A new and short convergent synthetic strategy to carbocyclic nucleosides

Article abstract of DOI:10.1080/15257770701507937

An efficient synthesis for racemic cyclopent-3-en-1-yl nucleoside analogues has been developed starting from cyclopentadiene. The key step is the regioselective hydroboration of a mixture of intermediate alkylatede cyclopentadienes to give one cyclopenten

Full text of DOI:10.1080/15257770701507937

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A New and Short Convergent Synthetic
Strategy to Carbocyclic Nucleosides
Bastian Reichardt a & Chris Meier a
a Department of Chemistry , Organic Chemistry, Faculty of Science,
University of Hamburg , Hamburg, Germany
Published online: 10 Dec 2007.
To cite this article: Bastian Reichardt & Chris Meier (2007) A New and Short Convergent Synthetic
Strategy to Carbocyclic Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 26:8-9, 935-937,
DOI: 10.1080/15257770701507937
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Nucleosides, Nucleotides, and Nucleic Acids, 26:935–937, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701507937
A NEW AND SHORT CONVERGENT SYNTHETIC STRATEGY
TO CARBOCYCLIC NUCLEOSIDES
Bastian Reichardt and Chris Meier
Department of Chemistry, Organic Chemistry,
2
Faculty of Science, University of Hamburg, Hamburg, Germany
An efficient synthesis for racemic cyclopent-3-en-1-yl nucleoside analogues has been developed
2
starting from cyclopentadiene. The key step is the regioselective hydroboration of a mixture of inter-
mediate alkylatede cyclopentadienes to give one cyclopentenol.
Keywords Carbocyclic nucleosides; cyclopentenyl nucleosides; Mitsunobu coupling;
purines; pyrimidines
INTRODUCTION
Carbocyclic nucleosides are compounds in which the furan ring has
been replaced by a carbocyclic system. These nucleoside analogues have
attracted considerable interest due to their important biological activity.[1]
Various structural modifications were introduced in both the heterocyclic
base and the sugar moiety.[2] Such compounds are stable to hydroly-
sis by phosphorylases that cleave the glycosidic bond in conventional
nucleosides.[3] The bioactivity of the naturally occurring carbocyclic nucleo-
sides (-)-aristeromycin and (-)-neplanocin A led to an interest in this class of
compounds, resulting in the generation of a number of antiviral carbocyclic
nucleosides. In the past, carbocyclic nucleoside analogues like Abacavir[4]
(Ziagen) and Entecavir[5] (Baraclude) showed encouraging in vitro and in
vivo activities. Recently, Abacavir was approved as a HIV-drug for clinical
application. Moreover, Entecavir was approved by FDA in 2005 for the treat-
ment of chronic HBV infections.
RESULTS AND DISCUSSION
Recently, we published a new procedure for the preparation of racemic
cyclopent-3-en-1-yl nucleoside analogues.[7] Cyclopentenol 4 was prepared
Address correspondence to Chris Meier, University of Hamburg, Department of Chemistry, Organic
Chemistry, Martin Luther King Platz 6, Hamburg 20146, Germany. E-mail: laborhenry@ gmx.de
935

936
B. Reichardt and C. Meier
for a convergent approach to carbocyclic nucleosides. This cyclopentenol
4 was developed from cyclopentadiene 1 that was deprotonated and alky-
lated with benzyloxymethyl chloride to give the diene 2. This material un-
dergoes isomerization into two thermodynamically more stable cyclopenta-
dienes 3a,b. These two dienes were hydroborated with 9-BBN as a sterically
demanding hydroboration reagent to ( )-3-[(benzyloxy)methyl]cyclopent-
3-en-1-ol 4 in 42% overall yield. Next, the diene mixture was treated with
0.3 equiv. of BH3 in THF. Surprisingly, also in this case cyclopentenol 4
was isolated as the sole product in 59% overall yield after alkaline work-up.
(Scheme 1).
SCHEME 1 a)NaH, 0◦C, 0.5 hours, THF; b) benzyloxymenlthyl chloride, −50◦C, 2 hours, rt, 12 hours,
THF; c) BH3 *THF, 24 hours, THF; d) NaOH/H2O2 12 hours, THF.
To prove the suitability of cyclopentenol to act as starting material for
the synthesis of carbocyclic nucleosides, pyrimidine heterocycles were in-
troduced using the modified Mitsunobu reaction conditions as reported
previously.[8,11] Thus, N 3-benzoylthymine and N 3-benzoyluracil were con-
densed successfully with cyclopentenol 4. Alkaline treatment of the crude
reaction product led to O-benzylcyclopentenyl nucleosides. In the case of
3-benzoylthymine the N 1/O2-regioselectivity was found to be 5:1 while a
9:1-regioselectivity was found for 3-benzoyluracil. Debenzylation of the nu-
cleosides proceeded in 76–82% yield using BCl3 at –78◦C to give cyclopen-
tenyl nucleoside analogues, respectively.[12] Mitsunobu coupling of precur-
sors ( )-4 with 6-chloropurine led to the formation of the protected purine
nucleosides in 54% yield, respectively.[7] The N 9/N 7-regioselectivity was 9:1
and the two isomers were separated by column chromatography. Finally, re-
moval of the O-benzyl group of the nucleoside proceeded in 82% yield using
BCl3 at –78◦C to give cyclopentenyl nucleoside analogues 5,6. In addition,
the purine analogue was converted to the inosine nucleoside analogue ( )-
7 by treatment of the chloropurine derivative with sodium methanolate and
2-mercaptoethanol in 68% yield (Scheme 2).
In summary, we have elaborated an interesting new pathway towards the
synthesis of carbocyclic pyrimidine and hypoxanthine nucleoside analogues.
The method starts from cheap cyclopentadiene and is a powerful addition

Carbocyclic Nucleosides
937
SCHEME 2 a) DIAD, PPh3, N3-BzUra/N3-BzThy, −40◦C, 2 hours, CH3 CN; b) NaOH/CH3 OH 1%,
12 hours; c) BCl3 5 hours, −78◦C, CH2Cl2; d) DIAD, PPh3, 6-chloropurine, 24 hours, THF; e)2-
mercaptoethanol, NaOMe, MeOH, 60◦C, 4 hours.
to our previously reported methodology. The biological evaluation of the
compounds is under investigation.
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