Stereoselective synthesis of conformationally rigid apio carbanucleosides as potential antiviral agents

Article abstract of DOI:10.1081/NCN-200060292

Apio north-methanocarbocyclic nucleosides 1-3 with bicyclo[3.1.0]hexane template were first synthesized. Introduction of hydroxymethyl substituent was efficiently and stereoselectively accomplished by aldol and retro-aldol reaction and fixed conformation

Full text of DOI:10.1081/NCN-200060292

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STEREOSELECTIVE SYNTHESIS OF CONFORMATIONALLY
RIGID APIO CARBANUCLEOSIDES AS POTENTIAL
ANTIVIRAL AGENTS
Hyung Ryong Moon a , Kyung Ran Kim a , Bum Tae Kim b , Ki Jun Hwang b , Moon Woo Chun c
& Lak Shin Jeong d
a College of Pharmacy, Pusan National University , Pusan, Korea
b Department of Chemistry , Chonbuk National University , Chonju, Korea
c College of Pharmacy, Ewha Womans University , Seoul, Korea
d College of Pharmacy, Seoul National University , Seoul, Korea
Published online: 15 Nov 2011.
To cite this article: Hyung Ryong Moon , Kyung Ran Kim , Bum Tae Kim , Ki Jun Hwang , Moon Woo Chun & Lak Shin Jeong
(2005) STEREOSELECTIVE SYNTHESIS OF CONFORMATIONALLY RIGID APIO CARBANUCLEOSIDES AS POTENTIAL ANTIVIRAL
AGENTS, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 709-711, DOI: 10.1081/NCN-200060292
To link to this article: http://dx.doi.org/10.1081/NCN-200060292
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):709–711, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060292
STEREOSELECTIVE SYNTHESIS OF CONFORMATIONALLY RIGID APIO
CARBANUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS
5
Hyung Ryong Moon and Kyung Ran Kim
College of Pharmacy, Pusan National
University, Pusan, Korea
5
Bum Tae Kim and Ki Jun Hwang
Department of Chemistry, Chonbuk National
University, Chonju, Korea
5
Moon Woo Chun
Lak Shin Jeong
College of Pharmacy, Ewha Womans University, Seoul, Korea
College of Pharmacy, Seoul National University, Seoul, Korea
5
5
Apio north-methanocarbocyclic nucleosides 1^3 with bicyclo[3.1.0]hexane template were first
synthesized. Introduction of hydroxymethyl substituent was efficiently and stereoselectively accomplished
by aldol and retro-aldol reaction and fixed conformation was achieved from a modified Simmons-Smith
cyclopropanation on a cyclopentane ring.
INTRODUCTION
Due to the lack of anomeric effect and gauche effect, carbocyclic nucleosides
have a different conformation at the sugar moiety from that of conventional
nucleosides and have seldom showed biological activities. Conventional nucleo-
sides exist in the equilibrium between south and north conformations in solution.
Since it has been suggested that conformation in sugar moiety of nucleosides was
closely related with their biological activities, a number of nucleosides with a fixed
conformation have been synthesized and evaluated for antiviral activity to identify
relationships between conformation and biological activity. Among them, the
representative is the nucleoside built on bicyclo[3.1.0]hexane template,[1] which
exists in one conformation, north or south, and the nucleoside analogues showed
significant antiviral activity. As a part of efforts to search for antiviral agents with
better biological profile, several groups including our laboratory have studied on
This research was supported by a grant from Korea Science and Engineering Research Foundation (KOSEF-
R01-2002-000-00114-0).
Address correspondence to Hyung Ryong Moon, College of Pharmacy, Pusan National University, Pusan
609-735, Korea.
709
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710
H. R. Moon et al.
SCHEME 1 Reagents and conditions: (a) acetone, conc. H2SO4, rt, 2.5 h; (b) vinylmagnesium bromide, THF,
À78°C to 0°C, 3 h; (c) NaIO4, CH2Cl2, H2O, 0°C to rt, 40 min; (d) K2CO3, 37% CH2O, MeOH, 80°C, 36 h;
(e) CH3PPh3Br, KOt-Bu, THF, rt, overnight; (f) Grubbs catalyst 2nd generation, CH2Cl2, rt, 2 h; (g) TrCl, DMAP,
pyridine, rt, 20 h; (h) Et2Zn, CH2I2, CH2Cl2, rt, 9 h; (i) 6-chloropurine, PPh3, DEAD, THF, 42°C, 4 h; (j) NH3/
MeOH, 80°C, 8 h, then 50% aq. CF3CO2H, THF, rt, 4 d for 1; 40% methylamine, MeOH, 80°C, 5 h, then 50% aq.
CF3CO2H, THF, rt, 4 d for 2; 1N HCl, 1,4-dioxane, reflux, overnight for 3.
SCHEME 2 The plausible mechanism of hydroxymethylation reaction.
the syntheses and biological activities of apio and isonucleosides. In addition to
isonucleosides, apio nucleosides have been reported to show better stability in
acidic conditions and potent biological activity.[2] On the basis of the hypothesis that
the fix of conformation in sugar moiety of carbocyclic nucleosides may elicit a
biological activity lost and the fact that apio nucleosides have potent biological
activity with an increased stability under acidic conditions, we designed and
synthesized apio north-methanocarbocyclic nucleosides 1, 2, and 3. Lactol 5 was
obtained starting from D-ribose via stereoselective Grignard reaction. In order to
synthesize apio-type sugar hydroxymethyl substituent was introduced at the C2-
position of 5 in stereoselective manner,[3] as shown in Scheme 1. The expected
mechanism may be explained, as depicted in Scheme 2. Carbocyclic sugar 7 was
synthesized by RCM reaction using second generation Grubbs catalyst and
stereoselective fusion of cyclopropane on a cyclopentane ring to fix conformation
was achieved by a modified Simmons-Smith cyclopropanation reaction using
diethyl zinc and diiodomethane. The final apio carbanucleosides were synthesized
via Mitsunobu reaction as a key step. The antiviral assay of the final nucleosides 1–
3 is in progress and will be reported in due course.
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