generated from the resin after the Mitsunobu reaction.
Alcohol 1 was protected by benzyl bromide to give the
(1) Mansour, T. S.; Storer, R. Curr. Pharm. Design 1997, 3, 227.
(2) (a) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R.; Guedj, R. Tetrahedron 1994, 50, 10611. (b) Borthwick, A.
D.; Biggadike, K. Tetrahedron 1992, 48, 571. (c) Crimmins, M. T.
Tetrahedron 1998, 54, 9229.
(3) (a) Bonnal, C.; Chavis, C.; Lucas, M. J. Chem. Soc., Perkin Trans.
1 1994, 1401. (b) Cadet, G.; Chan, C.-S.; Daniel, R. Y.; Davis, C. P.;
Guiadeen, D.; Rodriguez, G.; Thomas, T.; Walcott, S.; Sheiner, P. J. Org.
Chem. 1998, 63, 4574. (c) Diaz, Y.; Bravo, F.; Castillon, S. J. Org. Chem.
1999, 64, 6508.
(4) Crimmins, M. T.; Zuercher, W. J. Org. Lett. 2000, 2, 1065.
(5) Wang, P. Y.; Gullen, B.; Newton, M. G.; Cheng, Y.-C.; Schinazi, R.
F.; Chu, C. K. J. Med. Chem. 1999, 42, 3390.
(6) (a) Ali, M.; Ramesh, K.; Borchardt, R. T. Tetrahedron Lett. 1990,
31, 1509. (b) Wang, P. Y.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K.
Tetrahedron Lett. 1997, 38, 4207. (c) Wang, P. Y.; Agrofoglio, L. A.;
Newton, M. G.; Chu, C. K. J. Org. Chem. 1999, 64, 4173.
10.1021/ol015783n CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/18/2001

intermediate 11 was obtained by benzoylation followed by
deprotection of the TBDMS group in 98% yield in two steps.
The intermediate 11, which was used in the amount of 3
equiv, was loaded onto p-nitrophenyl carbonate resin 128 by
treatment with 10 equiv of DIPEA and 1.0 equiv of 4-DMAP
in CH2Cl2 under reflux for 24 h (Scheme 2). Unreacted 11
Scheme 1.a Synthesis of Carbocyclic Moiety 11
Scheme 2.a Solid Phase Syntheis of Carbocyclic
L-2′-Deoxynucleosides 17
a Reagents and conditions: (a) DMAP, DIPEA, CH2Cl2, 40 °C;
(b) PPTS, 1-butanol/1,2-dichloroethane, 60 °C; (c) B′H (15a-e),
DEAD, Ph3P, DMF/dioxane or DMF, rt; (d) K2CO3, THF/MeOH,
rt.
was recycled after the reaction. Resin 13 was deprotected
by PPTS in a 1:1 mixture of 1-butanol and 1,2-dichloroethane
at 60 °C for 24 h.9 The temperature was very critical in this
step. If the temperature was below 55 °C, the reaction did
a Reagents and conditions: (a) NaH, BnBr, THF, 0 °C; (b) TFA/
H2O, 60 °C, then 1 N NaOH; (c) TIPDSCl, pyr, 0 °C; (d) NaH,
CS2, MeI, THF, 0 °C to rt; (e) Bu3SnH, AIBN, toluene, reflux; (f)
Pd(OH)2, MeOH, H2; (g) DHP, PPTS, CH2Cl2, rt; (h) TBAF, THF,
rt; (i) TBDMSCl, imidazole, THF, 0 °C to rt; (j) BzCl, pyr, 0 °C.
(8) Dixit, D. M.; Leznoff, C. C. J. Chem. Soc., Chem. Commun. 1977,
798.
(9) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333.
(10) General procedure for Scheme 2: DIPEA (10 equiv) and 4-DMAP
(1 equiv) were added to a mixture of resin 12 and alcohol 11 (3 equiv) in
CH2Cl2 at room temperature. The mixture was refluxed under N2 for 24 h.
After cooling, the resulting resin 13 was filtered, washed, and dried. Resin
13 and PPTS (10 equiv) were added to a 1:1 mixture of 1,2-dichloroethane
and 1-butanol at room temperature. The resulting mixture was stirred
overnight at 60 °C. After cooling, the resulting resin 14 was filtered, washed,
and dried. PPh3 (10 equiv) and 15 (10 equiv) were added to a mixture of
resin 14 in the appropriate solvent. To this mixture was added DEAD (10
equiv) dropwise. After stirring for 24 h at room temperature, the resulting
resin 16 was filtered, washed, and dried. A mixture of resin 16 in THF/
MeOH (2:1) was treated with solid K2CO3 (10 equiv) at room temperature
for 24 h. The reaction mixture was filtered through a short silica gel pad.
The filtrate was concentrated and purified by column chromatography on
silica gel.
fully protected intermediate 2 in 88% yield, which was
deprotected by trifluoroacetic acid in water followed by
treatment with 1 N NaOH to give compound 3 in 97% yield
(Scheme 1). Compound 3 was treated with 1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane (TIPDSCl)7 in pyridine to
give compound 4 which was converted to a xanthate by
successive treatment with sodium hydride, carbon disulfide,
and methyl iodide. It was deoxygenated by tributyltin hydride
and AIBN to give compound 5 in 76% yield in two steps.
The benzyl group of compound 5 was removed by using
palladium(II) hydroxide and hydrogen to give compound 6.
Compound 6 was protected by treatment with DHP and PPTS
followed by deprotection of the TIPDS group to give
compound 8 in 71% yield in two steps. To differentiate 5′-
OH from 3′-OH, the TBDMS group was introduced to
compound 8 to give compound 9 in 99% yield. Key
(11) All carbocyclic nucleosides from solid phase synthesis were analyzed
by HPLC and/or MS and compared with those from solution phase synthesis.
(12) The scheme for the solution phase synthesis is as shown below:
(7) Markiewicz, W. T. J. Chem. Res. 1979, 24.
1472
Org. Lett., Vol. 3, No. 10, 2001

not go to completion even after 24 h. Completion of the
reaction was confirmed by the cleavage of a small portion
of resin 14. Resin 14 was condensed with 10 equiv of
heterocyclic bases 15a-e (Figure 1) under Mitsunobu
Regioselectivity of N1- and O2-alkylated pyrimidines was
increased in the case of uracil and thymine derivatives in
the solid phase synthesis (Table 1). The regioselectivity can
be explained by the relative stability of two resonance forms
of the conjugate anion of pyrimidines. As noted by Crimmins
et al.,4 the different environment of the solid phase, where
aromatic rings of the polystyrene resin solvate the reaction
sites, is probably responsible for the improved regioselec-
tivity. However, in the case of the cytosine derivative, the
fully aromatized resonance form of the conjugate anion is
more stable than the other one, and the preference for the
aromatized resonance form results in the formation of O2-
alkylated cytosine as a major product. This preference does
not seem to be effected by the unique environment of the
solid phase and can explain the similar ratios of N1- and O2-
alkylated cytosine in both solid and solution phase syntheses.
In the case of purine derivatives, there was no regioisomeric
problem in both syntheses.
Figure 1. Structures of heterocyclic bases (B′H).
This study on solid phase synthesis encouraged us to
optimize and standardize the conditions in the solid phase
synthesis in order to apply this method to automation.
Therefore, DMF was chosen as a general solvent because
of the favorable solubility of all the heterocyclic bases (15a-
e). The results are shown in Table 2. Changing the solvent
conditions. Carbocyclic nucleosides 17 were obtained from
resin 16 by treatment with 10 equiv of K2CO3 in THF/MeOH
(2:1) at room temperature for 24 h. The crude product was
purified by silica gel chromatography to give the pure
carbocyclic nucleosides 17 (Table 1).10,11
Table 2. Optimized Solid Phase Synthesis
Table 1. Comparison between Solid and Solution Phase
Syntheses
B′H (15)
17, B )
HPLC ratioa
% yieldb
a
b
c
d
e
uracil
98/2
90/10
30/70
100/0
100/0
74
80
82
69
58
solid phase
solution phase
thymine
cytosine
adenine
guanine
HPLC
ratioa
%
yieldb
isolation
ratioa
%
yieldc
B′H (15)
17, B )
a
b
c
d
e
uracil
97/3
85/15
20/80
100/0
100/0
51d
100d
97e
64/36
70/30
17/83
100/0
100/0
79d
88d
39e
43e
47e
a Ratio between N1- and O2-alkylated pyrimidines or N9- and N7-alkylated
purines. b Yield in four steps from 12 to 17.
thymine
cytosine
adenine
guanine
55e
62e
from a 1:2 mixture of DMF and 1,4-dioxane to DMF did
not affect the regioisomeric ratios significantly, which also
supported the explanation of the increased regioselectivity
in solid phase synthesis.
a Ratio between N1- and O2-alkylated pyrimidines or N9- adn N7-alkylated
purines. b Yield in four steps from 12 to 17. c Yield in three steps from 6
to 17. d Solvent: DMF/1,4-dioxane (1:2). e Solvent: DMF only.
In summary, we have demonstrated that pyrimidine and
purine derivatives of carbocyclic nucleosides were success-
fully synthesized on solid phase using the Mitsunobu
reaction. This method could be applied to the synthesis of
other nucleoside libraries.
The results of solid phase synthesis of carbocyclic nucleo-
sides 17 were compared with those of solution phase
synthesis,12 where the Mitsunobu reaction was used as a
condensation method. Even though the solvent system of
DMF/1,4-dioxane (1:2) was good in view of the yield,13 it
could not be generally used because the solubility of some
protected bases (15c-e) was poor in this solvent. Therefore,
in some cases (15c-e), the solvent was changed to DMF.
Acknowledgment. This research was supported by the
U.S. Public Health Service Research Grant AI 32351 and
UO1 AI48495 from the National Institute of Allergy and
Infectious Diseases, NIH.
(13) Chong, Y.; Gumina, G.; Chu, C. K. Tetrahedron: Asymmetry 2000,
11, 4853.
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