Asymmetric synthesis of carbocyclic pyrimidine nucleosides via π-allylpalladium complex

Article abstract of DOI:10.1081/NCN-100002557

Racemic and enantiomerically pure carbocyclic pyrimidine nucleosides were synthesized efficiently by a convergent approach using Trost nucleophilic addition of π-allylpalladium complexes.

Full text of DOI:10.1081/NCN-100002557

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ASYMMETRIC SYNTHESIS OF CARBOCYCLIC
PYRIMIDINE NUCLEOSIDES VIA π-ALLYLPALLADIUM
COMPLEX
Junxing Shi a & Raymond F. Schinazi b
a Pharmasset, Inc. , Tucker, 30084, Georgia
b Veterans Affairs Medical Center , Decatur, 30033, Georgia
Published online: 07 Feb 2007.
To cite this article: Junxing Shi & Raymond F. Schinazi (2001) ASYMMETRIC SYNTHESIS OF CARBOCYCLIC PYRIMIDINE
NUCLEOSIDES VIA π-ALLYLPALLADIUM COMPLEX, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1367-1370, DOI:
10.1081/NCN-100002557
To link to this article: http://dx.doi.org/10.1081/NCN-100002557
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1367–1370 (2001)
ASYMMETRIC SYNTHESIS OF CARBOCYCLIC
PYRIMIDINE NUCLEOSIDES VIA
π-ALLYLPALLADIUM COMPLEX
Junxing Shi1 and Raymond F. Schinazi2,3,∗
1Pharmasset, Inc., Tucker, Georgia, 30084
2Veterans Affairs Medical Center, Decatur, Georgia, 30033
3Emory University, Atlanta, Georgia, 30322
ABSTRACT
Racemic and enantiomerically pure carbocyclic pyrimidine nucleosides were
synthesized efficiently by a convergent approach using Trost nucleophilic ad-
dition of π-allylpalladium complexes.
INTRODUCTION
In the last two decades, nucleoside analogues have been investigated with re-
newed interest in the search for effective anticancer and/or antiviral agents in gen-
eral, and in particular against human immunodeficiency virus (HIV). Such efforts
have resulted in the discovery of certain nucleoside analogues possessing potent
antiviral activity, with several of these becoming clinically successful agents. Re-
cent examples are carbocyclic nucleosides abacavir (Ziagen) [1], which has been
approved for clinical use against HIV, and entecavir in clinical development for
hepatitis B virus [2]. Carbocyclic nucleosides continue to be studied intensively
chemically and biologically. In contrast to carbocyclic purine nucleosides that have
been the major focus due to their discovery in nature, carbocyclic pyrimidine nu-
cleosides have not drawn much attention. Previously, we reported the synthesis
and evaluation of racemic carbocyclic pyrimidine nucleosides, and demonstrated
∗Corresponding author.
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Copyright 2001 by Marcel Dekker, Inc.
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SHI AND SCHINAZI
that their triphosphates possess potent inhibitory activity against HIV reverse tran-
scriptase [3]. Given the vast potential for these analogues, a synthetic method for
the development of enantiomerically enriched carbocyclic pyrimidine nucleosides
is warranted. In our continued search for anticancer and antiviral agents, we em-
barked on the development of efficient, versatile approaches to the synthesis of
enantiomerically pure carbocyclic pyrimidine nucleosides.
RESULTS AND DISCUSSION
To date, the methods used in the synthesis of carbocyclic pyrimidine nucleo-
sides, especially for chiral compounds, are lengthy or require special chiral synthons
that are not commercially available. Among the current synthetic methods, a con-
vergent approach using Trost nucleophilic addition of π-allylpalladium complexes
was found to be attractive [4]. This approach allows for the attachment of different
nucleobases to a suitable cyclopentenyl moiety. The substrates previously used in
this condensation are reported as being predominately cyclopentenyl esters and car-
bonates that require multistep synthesis. Recently, it has been reported that allylic
nitrogen functionality can be used in the Trost reaction, and some cyclopentenyl
amides were used as starting blocks in the synthesis of racemic carbocyclic purine
Scheme 1. Synthesis of racemic carbocyclic pyrimidine nucleosides.

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CARBOCYCLIC PYRIMIDINE NUCLEOSIDES
1369
nucleosides [5,6]. We applied this same strategy for the synthesis of carbocyclic
pyrimidine nucleosides.
This approach was initially evaluated for the synthesis of racemic carbo-
cyclic pyrimidine nucleosides. The cylcopentenylditosylimde 5 was prepared by
adapting Jung’s procedure [4] with a minor modification. Starting from ( )-2-
azabicyclo[2.2.1]hept-5-en-3-one [1, ( )-ABH, also called Vince lactam], after
tosylation with n-BuLi/TsCl, the N-tosylated lactam 2 was prepared. Reduction
with NaBH4 gave the ring-opening product 3, which was acetylated to monosulfon-
amide 4. Upon further tosylation, cyclopentenylditosylimide 5 was obtained. Under
Trost conditions [4], reaction of 5 with Pd(0) catalyst formed the π-allylpalladium
complex 6 as an intermediate. Condensation of the latter with N4-acetylcytosine
afforded the carbanucleoside 7. In a similar manner, reaction of complex 6 with
5-fluorouracil produced the acetylated uracil carbanucleoside 8. After deprotection
Scheme 2. Synthesis of enantiomerically pure carbocyclic pyrimidine nucleosides.

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SHI AND SCHINAZI
of 7 and 8, the desired pyrimidine carbanucleosides 9 and 10, respectively, were
obtained (Scheme 1).
Usingthisstrategyinthesynthesisofenantiomericallypurecarbocyclicnucle-
osides, the chiral cyclopentenylditosylimide 12 was prepared, starting from chiral
lactam 11, (1R)-(−)-ABH, via tosylation, reduction, acetylation, and a second tosy-
lation. UnderTrostconditions[4], theditosylimide 12, throughthe π-allylpalladium
complex13, wascondensedwith N4-acetylcytosineand N4-acetyl-5-fluorocytosine
to give the protected carbanucleosides 14 and 15. Upon saponification, compounds
14 and 15 gave rise to chiral carbocyclic nucleosides 16 and 17, respectively
(Scheme 2a).
The enantiomeric counterparts of these carbanucleosides were also prepared
in a similar manner. Conversion of (1S)-(+)-ABH 18 into chiral cyclopentenyldito-
sylimide 19, followed by coupling with N4-acetylcytosine and N4-acetyl-5-
fluorocytosine, through π-allylpalladium complex 20, yielded the protected nu-
cleosides 21 and 22. Upon deprotection, the enantiomerically pure carbocyclic
cytosine nucleosides 23 and 24, respectively, were obtained (Scheme 2b). These
nucleosides were characterized by NMR, high-resolution mass spectra, and HPLC.
In summary, a facile and efficient method for the synthesis of carbocyclic
pyrimidine nucleosides was successfully developed. Starting with readily available
chiral building blocks, both enantiomers of carbocyclic pyrimidine nucleosides
were synthesized by the procedure that requires fewer steps, and produced a better
overall yield compared to other methods. More importantly, it provides a simple
and concise route to the enantiomerically pure carbocyclic pyrimidine nucleosides
that previously were not easily attainable.
RFS is supported by NIH grant R01-AI-41980 and the Department of Veterans
Affairs.
REFERENCES
1. Daluge, S.M. U.S. Patent 5,034,394, 1991.
2. Furman, P.A.; Schinazi, R.F. Therapies for Viral Hepatitis, Schinazi, R.F.; Sommadossi,
J.-P.; and Thomas, H.C. Eds.; International Medical Press, London, (1998), pp. 273–
283.
3. Shi, J.; McAtee, J.J.; Schlueter-Wirtz, S.; Tharnish, P.; Juodawlkis, A.; Liotta, D.C.;
Schinazi, R.F. J. Med. Chem., 1999, 42, 859–867.
4. Trost, B.M. Angew. Chem., Int. Ed. Engl., 1986, 25, 1–20.
5. Jung, M.E.; Rhee, H. J. Org. Chem., 1994, 59, 4719–4720.
6. Katagiri, N.; Takebayashi, M.; Kokufuda, H.; Kaneko, C.; Kanehira, K.; Torihara, M.
J. Org. Chem., 1997, 62, 1580–1581.

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