Stereoselective synthesis of 2′-C-methyl-cyclopropyl-fused carbanucleosides as potential anti-HCV agents

Article abstract of DOI:10.1021/ol061959f

(Chemical Equation Presented) Stereoselective synthesis of 2′-C-methyl-cyclopropyl-fused carbanucleosides was accomplished via stereoselective cyclopropanation, regioselective cleavage of the isopropylidene group, stereoselective Grignard reaction, and cy

Full text of DOI:10.1021/ol061959f

ORGANIC
LETTERS
2
006
Vol. 8, No. 22
081-5083
Stereoselective Synthesis of
-C-Methyl-cyclopropyl-Fused
5
2′
Carbanucleosides as Potential Anti-HCV
Agents
†
†
†
‡
Jeong A Lee, Hea Ok Kim, Dilip K. Tosh, Hyung Ryong Moon,
§
,†
Sanghee Kim, and Lak Shin Jeong*
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans UniVersity,
Seoul 120-750, Korea, College of Pharmacy, Pusan National UniVersity,
Busan 609-735, Korea, and College of Pharmacy, Seoul National UniVersity,
Seoul 151-742, Korea
lakjeong@ewha.ac.kr
Received August 8, 2006
ABSTRACT
Stereoselective synthesis of
2′-C-methyl-cyclopropyl-fused carbanucleosides was accomplished via stereoselective cyclopropanation,
regioselective cleavage of the isopropylidene group, stereoselective Grignard reaction, and cyclic sulfate chemistry.
The hepatitis C virus (HCV) is a lethal single-stranded RNA
virus with which 170 million people are infected worldwide.
discovered as potent HCV inhibitors (EC50 ) 0.26 and 3.5
1
µM, respectively) in a cell-based HCV replicon assay (Figure
5
Its chronic infection is the cause of liver cirrhosis and
1). These nucleosides exhibit their anti-HCV activity by
2
hepatocellular carcinoma. The only approved treatment of
RNA-chain termination because the 2′-methyl group of 1
and 2 prevents subsequent incorporation of an incoming
HCV infection is immunotherapy using recombinant inter-
3
6
feron-R in combination with ribavirin. Thus, it is highly
natural substrate, the nucleoside triphosphate.
desirable to develop effective chemotherapeutic agents for
the treatment of HCV-infected patients.
Many nucleoside and nonnucleoside derivatives have been
synthesized as anti-HCV agents.4 Among these, 2′-C-
methyladenosine (1) and 2′-C-methylguanosine (2) were
Compounds 1 and 2 were reported to display a strong
preference for a Northern C3′-endo conformation (pseudoro-
tation angle P ) 15.6°), as shown in Figure 1. It has been
known that the bicyclo[3.1.0]hexane carbocyclic nucleosides
adapt an extreme Northern or Southern conformation because
5
(
5) Eldrup, A. B.; Allerson, C. R.; Bennett, C. F.; Bera, S.; Bhat, B.;
†
Ewha Womans University.
Pusan National University.
Seoul National University.
Bhat, N.; Bosserman, M. R.; Brooks, J.; Burlein, C.; Carroll, S. S.; Cook,
P. D.; Getty, K. L.; MacCoss, M.; McMasters, D. R.; Olsen, D. B.; Prakash,
T. P.; Prhavc, M.; Song, Q.; Tomassini, J. E.; Xia, J. J. Med. Chem. 2004,
47, 2283-2295.
(6) Migliaccio, G.; Tomassini, J. E.; Carroll, S. S.; Tomei, L.; Altamura,
S.; Bhat, B.; Bartholomew, L.; Bosserman, M. R.; Ceccacci, A.; Colwell,
L. F.; Cortese, R.; De Francesco, R.; Eldrup, A. B.; Getty, K. L.; Hou, X.
S.; LaFemina, R. L.; Ludmerer, S. W.; MacCoss, M.; McMasters, D. R.;
Stahlhut, M. W.; Olsen, D. B.; Hazuda, D. J.; Flores, O. A. J. Biol. Chem.
2003, 278, 49164-49170.
‡
§
(1) Szabo, E.; Lotz, G.; Paska, C.; Kiss, A.; Schaff, Z. Pathol. Oncol.
Res. 2003, 9, 215-221.
(
2) Hoofnagle, J. H. Hepatology 1997, 26, 15S-20S.
(3) Lake-Bakaar, G. Curr. Drug Targets Infect. Disord. 2003, 3, 247-
2
53.
(
4) Gordon, C. P.; Keller, P. A. J. Med. Chem. 2005, 48, 1-20 and
references cited therein.
1
0.1021/ol061959f CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/29/2006

Cyclic sulfite or cyclic sulfate I could be prepared from
ketone II via stereoselective methyl addition as a key step.
Ketone II might be derived from isopropylidene derivative
III using regioselective cleavage of the isopropylidene group
as a key step. It was further thought that compound III would
be easily synthesized from cyclopentenone derivative IV
which could be derived from D-ribose.
Our synthesis began by preparing the known cyclopen-
tenone 4 from D-ribose, according to our previously reported
8
procedure. The obtained enone 4 was stereoselectively
4
reduced to allylic alcohol 5 by treating with NaBH in the
9
presence of ceric chloride (Scheme 2). The hydroxyl-
Scheme 2. Synthesis of the Glycosyl Donor 13
Figure 1. Rationale for the design of the target nucleosides.
of their rigid pseudoboat conformation.7 For example,
conformationally restricted nucleosides in which the cyclo-
propane ring is fused between C4′ and C6′ lock the positions
of the carbasugars at the typical range of Northern C3′-endo
conformers (P ) 0 ( 18°), and carbanucleosides in which
the cyclopropane ring is fused between C1′ and C2′ take
the typical Southern C3′-exo conformation. On the basis of
this conformational information, we designed the cyclopro-
pyl-fused analogues 3a and 3b because these compounds
could take the Northern C3′-endo conformation similar to
that for compounds 1 and 2 as demonstrated in Figure 1.
Herein, we report the stereoselective synthesis of our
designed 2′-C-methyl-cyclopropyl-fused carbocyclic nucleo-
sides 3a and 3b as potential anti-HCV agents.
Our synthetic strategy to the target nucleosides is illustrated
in Scheme 1. The final nucleosides 3a and 3b might be
directed Simmons-Smith cyclopropanation10 of 5 using
diethyl zinc and methylene diiodide afforded cyclopropane
derivative 6 as a single stereoisomer. Regioselective cleavage
of the isopropylidene group was achieved by treating 6 with
Scheme 1. Retrosynthetic Analysis of the Desired Nucleosides
3
a and 3b
11
trimethylaluminum at room temperature to give 7. Selective
protection of diol 7 with a bulky silyl group could be
accomplished at the pseudoequatorial positioned secondary
hydroxyl group to give the desired alcohol 8 in excellent
yield. Swern oxidation of the remaining secondary alcohol
of 8 gave the ketone 9 which was subjected to the Grignard
reaction using methylmagnesium iodide to afford the tertiary
alcohol 10 as a single stereoisomer. This stereochemical
outcome can be explained by considering the attack of the
Grignard reagent from the less-hindered convex side. For
derived from a common precursor, cyclic sulfite (n ) 1) or
cyclic sulfate (n ) 2) I, by condensation with a nucleobase.
(8) Choi, W. J.; Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.; Shin,
D. H.; Jeong, L. S. J. Org. Chem. 2004, 69, 2634-2636.
(9) Marquez, V. E.; Lim, M.-I.; Tseng, C. K.-H.; Markovac, A.; Priest,
M. A.; Khan, M. S.; Kaskar, B. J. Org. Chem. 1988, 53, 5709-5714.
(10) Altmann, K. H.; Kesselring, R.; Trancotte, E.; Rihs, G. Tetrahedron
Lett. 1994, 35, 2331-2334.
(11) (a) Takano, S.; Ohkawa, T.; Ogasawara, K. Tetrahedron Lett. 1988,
29, 1823-1824. (b) Siddiqui, M. A.; Ford, H., Jr.; George, C.; Marquez,
V. E. Nucleosides Nucleotides 1996, 15, 235-250.
(
7) (a) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.; Ford,
H., Jr.; Feldman, R. J.; Mitsuya, H.; George, C.; Barchi, J. J., Jr. J. Am.
Chem. Soc. 1998, 120, 2780-2789. (b) Marquez, V. E.; Ben-Kasus, T.;
Barchi, J. J., Jr.; Green, K. M.; Nicklaus, M. C.; Agbaria, R. J. Am. Chem.
Soc. 2004, 126, 543-549. (c) Marquez, V. E.; Choi, Y.; Comin, M. J.;
Russ, P.; George, C.; Huleihel, M.; Ben-Kasus, T.; Agbaria, R. J. Am. Chem.
Soc. 2005, 127, 15145-15150.
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Org. Lett., Vol. 8, No. 22, 2006

the synthesis of the glycosyl donor, TBDPS groups of 10
were removed to give the triol 11, whose primary alcohol
was selectively protected as TBS ether to give 12. Treatment
of diol 12 with thionyl chloride gave the cyclic sulfite 13
H
2
O.14 To our delight, the regioselective nucleophilic
substitution of cyclic sulfate 14 with an adenine anion led,
after hydrolysis of the resulting sulfate ester intermediate
with aqueous sulfuric acid, to the formation of the desired
1
2
N
9
-isomer 15 (58%) without forming the N
However, condensation with a 2-amino-6-chloropurine anion
yielded the desired N -isomer 16 (58%) with concomitant
formation of the corresponding N -isomer (14%). The
structural assignment of the N -isomer and the N -isomer
was accomplished by the comparison of UV and C NMR
-isomer.15
7
which is ready for the condensation with nucleobases.
Condensation of cyclic sulfite 13 with an adenine anion
in DMF at high temperature resulted in decomposition
instead of giving the desired condensed product (Scheme
9
7
9
7
13
13
3
). Thus, we turned our attention to the more reactive cyclic
1
6
data reported in the literature. Removal of the tert-butyl
group of 15 using 70% trifluoroacetic acid afforded the
adenosine derivative 3a. Similarly, removal of the tert-butyl
group of 16 under the same conditions followed by treatment
of the resulting 6-chloro derivative with 3 N HCl gave the
guanosine derivative 3b.
Scheme 3. Synthesis of the Final Nucleosides 3a and 3b
Antiviral activity of 3a and 3b against HCV was measured,
but these compounds did not show any significant anti-HCV
activity in a cell-based HCV replicon assay, indicating that
cellular kinases might prefer the Southern conformation to
the Northern conformation for the phosphorylations.7
In summary, on the basis of potent anti-HCV activity of
2′-C-methyladenosine (1) and 2′-C-methylguanosine (2), we
have designed the conformationally restricted 2′-C-methyl-
adenosine and -guanosine derivatives. For the efficient
synthesis of the desired nucleosides, stereoselective cyclo-
propanation, regioselective cleavage of the isopropylidene
group, stereoselective Grignard reaction, and cyclic sulfate
chemistry for the condensation were utilized as key steps.
Although we did not discover potent anti-HCV compounds,
all chemistries employed in this study will greatly contribute
to the development of new carbasugar templates by organic
and medicinal chemists.
Acknowledgment. This research was supported by a
grant from the Korea Research Foundation (KRF-2005-005-
J01502) and the National Research Laboratory Program
(2005-01319). The anti-HCV assay by Gilead Sciences is
greatly appreciated.
Supporting Information Available: Complete experi-
mental procedure for all compounds described herein and
1
13
12
H and C NMR copies of 7, 10, 3a, and 3b. This material
sulfate for the condensation. Cyclic sulfite 13 was oxidized
to cyclic sulfate 14 by treating with ruthenium chloride and
is available free of charge via the Internet at http://pubs.acs.org.
4 3
sodium metaperiodate in a mixture of CCl , CH CN, and
OL061959F
(
14) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-
7539.
(15) For the previous nucleophilic substitution of cyclic sulfate with
(12) For a review of cyclic sulfites and cyclic sulfates, see: (a) Lohray,
B. B. Synthesis 1992, 1035-1052. (b) Lohray, B. B.; Bhushan, V. AdV.
Heterocycl. Chem. 1997, 68, 89-180. (c) Byun, H.-S.; He, L.; Bittman, R.
Tetrahedron 2000, 56, 7051-7091.
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2004, 23, 183-193. (c) Hrebabecky, H.; Masojidkova, M.; Holy, A. Collect.
Czech. Chem. Commun. 2005, 70, 519-538.
(
13) (a) Jeong, L. S.; Marquez, V. E. Tetrahedron Lett. 1996, 37, 2353-
2
356. (b) Moon, H. R.; Kim, H. O.; Chun, M. W.; Jeong, L. S.; Marquez,
V. E. J. Org. Chem. 1999, 64, 4733-4741.
(16) Paquette, L. A.; Dong, S. J. Org. Chem. 2005, 70, 5655-5664.
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