Cyclopentane-nucleobase coupling in the synthesis of carbocyclic L-nucleosides: Is a SN2-reaction an alternative to the mitsunobu-reaction?

Article abstract of DOI:10.1080/15257770701527745

Several carbocyclic L-nucleosides have been synthesized by coupling a cyclopentane-system with heterocycles according to a modified Mitsunobu-protocol. This reaction gave two regioisomers, the N1-alkylated product and an unwanted O2-product. A simple SN2-reaction has been investigated as an alternative for such couplings. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701527745

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Cyclopentane-Nucleobase Coupling
in the Synthesis of Carbocyclic L-
Nucleosides: is A S N 2-Reaction an
Alternative to the Mitsunobu-Reaction?
S. Jessel a , E. Hense a & C. 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: S. Jessel , E. Hense & C. Meier (2007) Cyclopentane-Nucleobase Coupling in the
Synthesis of Carbocyclic L-Nucleosides: is A S N 2-Reaction an Alternative to the Mitsunobu-Reaction?,
Nucleosides, Nucleotides and Nucleic Acids, 26:8-9, 1181-1184, DOI: 10.1080/15257770701527745
To link to this article: http://dx.doi.org/10.1080/15257770701527745
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1181–1184, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701527745
CYCLOPENTANE-NUCLEOBASE COUPLING IN THE SYNTHESIS
OF CARBOCYCLIC L-NUCLEOSIDES: IS A SN2-REACTION
AN ALTERNATIVE TO THE MITSUNOBU-REACTION?
S. Jessel, E. Hense, and C. Meier
Department of Chemistry, Organic Chemistry,
2
Faculty of Science, University of Hamburg, Hamburg, Germany
Several carbocyclic L-nucleosides have been synthesized by coupling a cyclopentane-system with
2
heterocycles according to a modified Mitsunobu-protocol. This reaction gave two regioisomers, the
N1-alkylated product and an unwanted O2-product. A simple SN 2-reaction has been investigated
as an alternative for such couplings.
Keywords Cyclopentane-nucleobase coupling; carbocyclic nucleosides
INTRODUCTION
In recent years carbocyclic nucleosides have attracted considerable in-
terest in antitumor and antiviral therapy.[1] The discovered bioactivity of
some naturally emerging carbocyclic nucleosides led to a range of modified
nucleosides with a cyclopentane system as sugar mimic.[2] These compounds
have a reduced toxicity and are stable toward hydrolysis by phosphorylases
and, therefore, show an increased biostability.[3]
L-nucleosides, another group of unnatural nucleosides, also have re-
ceived enhanced interest as antiviral therapeutic agents. Especially for the
treatment of hepatitis B the application of L-nucleosides seems to be suc-
cessful. There is one FDA approved L-nucleosides (lamivudine) and two ad-
ditional ones are in clinical phase III (telbivudine and clevudine).[4]
Our group is interested in the synthesis and biological evaluation of un-
natural nucleosides. The aim is to combine the concepts of carbocyclic and
L-nucleosides to yield new potentially bioactive compounds. Carbocyclic
nucleosides are synthetically the most demanding class of nucleosides, be-
cause they require multiple steps and sophisticated syntheses to build up
the stereogenic centers. In the past several synthetic approaches have been
Address correspondence to C. Meier, Department of Chemistry, Faculty of Science, University of
Hamburg, Martin Luther King Platz 6, D-20146 Hamburg, Germany. E-mail: chris.meier@chemie.uni-
hamburg.de
1181

1182
S. Jessel et al.
SCHEME 1 a) NaH, BOMCI, THF, −60◦C, 3 hours; b) (+)-ipC2BH (1) or (−)-ipC2BH (2), −60◦C
to r.t., 15 hours 45%; c) NaH, BnBr, TBAI, THF, r.t., 12 hours, 91%; d) 9-BBN, THF, r.t., 12 hours,
3N NaOH, 30% H2O2, 0◦C, 79%; e) PPh3, DIAD, benzoic acid 0◦C to r.t., 96%; f) PPh3, DIAD, N3-
benzoylphyrimidines, CH3CN, −40◦C to r.t., 15 hours, 1% NaOH in CH3OH, r.t., 4 hours; g) Pd/C, H2,
EtOH; h) triazole, POCl3, Et3N, CH3CN, 0◦C, 24 hours, NH3/H2O, CH3CN, r.t., 48 hours; i) I2, dioxane,
100◦C, 1.5 hours, 62%.
reported.[3a] Recently we reported a route, that allows the preparation of
stereochemically pure carbocyclic nucleosides in gram quantities.[5] This
convergent strategy was optimized for the synthesis of D-carba-dT. The same
strategy was also used to synthesize further pyrimidine analogues in good
yields, for example, D-carba-dC or D-carba-dU.
The key step is the stereoselective synthesis of the cyclopentane system 2.
Starting from cyclopentadiene an alkylation with BOMCl followed by a stere-
oselective hydroboration introduces the 3ꢁ-hydroxy group of the needed nu-
cleoside sugar moiety (Scheme 1).
This step allows the subsequent synthesis of L- or D-nucleosides using
(+)-diisopinocampheylborane or (−)-(ipc)2-borane, respectively. Following
this method several carbocyclic L-nucleosides were synthesized, e.g. L-carba-
dU 6, L-carba-dT 7, L-carba-FdU 8 and L-carba-BVDU 9 and L-carba-dC 10
(Scheme 1).
Another important step in this convergent strategy is the coupling of a
heterocycle to the cyclopentane system 5. It enables a high flexibility in yield-
ing different carbocyclic nucleosides by using a wide range of pyrimidines
or purines. This step was achieved by using a modified Mitsunobu-protocol.
However, after introduction of the N3-protected heterocycles varying ratios

Cyclopentane-Nucleobase Coupling
1183
SCHEME 2 a) PPh3, CBr4, CH2Cl2, −75◦C to r.t., 3 hours, 84%; b) PPh3, NIS, CH2Cl2 0◦C, 1 hour,
r.t., 3 hours, 84%; c) MsCl, THF, Et3N, 0◦C, 10 minutes, 99%; d) NaH, THF, 0◦C, 30 minutes, TsCl, r.t.,
3 hours, 68%; e) K2CO3, N3-Bz-pyrimidine, DMF, r.t., 30 minutes, 150◦C, 3 hours yields: see Table 1.
of N1/O2-alkylation were found, for example, 3:1 for 16 and 1:1 for 17. The
ratio depends on several factors like the solvent, the N3-protecting group,
the temperature or the heterocycle.[6] The challenge of this method is the
separation of the N1-alkylated product from the undesired O2-alkylated side
product and the converted Mitsunobu reagents. Especially 17 cannot be sep-
arated from ist O2-alkylated sideproduct. An alternative to the Mitsunobu-
method may be a simple SN2-reaction. Here, eventually an improved alkyla-
tion ratio and/or less side products may be possible. To prove this strategy
the hydroxyl group in 5 was replaced by several leaving groups like bromide,
iodide, mesylate or tosylate. The halogenation was accomplished by redox
condensation according to Mukaiyama in good chemical yields.[7] Thus, the
bromo derivative 12 was obtained by reacting 4 with triphenylphosphine
(PPh3) and CBr4. Analogously, cyclopentanol 4 was treated with PPh3 and
NIS to give the iodo derivative 13. The mesylate and tosylate were intro-
duced by reaction of the corresponding acid chlorides and compound 5
(Scheme 2).
The precursors for the SN2-displacement were reacted with depro-
tonated N3-benzoylthymine and N3-benzoyl-5-fluorouracil. The reaction
with the leaving groups bromide and mesylate led in fact to an exclu-
sive formation of the N1-alkylated product (Table 1). However, the yields
of 22% (Br) and 18% (OMs) for 16 and 18% (Br) and 15% (OMs) for
the 17 were not satisfying. In contrast, the yield increased about three-
fold with the better leaving groups iodide or tosylate. Interestingly, now
the O2-alkylated side product also was formed. The SN2-coupling gener-
ates mostly the N1-product but there is always a noticeable fraction of
elimination products like L-2 causing the poor yields. In summary, un-
der certain circumstances, the SN2-reaction can be used as a useful alter-
native to the Mitsunobu-protocol, especially when there are problems in
the purification and isolation of the alkylation products like in the case of
17.

1184
S. Jessel et al.
TABLE 1 Coupling of cyclopentane derivatives with pyrimidines
Leaving group X
Nucleobase
N1-/O2-ratio Yield of N1-product
Br
I
OMs
OTs
Br
3-benzoyl-thymine
3-benzoyl-thymine
3-benzoyl-thymine
3-benzoyl-thymine
3-benzoyl-5-fluoro-uracil
3-benzoyl-5-fluoro-uracil
3-benzoyl-5-fluoro-uracil
3-benzoyl-5-fluoro-uracil
100/0
75/25
100/0
70/30
100/0
60/40
100/0
50/50
22%
56%
15%
43%
15%
44%
14%
38%
I
OMs
OTs
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