Asymmetric synthesis of novel apio carbocyclic nucleoside analogues as potential antiviral and antitumor agent

Article abstract of DOI:10.1080/15257770701493237

Novel apio carbocyclic nucleosides 18-21 were asymmetrically synthesized as potential antiviral and antitumor agent, starting from D-ribose employing aldol reaction, RCM reaction and Mitsunobu reaction as key reactions. Copyright Taylor & Francis Group, L

Full text of DOI:10.1080/15257770701493237

Nucleosides, Nucleotides, and Nucleic Acids, 26:721–724, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701493237
ASYMMETRIC SYNTHESIS OF NOVEL APIO CARBOCYCLIC
NUCLEOSIDE ANALOGUES AS POTENTIAL ANTIVIRAL AND
ANTITUMOR AGENT
Lak Shin Jeong and Jeong A. Lee
College of Pharmacy, Ewha Womans
2
University, Seoul, Korea
Hyung Ryong Moon
College of Pharmacy and Research Institute for Drug
2
Development, Pusan National University, Busan, Korea
Hea Ok Kim, Kang Man Lee, and Hyun Joo Lee
College of Pharmacy, Ewha
2
Womans University, Seoul, Korea
Moon Woo Chun
College of Pharmacy, Seoul National University, Seoul, Korea
2
Novel apio carbocyclic nucleosides 18–21 were asymmetrically synthesized as potential antiviral
2
and antitumor agent, starting from D-ribose employing aldol reaction, RCM reaction and Mit-
sunobu reaction as key reactions.
Keywords Apio carbocyclic nucleoside; stereoselective hydroxymethylation; ring-
closing metathesis; Mitsunobu condensation; asymmetric synthesis
INTRODUCTION
Neplanocin A (1)[1] and aristeromycin are the representatives of the
carbocyclic nucleosides, which possess inherent stability of the glycosidic
bond, and exhibit potent biological activity such as antiviral and antitu-
mor activities. Their biological activity is known to result from inhibition
of S-adenosylhomocysteine (AdoHcy) hydrolase.[2] However, compound 1
and aristeromycin could not be further developed as clinically useful drugs
due to their high cytotoxicity. Fluoro-neplanocin A (2),[3] developed by
our laboratory, also has shown significant antiviral activity with inhibition
of AdoHcy hydrolase, but exhibited high cytotoxicity. These results seem
to imply that ribo-cyclopentenyl structure is essential to potent biological
This research was supported by a grant from the Korea Research Foundation (KRF-2005-005-
J01502).
Address correspondence to Lak Shin Jeong, Department of Pharmacy, Ewha Womans University,
Seoul 120-750, Korea. E-mail: lakjeong@ewha.ac.kr
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L. S. Jeong et al.
FIGURE 1 Rationale for the design of apio carbocylic purine nucleosides 5–8.
activity. On the other hand, a number of apio nucleosides,[4,5] in which
4ꢁ-hydroxymethyl group are shifted to C3ꢁ position have been designed
and synthesized in order to search for novel antiviral agent. Apio-ddA (3),
mimicking the parent compound ddA, exhibited comparable anti-HIV ac-
tivity to ddA. On the basis of these findings, apio-neplanocin A (4) was syn-
thesized by our laboratory, but unlike compounds 1 and 2, it did not show
inhibitory activity against AdoHcy hydrolase (Figure 1).[6]
Here, we report the synthesis of purine base modified analogues 5–8 of
compound 4 to study structure-activity relationship (SAR) of apiocarbocyclic
nucleosides.
RESULT AND DISCUSSION
It was envisioned that cyclopentenyl alcohol 13 could be an appropriate
glycosyl donor for the condensation with a variety of nucleobases. Synthesis
of glycosyl donor, cyclopentenyl alcohol 13 is described in Scheme 1.
Triol 9 was easily synthesized from D-ribose using subsequent two reac-
tion steps. Treatment of D-ribose with anhydrous acetone under acidic con-
ditions afforded the corresponding 2,3-acetonide in 93% yield, which was
subjected to Grigard reaction with excess vinylmagnesium bromide. Oxida-
tive C-C cleavage of vicinal diol 9 through two-phase reaction gave lactol 10.
Stereoselective introduction of hydroxymethyl group at C3ꢁ position was ac-
complished by treatment with formaldehyde and K2CO3 in methanol.[6] Af-
ter hydroxymethylation, Wittig reaction with methyltriphenylphosphonium
SCHEME 1 Reagents and conditions: a) i. acetone, c-H2SO4; ii. CH2 = CHMgBr, THF; b) NaIo4,
CH2Cl2, H2O; c) i. CH2O, K2CO3, MeOH; ii. CH3PPh3Br, KOt -Bu, THF; d) second generation Grubbs
catalyst, CH2Cl2; e) TrCl, DMAP, pyridine.

Apio Carbocyclic Nucleoside Analogues
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SCHEME 2 Reagents and conditions: a) 2-amino-6-chloropurine or 2,6-dichloropurine, DEAD, Ph3P,
THF, 78% for 14 and 15; b) 40% CH3NH2, EtOH, 98%; c) 3-iodobenzylamine hydrochloride, EtOH,
Et3N, 98%; d) 3 M HCl, THF, 37% from 13 for 18, 19% to 19, 21%, 21% to 20; e) NH3, MeOH, 36%.
bromide in the presence of potassium carbonate generated diene 11 in 77%
from 10. Ring-closing metathesis (RCM)[7,8] of diene 11 with second gen-
eration Grubbs catalyst formed cyclopentene ring, giving 12 in a quantita-
tive yield. Regioselective protection at the primary hydroxyl group of 12 was
achieved by bulky trityl chloride in 78% yield, affording cyclopentenyl al-
cohol 13, which played a role as glycosyl donor for the condensation with
various nucleobases.
Synthesis of purine nucleoside derivatives 18–21 from cyclopentenyl al-
cohol 13 is depicted in Scheme 2.
Condensation of 13 with 2-amino-6-chloropurine and 2,6-dichloro-
purine under general Mitsunobu conditions afforded 14 and 15 (78%),
respectively. 2,6-Dichloropurine nucleoside 15 was converted to 6-
methylamino- and 6-iodobenzylaminopurine nucleosides 16 (98%) and 17
(98%), using 40% methylamine and 3-iodobenzylamine hydrochloride and
Et3N, respectively. Treatment of 14, 16, and 17 with 3 M HCl to remove trityl
and isopropylidene group generated 18, 19, and 20. However, all the depro-
tecting steps gave less than 40%, maybe due to existence of tert-allylic ether.
Finally, diaminopurine nucleoside 21 was obtained from 19 by treating with
methanolic ammonia.
Biological assay of all the final compounds 18–21 are in progress to study
SAR of apio carbocyclic nucleosides. In conclusion, synthesis of apio car-
bocyclic 2,6-disubstituted purine nucleosides 18–21 was efficiently accom-
plished as potential antiviral and antitumor agent starting from D-ribose
using RCM reaction, stereoselective hydroxymethylation and Mitsunobu re-
action. All the final compounds 18–21 will be used for the SAR study of apio
carbocyclic nucleosides.
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