Asymmetric synthesis of cyclopropyl-fused 2′-C-methylcarbanucleosides as potential anti-HCV agents

Article abstract of DOI:10.1080/15257770701508612

Novel 2′-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic sulfate chemistry as key steps. Copyright Taylor & Franci

Full text of DOI:10.1080/15257770701508612

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Asymmetric Synthesis of Cyclopropyl-
fused 2′- C -Methylcarbanucleosides as
Potential Anti-HCV Agents
Lak Shin Jeong a , Jeong A. Lee a , Hea Ok Kim a , Dilip K. Tosh a ,
Hyung Ryong Moon b , Seung-Jin Lee a , Kang Man Lee a , Yhun Y.
Sheen a & Moon Woo Chun c
a College of Pharmacy , Ewha Womans University , Seoul, Korea
b College of Pharmacy , Pusan National University , Busan, Korea
c College of Pharmacy , Seoul National University , Seoul, Korea
Published online: 10 Dec 2007.
To cite this article: Lak Shin Jeong , Jeong A. Lee , Hea Ok Kim , Dilip K. Tosh , Hyung Ryong Moon ,
Seung-Jin Lee , Kang Man Lee , Yhun Y. Sheen & Moon Woo Chun (2007) Asymmetric Synthesis
of Cyclopropyl-fused 2′- C -Methylcarbanucleosides as Potential Anti-HCV Agents, Nucleosides,
Nucleotides and Nucleic Acids, 26:8-9, 1021-1024, DOI: 10.1080/15257770701508612
To link to this article: http://dx.doi.org/10.1080/15257770701508612
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1021–1024, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701508612
ASYMMETRIC SYNTHESIS OF CYCLOPROPYL-FUSED
2ꢀ-C-METHYLCARBANUCLEOSIDES AS POTENTIAL
ANTI-HCV AGENTS
Lak Shin Jeong, Jeong A. Lee, Hea Ok Kim, and Dilip K. Tosh
College of
2
Pharmacy, Ewha Womans University, Seoul, Korea
Hyung Ryong Moon
College of Pharmacy, Pusan National University, Busan,
2
Korea
Seung-Jin Lee, Kang Man Lee, and Yhun Y. Sheen
College of Pharmacy,
2
Ewha Womans University, Seoul, Korea
Moon Woo Chun
College of Pharmacy, Seoul National University, Seoul, Korea
2
Novel 2 ꢁ-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were
2
stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic
sulfate chemistry as key steps.
Keywords anti-HCV agents; hepatitis C virus; cyclic sulfate chemistry; regioselective
opening
INTRODUCTION
About 170 million people are infected with hepatitis C virus (HCV)
worldwide and its chronic infection causes liver cirrhosis and hepato-
cellular carcinoma.[1,2] Thus, worldwide efforts to search for effective
chemotherapeutic agents have been made, but ribavirin in combination
with α-interferon is the only approved for the treatment of HCV-infected
patients.[3]
2ꢁ-C-methyladenosine (1a) and 2ꢁ-C-methylguanosine (1b) showed po-
tent anti-HCV activity in a cell-based HCV replicon assay, in which
2ꢁ-methyl group prevents the incorporation of incoming nucleosides
This research was supported by a grant from the Korea Research Foundation (KRF-2005-005-
J01502). Anti-HCV assay by Gilead Sciences is greatly appreciated.
Address correspondence to Lak Shin Jeong, College of Pharmacy, Ewha Womans University, Seoul
120 750, Korea. E-mail: lakjeong@ewha.ac.kr
1021

1022
L. S. Jeong et al.
FIGURE 1 Design of the target nucleosides 2 based on the conformational similarity between1 and 2.
triphosphates.[4] These nucleosides were reported to adopt a Northern C3ꢁ-
endo conformation (pseudorotation angle P = 15.6◦).[4] Carbocyclic nucle-
osides in which the cyclopropane ring is fused between C4ꢁ and C6ꢁ also
fix the conformation of the carbasugars to a Northern C3ꢁ-endo conforma-
tion (P = 0 18◦).[5] Thus, this conformational information prompted us
to design the cyclopropyl-fused-carbanucleosides 2a-d, as demonstrated in
Figure 1. Herein, we report the stereoselective synthesis of conformation-
ally restricted carbocyclic nucleosides 2a-d and their anti-HCV activity.
SCHEME 1 Reagents and conditions: a) NaBH4, CeCI3 7H2O, MeOH, 0◦C, 30 minutes; b) Et2Zn,
CH2l2, CH2Cl2, rt, 5 hours; c) Me3AI, CH2Cl2, rt, 4 days; d) TBDPSCl, imidazole, CH2Cl2, rt, 20 minutes;
e) (COCl)2, DMSO, TEA, CH2Cl2, rt, 1 days; f) MeMgl, Et2O, rt, 2.5 hours; g) TBAF, THF, rt, 1 days; h)
TBDMSCI, imidazole, CH2Cl2, 0◦C, 2 hours; i) SOCl2, TEA, CH2Cl2, 0◦C, 10 minutes; j) RuCl3-3H2O,
NalO4, CCl4:CH3CN:H2O = 1:1:1.5, rt, 10 minutes.

Cyclopropyl-Fused 2ꢁ-C-Methylcarbanucleosides
1023
SCHEME 2 Reagents and conditions: a) i) adenine or 2-amino-6-chloropurine, NaH, DMF, ii) 20% aq
H2SO4; b) 70% CF3COOH, rt, 50 minutes; c) NaNO2, AcOH, rt, 3 hours; d) 3N aq HCl, rt, 2 days;
e) cyclopropylamine, ethanol, rt, 1 day.
RESULTS AND DISCUSSION
Our synthetic strategy was to utilize the cyclic sulfate 12 as a glycosyl
donor as illustrated in Scheme 1.
The cyclopentenone 4, which was efficiently synthesized from -ribose
D
according to the procedure[6] developed by our laboratory, was stereoselec-
tivity reduced to α-allylic alcohol 5. Modified Simmons-Smith cyclopropana-
tion of 5 using diethyl zinc and methylene iodide gave bicyclo[3.1.0]hexane
derivative 6 as a single stereoisomer. Regioselective cleavage of the isopropy-
lidene group was achieved using trimethylaluminum[7] in CH2Cl2 to give
the tert-butoxy diol 7. Selective protection of the least hindered alcohol in
diol 7 with a TBDPS group followed by Swern oxidation of the remaining

1024
L. S. Jeong et al.
alcohol afforded the ketone 9. Stereoselective Grignard reaction on 9 with
methylmagnesium iodide was achieved by the attack of methyl nucleophile
from less hindered convex side. For the synthesis of cyclic sulfate 12, both
silyl protecting groups were removed to give the diol, whose primary alcohol
was selectively protected as TBS ether 11. Diol 11 was treated with SOCl2 in
presence of triethyl amine and oxidation of the resulting cyclic sulfite, with
sodium periodate in presence of RuCl3-3H2O to give the glycosyl donor 12,
which is ready for the condensation with a nucleobase.
Condensation of cyclic sulfate 12 with adenine and 2-amino-6-
chloropurine anions followed by acid hydrolysis gave the tert-butoxy deriva-
tives 13 and 14, respectively (Scheme 2). Removal of tert-butyl group of 13
under acidic conditions afforded the adenine derivative 2a, which was con-
verted to the hypoxanthine derivative 2b by diazotization method. In a simi-
lar manner, deprotection of tert-butyl group of 14 followed by conversion of
6-chloro group to 6-keto group and 6-cyclopropylamino group gave guanine
derivative 2c and 2-amino-6-cyclopropylamino purine derivative 2d, respec-
tively. Antiviral assay of 2a-d against HCV was performed, but these com-
pounds did not show any significant anti-HCV activity in a cell-based HCV
replicon assay.
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