Novel synthesis of 4′C-aryl-branched acyclic nucleoside using [3,3]-sigmatropic rearrangement

Article abstract of DOI:10.1081/NCN-120023272

A very efficient synthetic route for preparing a novel 4′-C-aryl branched-1′,2′-seco-2′,3′-dideoxy-2′, 3′-didehydro-nucleoside is described. Mesylate 7 was successfully synthesized via a Horner-Wadsworth-Emmons reaction and a [3,3]-sigmatropic rearrangeme

Full text of DOI:10.1081/NCN-120023272

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Novel Synthesis of 4′C-Aryl-Branched Acyclic
Nucleoside Using [3,3]-Sigmatropic Rearrangement
Gun Ha Baik a , Bong Young Chung a , Chang-Hyun Oh b , Jung-Hyuck Cho b , Ok Hyun Ko c &
Joon Hee Hong c d
a Department of Chemistry, Korea University, Anam-dong, Sungbuk-ku, Seoul, South Korea
b Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul,
South Korea
c College of Pharmacy, Chosun University, Kwangju, South Korea
d College of Pharmacy, Chosun University, Kwangju, 501-759, South Korea
Published online: 07 Feb 2007.
To cite this article: Gun Ha Baik , Bong Young Chung , Chang-Hyun Oh , Jung-Hyuck Cho , Ok Hyun Ko & Joon Hee Hong (2003)
Novel Synthesis of 4′C-Aryl-Branched Acyclic Nucleoside Using [3,3]-Sigmatropic Rearrangement, Nucleosides, Nucleotides and
Nucleic Acids, 22:9, 1781-1788, DOI: 10.1081/NCN-120023272
To link to this article: http://dx.doi.org/10.1081/NCN-120023272
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, No. 9, pp. 1781–1788, 2003
Novel Synthesis of 40C-Aryl-Branched Acyclic Nucleoside
Using [3,3]-Sigmatropic Rearrangement
Gun Ha Baik,1 Bong Young Chung,1 Chang-Hyun Oh,2 Jung-Hyuck Cho,2
Ok Hyun Ko,3 and Joon Hee Hong3,
*
1Department of Chemistry, Korea University, Anam-dong,
Sungbuk-ku, Seoul, South Korea
2Medicinal Chemistry Research Center, Korea Institute of Science
and Technology, Seoul, South Korea
3College of Pharmacy, Chosun University,
Kwangju, South Korea
ABSTRACT
A very efficient synthetic route for preparing a novel 40-C-aryl branched-
10,20-seco-20,30-dideoxy-20,30-didehydro-nucleoside is described. Mesylate 7 was
successfully synthesized via a Horner-Wadsworth-Emmons reaction and a
[3,3]-sigmatropic rearrangement, with which an adenine base was coupled by
nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) to give the
target nucleoside 9.
Key Words: Acyclic nucleoside; [3,3]-Sigmatropic rearrangement; Antiviral
agent.
*Correspondence: Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju 501-
759, South Korea; Fax: 82-62-222-5414; E-mail: hongjh@mail.chosun.ac.kr.
1781
DOI: 10.1081/NCN-120023272
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

1782
Baik et al.
INTRODUCTION
The discovery of novel nucleosides for use as antiviral and anticancer agents has
been the ambition of nucleoside chemists for decades. Since the emergence of the
HIV pandemic, extensive effort have been concentrated on various modifica-
tions of the sugar moiety of nucleosides, which have resulted in FDA approved
anti-HIV agents such as AZT,[1] ddC,[2] ddI,[3] d4T,[4] 3TC,[5] and Abacavir.[6] In
addition, several nucleosides used as anti-HBV agents including L-F-ddC,[7] and
L-FMAU[8] have been synthesized. The recent approval of Bis(POC) PMPA[9] by
the FDA as an anti-HIV agent has strongly warranted a further search of novel
nucleosides in this class.
More recently, several branched-nucleosides[10] have been synthesized and eval-
uated as potent antitumor or antiviral agents. Among them, 40a-C-ethenyl[11] and
40a-C-ethynyl[12] nucleosides, which possess an additional double or triple bond at
the 40-position were reported to have potent antiviral and antitumor activities.
Encouraged by these interesting structures and antiviral activities, this study aimed
to synthesize novel classes of nucleosides, which are hybrids of branched carbocyclic
and 10,20-seco-acyclic nucleoside analogues showing marginal anti-HIV activity
(Fig. 1).
RESULTS AND DISCUSSION
As depicted in Sch. 1, the synthetic route is straightforward. It was envisaged
that a [3,3]-sigmatropic rearrangement[13] of 4 would produce the desired quaternary
carbon 5 with the suitable functional groups. Subjecting 7 to nucleophilic substitu-
tion conditions and desilyation produced the desired nucleoside 9.
The silyl protection of the alcohol of a commercially available starting material,
2-hydroxy acetophenone 1, followed by a Horner-Wadsworth-Emmons (HWE)
reaction,[14] provided the a,b-unsaturated ethyl ester 3 in a cis=trans isomeric
mixture. It is not necessary to separate the isomers, as they will be merged into
one isomer in subsequent reaction. Ester 3 was reduced to the allylic alcohol 4 by
using diisobutylaluminum hydride (DIBALH) in an 83% yield. The compound 4
was subjected to a normal Johnson’s orthoester A Claisen rearrangement using
Figure 1.

Novel Synthesis of 40C-Aryl-Branched Acyclic Nucleoside
1783
Scheme 1. Reagents: i) TBDMSCI, Imidazole, CH2Cl2, rt, 5 h, 90%; ii) Triethylphosphono-
acetate, NaH, THF, 0ꢁC, 1 h, 83%; iii) DIBALH, CH2Cl2, ꢀ20ꢁC, 3 h, 83%; iv) Triethyl
orthoacetate, propionic acid, ovemight, 130–135ꢁC, 81% v) DIBALH, CH2Cl2, ꢀ20ꢁC, 2 h,
89%; vi) MsCl, CH2Cl2, TEA, 0ꢁC, 1 h, 83%; vii) adenine, K2CO3, 18-C-6, DMF, 90ꢁC, over-
nignt, 50%; viii) TBAF, THF, rt, 4 h, 86%.
triethyl orthoacetate gave the g,d–unsaturated ester 5 in an 81% yield. The slow addi-
tion of DIBALH to a solution of ester 5 in CH2Cl2 at ꢀ20ꢁC furnished alcohol 6 in
an 89% yield. The hydroxyl group of 6 was mesylated with methanesulfonyl chloride
(MsCl) in an anhydrous CH2Cl2 solvent to give the key intermediate 7 in an 83%
yield. The mesylate 7 was coupled with the nucleobase (adenine) under well-known
nucleophilic substitution conditions (K2CO3, 18-C-6, DMF)[15] to give the adenine
derivative 8 in a 50% yield. The deblocking of 8 was accomplished using tetrabutyl
ammonium fluoride (TBAF) to furnish the final nucleoside 9 in an 86% yield.
Although other analogs (Fig. 1) were previously reported by another group,[16] com-
pound 9 is novel nucleoside based on an extensive literature search.
An antiviral assay of the synthesized nucleoside 9 against the human immuno-
deficiency virus 1 (HIV-1), the herpes simplex virus 1,2 (HSV-1, 2) and HCMV
was performed. However, no significant antiviral activity or cytotoxicity up to
100 mM was found.
CONCLUSION
A novel acyclic nucleoside was successfully synthesized from the starting mate-
rial, 2-hydroxy acetophenone. The strategy for elaborating the quaternary carbon

1784
Baik et al.
is highly efficient and convenient. Furthermore, it has the flexibility for further
applications to the synthesis of other novel acyclic and carbocyclic nucleosides.
EXPERIMENTAL SECTION
The melting points were determined on a Mel-tem II laboratory device and were
uncorrected. The NMR spectra were recorded on a Bruker 300 Fourier transform
spectrometer. The elemental analyses were performed at the Korea Basic Science
Institute. The UV spectra were obtained on a Beckman DU-7 spectrophotometer.
The TLC was performed on Uniplates (silica gel) purchased from Analtech Co.
All reactions were carried out under N2 unless otherwise specified. Dry dichloro-
methane, benzene and pyridine were obtained by a distillation from CaH2. Dry
THF was obtained by distillation from Na and benzophenone immediately prior
to use.
2-(t-Butyldimethylsilyloxy)-acetophenone (2). To a solution of 2-hydroxy aceto-
phenone 1 (10 g, 73.4 mmol) and imidazole (7.49 g, 110.1 mmol) in CH2Cl2 (150 mL),
TBDMSCl (12.1 g, 80.74 mmol) was added slowly at 0ꢁC, and stirred for 5 h at room
temperature. The reaction solvent was evaporated under reduced pressure, and the
residue was extracted with EtOAc (100 ꢂ 2). The combined organic layer was dried
over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The resi-
due was then purified by silica gel column chromatography (EtOAc=hexane, 1:7) to
give compound 2 (16.5 g, 90%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) d 7.80
(d, J ¼ 7.2 Hz, 2H), 7.46–7.30 (m, 3H), 4.79 (s, 2H), 0.80 (s, 9H), ꢀ0.01 (s, 6H); 13C
NMR (CDCl3) d 197.42, 134.85, 133.22, 128.56, 127.83, 67.40, 25.78, 18.44, ꢀ5.36;
Anal calc for C14H22O2Si: C, 67.15; H, 8.86. Found: C, 66.97; H, 8.65.
(E) and (Z)-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-enoic acid ethyl ester
(3). To a suspension of sodium hydride (60% in mineral oil, 0.74 g, 18.5 mmol) in
distilled THF triethyl phosphonoacetate (2.81 mL, 18.5 mmol) was added drop wise
at 0ꢁC and the mixture was stirred at room temperature for 1 h. Ketone 2 (4.63 g,
18.5 mmol) was added to this mixture and the mixture was stirred for 1 h. The solu-
tion was neutralized with AcOH, and extracted with EtOAc. The organic layer was
washed with brine and dried over anhydrous MgSO4, filtered and evaporated. The
residue was purified by silica gel column chromatography (EtOAc=hexane, 1:12)
1
to give 3 (4.92 g, 83%) as a colorless oil: H NMR (CDCl3, 300 MHz) d 7.39–7.04
(m, 5H), 6.09, 5.93 (dt, J ¼ 1.3, 1.8 Hz, 1H), 5.08, 4.23 (dd, J ¼ 0.9, 2.1 Hz, 2H),
4.22, 3.90 (dq, J ¼ 6.9, 6.9 Hz, 2H), 1.20, 0.95 (dt, J ¼ 6.9, 6.9 Hz, 3H), 0.84, 0.65
(s, s, 9H), 0.02, ꢀ0.10 (s, s, 6H); Anal calc for C18H28O3Si: C, 67.46; H, 8.81. Found:
C, 67.66; H, 8.95.
(E) and (Z)-4-(t-Butyldimethylsilyloxy)-3-phenyl-but-2-en-1-ol (4). To a solu-
tion of 3 (5 g, 15.6 mmol) in CH2Cl2 (100 mL), DIBALH (34.3 mL, 1.0 M solution
in hexane) was added slowly at ꢀ20ꢁC, and stirred for 3 h at the same temperature.
To the mixture, methanol (30 mL) was added. The mixture was stirred at room

Novel Synthesis of 40C-Aryl-Branched Acyclic Nucleoside
1785
temperature for 3 h, and the resulting solid was filtered through a Celite pad. The
filtrate was concentrated under vacuum and the residue was purified by silica gel
column chromatography (EtOAc=hexane, 1:4) to give the allylic alcohol 4 (3.6 g,
1
83%) as a colorless oil: H NMR (CDCl3, 300 MHz) d 7.32–7.07 (m, 5H), 5.99,
5.91 (dt, J ¼ 6.6, 6.6 Hz, 1H), 4.31 (d, J ¼ 6.6 Hz, 1H), 4.27 (s, 1H), 0.85, 0.81 (s, s,
9H), 0.02 (m, 6H); Anal calc for C16H26O2Si: C, 69.01; H, 9.41. Found: C, 69.18;
H, 9.26.
( )-3-(t-Butyldimethylsilyloxymethyl)-3-phenyl-pent-4-enoic acid ethyl ester (5).
A
solution of the allylic alcohol 4 (12 g, 43.09 mmol) in triethyl orthoacetate
(200 mL) and 0.5 mL of propionic acid was heated at 130–135ꢁC overnight. An
excess of triethyl orthoacetate was distilled off and the residue was purified by silica
gel column chromatography (EtOAc=hexane, 1:15) to give 5 (12.16 g, 81%) as a
colorless oil: 1H NMR (CDCl3, 300 MHz) d 7.36–7.25 (m, 5H), 6.26 (dd,
J ¼ 18.0, 11.1 Hz, 1H), 5.31 (dd, J ¼ 11.4, 1.2 Hz, 1H), 5.16 (dd, J ¼ 17.7, 0.6 Hz,
1H), 4.10–3.99 (m, 4H), 3.00 (s, 2H), 1.18 (t, J ¼ 6.9 Hz, 3H), 0.99 (s, 9H), 0.02
(d, J ¼ 8.1, 6H); 13C NMR (CDCl3) d 171.51, 143.17, 142.33, 127.82, 127.34,
126.30, 114.34, 67.73, 59.94, 48.70, 39.74, 25.76, 18.19, 14.07, ꢀ5.71; Anal calc
for C20H32O3Si: C, 68.92; H, 9.25. Found: C, 68.69; H, 9.05.
( )-3-(t-Butyldimethylsilyloxymethyl)-3-phenyl-pent-4-en-1-ol (6). To a solution
of 5 (3.2 g, 9.18 mmol) in CH2Cl2 (50 mL), DIBALH (20.1 mL, 1.0 M solution in
hexane) was added slowly at ꢀ78ꢁC, and stirred for 2 h at the same temperature.
To the mixture, methanol (10 mL) was added. The mixture was stirred at room tem-
perature for 2 h, and the resulting solid was filtered through a Celite pad. The filtrate
was concentrated under vacuum and the residue was purified by silica gel column
1
chromatography (EtOAc=hexane, 1:4) to give 6 (2.5 g, 89%) as a colorless oil: H
NMR (CDCl3, 300 MHz) d 7.33–7.28 (m, 5H), 5.82 (dd, J ¼ 17.4, 10.8 Hz, 1H),
5.33 (d, J ¼ 10.7 Hz, 1H), 5.13 (d, J ¼ 10.5 Hz, 1H), 4.24 (t, J ¼ 6.9 Hz, 2H), 3.80
(s, 2H), 1.72 (m, 2H), 0.90 (s, 9H), ꢀ0.02 (s, 6H); 13C NMR (CDCl3) d 142.48,
141.65, 128.20, 127.32, 126.60, 115.09, 68.80, 67.72, 48.59, 34.18, 25.74, 18.13,
ꢀ5.71; Anal calc for C18H30O2Si: C, 70.53; H, 9.87. Found: C, 70.26; H, 9.66.
( )-1-O-Methanesulfonic acid-3-(t-butyldimethylsilyloxymethyl)-3-phenyl-pent-4-
enyl ester (7). To a solution of alcohol 6 (2.5 g, 8.15 mmol) in anhydrous CH2Cl2
(30 mL), anhydrous triethyl amine (2.27 mL, 16.3 mmol) and MsCl (1.39 g,
12.2 mmol) was added at 0ꢁC. The mixture was stirred at the same temperature
for 1 h, and quenched by adding a cold saturated NaHCO3 solution (2 mL). The mix-
ture was extracted with CH2Cl2 (100 mL) and water (50 mL). The organic layer was
dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated
under vacuum, and the residue was purified by silica gel column chromatography
1
(EtOAc=hexane, 1:3) to give 7 (2.6 g, 83%) as a colorless oil: H NMR (CDCl3,
300 MHz) d 7.35–7.29 (m, 5H), 6.02 (dd, J ¼ 17.4, 10.8 Hz, 1H), 5.34 (d, J ¼ 9.9 Hz,
Hz, 1H), 5.17 (d, J ¼ 17.7 Hz, 1H), 4.25 (t, J ¼ 6.9 Hz, 2H), 3.83 (s, 2H), 2.93 (s, 3H,
mesyl), 2.44 (m, 2H), 0.95 (s, 9H), ꢀ0.02 (s, 6H); Anal calc for C19H32O4SSi: C,
59.33; H, 8.39. Found: C, 59.68; H, 8.54.

1786
Baik et al.
( )-9-[3-(t-Butyldimethylsilyloxymethyl)-3-phenyl-4-pent-1-enyl] adenine (8).
A
solution of mesylate 7 (560 mg, 1.45 mmol), K2CO3 (401 mg, 2.9 mmol), 18-crown-
6 (329 mg, 1.26 mmol), adenine (195 mg, 1.45 mmol) in dry DMF (10 mL) was stirred
overnight at 90ꢁC. The mixture was cooled to room temperature and concentrated
under vacuum. The residue was diluted with brine (10 mL) and extracted with
CH2Cl2 (10 mL ꢂ 4). The combined organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (MeOH=CH2Cl2, 1:15) to give 8 (307 mg, 50%) as a
white solid: mp 167–170ꢁC; 1H NMR (CDCl3, 300 MHz) d 8.31 (s, 1H), 7.68 (s, 1H),
7.42–7.26 (m, 5H), 6.67 (br s, 2H), 6.13 (dd, J ¼ 17.7, 11.1 Hz, 1H) 5.39 (dd, J ¼ 10.8,
0.6 Hz, 1H), 5.27 (d, J ¼ 18.0 Hz, 1H), 4.19 (t, J ¼ 8.1 Hz, 2H), 3.90 (dd, J ¼ 14.1,
9.9 Hz, 2H), 2.57–2.48 (m, 2H), 0.87 (s, 9H), ꢀ0.03 (s, 6H); 13C NMR (CDCl3) d
155.44, 152.20, 149.75, 142.51, 141.64, 140.09, 128.25, 127.42, 126.67, 115.42, 68.70,
49.02, 40.73, 25.76, 18.15, ꢀ5.70; Anal calc for C23H33N5OSi: C, 65.21; H, 7.85; N,
16.53. Found: C, 65.44; H, 7.69; N, 16.32.
( )-9-[3-(t-Hydroxymethyl)-3-phenyl-4-pent-1-enyl] adenine (9). To a solution
of 8 (250 mg, 0.59 mmol) in tetrahydrofuran (10 mL), tetrabutylammonium fluo-
ride (TBAF) (0.88 mL, 1.0 M solution in THF) was added at 0ꢁC. The mixture
was stirred at room temperature for 4 h, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (MeOH=CH2Cl2, 1:7)
to give 9 (160 mg, 86%) as a white solid: mp 182–185ꢁC; UV (H2O) lmax 261.0 nm;
1H NMR (DMSO-d6, 300 MHz) d 8.12 (s, 1H, H-8), 8.08 (s, 1H), 7.41–7.15 (m, 5H),
6.05 (dd, J ¼ 15.9, 11.1 Hz, 1H), 5.27 (d, J ¼ 11.7, 1H), 5.17 (s, 1H), 4.87 (t. J ¼ 6.4 Hz,
Hz, 1H, D2O exchangeable), 4.01 (br s, 2H), 3.76 (m, 2H), 2.36 (br d, J ¼ 7.8 Hz, 2H);
13C NMR (DMSO-d6) d 155.91, 152.30, 149.39, 143.25, 142.46, 140.60, 128.07, 127.35,
126.10, 114.62, 66.68, 48.58, 34.67, 23.05, 13.47; Anal calc for C17H19N5O: C, 66.00; H,
6.19; N, 22.64. Found: C, 66.38; H, 6.31; N, 22.48.
ACKNOWLEDGMENT
We thank Dr. C.-K Lee (Korea Research Institute of Chemical Technology) for
antiviral assays.
REFERENCES
1. Furman, P.A.; Fyfe, J.A.; St. Clair, M.H.; Weinhold, K.; Rideout, J.L.;
Freeman, G.A.; Lehrman, S.N.; Bolognesi, D.P.; Broder, S.; Mitsuya, H.;
Barry, D.W. Phosphorylation of 30-azido-30-deoxythymidine and selective
interaction of the 50-triphosphate with human immunodeficiency virus reverse
transcriptase. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 8333–8337.
2. Yarchoan, R.; Perno, C.F.; Thomas, R.V.; Klecker, R.W.; Allain, J.-P.; Wills,
R.J.; McAtee, N.; Leuther, M.; Collins, J.M.; Broder, S.; Fischl, M.A.;

Novel Synthesis of 40C-Aryl-Branched Acyclic Nucleoside
1787
Dubinsky, R.; McNeely, M.C.; Mitsuya, H.; Lawley, T.J.; Safai, B.;
Myers, C.E. Phase 1 studies of 20,30-dideoxycytidine in selective human immu-
nodeficiency virus infection as a single agent and alternating with zidovudine
(AZT). Lancet 1988, 1, 76–81.
3. Yarchoan, R.; Mitsuya, H.; Thomas, R.V.; Pluda, J.M.; Hartman, N.R.;
Perno, C.F.; Marczyk, K.S.; Allain, J.-P.; Johns, D.G.; Broder, S. In vivo activ-
ity against HIV and favorable toxicity profile of 20,30-dideoxyinosine. Science
1989, 245, 412–415.
4. Lin, T.-S.; Schinazi, R.F.; Prusoff, W.H. Potent and selective in vitro activity
of 30,deoxythymidin-20-ene(30-deoxy-20,30-didehydrothymidine) against human
immunodeficiency virus. Biochem. Pharmacol. 1987, 36, 2713–2718.
5. Schinazi, R.F.; Chu, C.K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.;
Jeong, L.S.; Beach, J.W.; Choi, W.B.; Yeola, S.; Liotta, D.C. Activities of
the four optical isomers of 20,30-dideoxy-30-thiacytidine (BCH-189) against
human immunodeficiency virus type 1 in human lymphocytes. Antimicrob.
Agents Chemother. 1992, 36, 672–676.
6. Daluge, S.M.; Good, S.S.; Faletto, M.B.; Miller, W.H.; StClair, M.H.; Boone,
L.R.; Tisdale, M.; Parry, N.R.; Reardon, J.E.; Dornsife, R.E.; Averett, D.R.;
Krenitsky, T.A. 1592U89, a novel carbocyclic nucleoside analog with potent,
selective anti-human immunodeficiency virus activity. Antimicrob. Agents
Chemother. 1997, 41, 1082–1093.
7. Lin, T.S.; Luo, M.Z.; Liu, M.C.; Pai, S.B.; Dutschman, G.E.; Cheng, Y.-C.
Synthesis and biological evaluation of 20,30-dideoxy-L-pyrimidine nucleosides
as potential antiviral agents against human immunodeficiency virus (HIV)
and hepatitis B virus (HBV). J. Med. Chem. 1994, 37, 798–803.
8. Chu, C.K.; Ma, T.W.; Shanmuganathan, K.; Wang, C.G.; Xiang, Y.J.; Pai,
S.B.; Yao, G.Q.; Sommadossi, J.P.; Cheng, Y.-C. Use of 20-fluoro-5-methyl-
beta-L-arabinofuranosyl uracil as a novel antiviral agent for hepatitis B virus
and Epstein-Barr virus. Antimicrob. Agents Chemother. 1995, 39, 979–981.
9. Arimilli, M.N.; Kim, C.U.; Dougherty, J.; Mulato, A.; Oliyai, R.; Shaw, J.P.;
Cundy, K.C.; Bischofberger, N. Use of 20-fluoro-5-methyl-b-L-arabinofurano-
syluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus.
Antiviral Chem. Chemother. 1997, 8, 557–564.
10. (a) Hong, J.H.; Shim, M.J.; Ro, B.O.; Ko, O.H. An efficient synthesis of novel
carbocyclic nucleosides with use of ring-closing metathesis from D-lactose.
J. Org. Chem. 2002, 67, 6387–6840; (b) Jung, M. E.; Toyota, A. Preparation
of 40-substituted thymidins by substitution of the thymidine 50-esters. J. Org.
Chem. 2001, 66, 2624–2635; (c) Crich, D.; Hao, X. Asymmetric synthesis of
C-40a-carboxylated 20-deoxynucleosides. Preparation of oxetanocine deriva-
tives and influence of solvent on the stereochemistry of base introduction.
J. Org. Chem. 1999, 64, 4016–4024.
11. Sugimoto, I.; Shuto, S.; Mori, S.; Shigeta, S.; Matuda, A. Synthesis of 40a-
branched thymidines as a new type of antiviral agent. Bioorg. Med. Chem.
Lett. 1999, 9, 385–388.
12. Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki, T.; Mori, S.; Shigeta, S.;
Matsuda, A. Synthesis and biological activities of 40a-C-branched-chain sugar
pyrimidine nucleosides. J. Med. Chem. 1999, 42, 2901–2908.

1788
Baik et al.
13. (a) Ko, O.H.; Hong, J.H. Efficient synthesis of novel carbocyclic nucleosides
via sequential Claisen rearrangement and ring-closing metathesis. Tetrahedron
Lett. 2002, 43, 6399–6402; (b) Hong, J.H.; Gao, M.Y.; Chu, C.K. Synthesis of
novel 30-C-methyl-40-thio apionucleosides via highly enantioselective elabora-
tion of quaternary carbon by [3,3]-sigmatropic rearrangement. Tetrahedron
Lett. 1999, 40, 231–234.
14. Jeong, L.S.; Lee, Y.A.; Moon, H.R.; Chun, M.W. Synthesis and antiviral activ-
ity of apio dideoxy nucleosides with azido or amino substituent. Nucleosides &
Nucleotides 1998, 17, 1473–1487.
15. (a) Lee, J.Y.; Oh, C.H.; Ko, O.H.; Hong, J.H. Synthesis and anti-HCMV activ-
ity of novel acyclic nucleosides. Nucleosides, Nucleotides & Nucleic Acids
2002, 21, 709–721; (b) Hossain, N.; Rozenski, J.; DeClercq, E.; Herdewjn, P.
Synthesis and antiviral activity of acyclic analogues of 1,5-anhydrohexitol
nucleosides using Mitsunobu reaction. Tetrahedron 1996, 52, 13,655–13,670.
16. Azymah, M.; Chavis, C.; Lucas, M.; Imbach, J.-L. Synthesis of 10,20-seco-
analogue of dideoxy didehydro nucleosides as potential antiviral agents.
J. Chem. Soc. Perkin Trans. 1 1991, 1561–1563.
Received January 7, 2003
Accepted April 8, 2003