Practical synthesis of D-cyclopent-2-enone, the key intermediate of carbocyclic nucleosides

Article abstract of DOI:10.1081/NCN-120022631

An efficient and practical method for the synthesis of (4R,5R)-4,5-O-isopropylidene-cyclopent-2-enone was developed from D-ribose by using a ring-closing metathesis reaction.

Full text of DOI:10.1081/NCN-120022631

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Nucleosides, Nucleotides and Nucleic Acids
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Practical Synthesis of D-Cyclopent-2-enone, the Key
Intermediate of Carbocyclic Nucleosides
a
a b
Y. H. Jin & C. K. Chu
a
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The
University of Georgia, Athens, Georgia, USA
b
College of Pharmacy, University of Georgia, Athens, GA, 30602-2352, USA
Published online: 31 Aug 2006.
To cite this article: Y. H. Jin & C. K. Chu (2003) Practical Synthesis of D-Cyclopent-2-enone, the Key Intermediate of
Carbocyclic Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 771-773, DOI: 10.1081/NCN-120022631
To link to this article: http://dx.doi.org/10.1081/NCN-120022631
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 771–773, 2003
Practical Synthesis of D-Cyclopent-2-enone, the Key
Intermediate of Carbocyclic Nucleosides
*
Y. H. Jin and C. K. Chu
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy,
The University of Georgia, Athens, Georgia, USA
ABSTRACT
An efficient and practical method for the synthesis of (4R,5R)-4,5-O-isopropy-
lidene-cyclopent-2-enone was developed from d-ribose by using a ring-closing
metathesis reaction.
INTRODUCTION
Carbocyclic nucleosides have been an interesting class of compounds, some of
which exhibit potent biological activities. Aristeromycin and neplanocin A were ori-
[
1]
ginally isolated from natural sources. As part of our drug discovery program,
recently we have developed the synthesis of enantiomerically pure aristeromycin
[
2]
and neplanocin A analogs. We also synthesized enantiomerically pure cytosine
and 5-F-cytosine analogs, which exhibit significant anti-HIV, anti-Smallpox Virus
[
2]
and anti-West Nile Virus activities. Therefore, additional biological evaluation
of these carbocyclic nucleosides as well as the structure-activity relationships studies
*
3
Correspondence: C. K. Chu, College of Pharmacy, University of Georgia, Athens, GA
0602-2352, USA; Fax: +1 706 542 5381; E-mail: dchu@rx.uga.edu.
7
71
DOI: 10.1081/NCN-120022631
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

772
Jin and Chu
required a large amount of key intermediates. For these carbocyclic nucleosides,
[
d-cyclopent-2-enone serves as a key intermediate. However, the availability of this
3]
[
4]
intermediate has been so far limited due to low and inconsistent yields. Therefore,
an efficient synthetic methodology for the key intermediate, d-cyclopent-2-enone,
is highly desirable.
CHEMISTRY
The isopropylidene protected derivative 2 (Sch. 1) was obtained from d-ribose
with 2,2-dimethoxy propane in the presence of catalytic amount of p-toluenesulfonic
acid in 90% yield, followed by t-butyldimethylsilane chloride with immidazole to
afford the silylated lactol 3 in 85% yield. To introduce an olefin moiety, Grignard
reaction was carried out with vinylmagnesium bromide to provide alcohol 4 in
1
00% yield. The deprotection of the silyl group using 1M solution of tetrabutyl-
ammonium fluoride in THF followed by an oxidative cleavage with sodium period-
ate afforded lactol 6. Wittig reaction was carried out using NaH and DMSO in THF
to give diene 7 in 86% yield which underwent a ring-closing metathesis (RCM) reac-
tion. Several RCM reaction conditions using the Grubbs catalyst from diene 7 to
ꢀ
cyclopentenol 8 were investigated, among which 1% Grubbs catalyst at 24 C in
anhydrous CH Cl provided the best result to obtain cyclopentenol 8. As the
2
2
Scheme 1. Reagents and conditions: (a) 2,2-Dimethoxypropane, p-Toluenesulfonic acid, acet-
ꢀ
one, 0 C to rt, 1 h; (b) TBDMSCl, imidazole, CH
ꢀ
2
Cl , rt, 1 h; (c) Vinylmagnesium bromide,
anhydrous THF, À78 C to rt, 1 h; (d) TBAF, THF, rt, 1 h; (e) NaIO , H O, rt 1 h; (f)
2
4
2
ꢀ
NaH, DMSO, Methyltriphenylphosphonium bromide, THF, 0 C to reflux, 3 h; (g) Grubbs
ꢀ
˚
Cl , 24 C, 4 h; (h) Pyridinium chlorochromate, 4 A molecular sieve,
catalyst, anhydrous CH
AcOH, CH Cl , rt, 12 h.
2 2
2
2

Intermediate for Carbocyclic Nucleoside Synthesis
773
obtained cyclopentenol 8 was volatile, the desired cyclopentenone 9 was directly
obtained in two steps 93% yield from diene 7 by PCC oxidation of cyclopentenol
8
without purification.
In summary, we have developed a significantly improved synthetic method for
d-cyclopent-2-enone 9 in a preparative scale, which is a versatile intermediate for
the synthesis of carbocyclic nucleosides in 56% overall yield from d-ribose.
ACKNOWLEDGMENTS
This research was supported by grants of National Institute of Allergy and
Infectious Diseases (U01 AI48495 and AI 32351).
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