Synthesis of carbocyclic pyrimidine nucleosides using the Mitsunobu reaction - Part I: Influence of the alcohol on N1- versus O2- alkylation

Article abstract of DOI:10.1055/s-2005-922746

The Mitsunobu reaction is an important tool in carbocyclic nucleoside chemistry for the direct coupling of alcohols with heterocyclic bases under mild conditions. Here, we report on the influence of the alcohol on the N1- vs. O²-alkylation of N

Full text of DOI:10.1055/s-2005-922746

LETTER
3145
Synthesis of Carbocyclic Pyrimidine Nucleosides Using the Mitsunobu
Reaction – Part I: Influence of the Alcohol on N1- versus O2-Alkylation
T
uning of Mitsuno
l
bu Cou
a
plings in
C
f
arbocyclic
NuR
.s
Ludek, Chris Meier*
Institut für Organische Chemie, Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax +49(40)428382495; E-mail: chris.meier@chemie.uni-hamburg.de
Received 30 September 2005
As they lack a glycosidic bond, these nucleosides are sta-
ble towards hydrolysis by phosphorylases and therefore
display enhanced biostability.6 Moreover, in contrast to
natural nucleosides particularly, carbocyclic 2¢,3¢-
Abstract: The Mitsunobu reaction is an important tool in carbo-
cyclic nucleoside chemistry for the direct coupling of alcohols with
heterocyclic bases under mild conditions. Here, we report on the in-
fluence of the alcohol on the N1- vs. O2-alkylation of N3-benzoyl-
thymine under Mitsunobu conditions. Moreover, a method for dideoxy- or 2¢,3¢-dideoxy-2¢,3¢-didehydro-purine nucleo-
predicting the product ratio of the alkylation reaction will be intro-
sides are acid-stable due to the missing hemiaminal
duced.
structure. However, the removal of the hemiaminal oxy-
Key words: Mitsunobu reaction, carbocyclic nucleosides, regio-
selectivity, antiviral agents, medicinal chemistry
gen abolishes the anomeric and gauche effects responsible
for forcing the furan system into two distinct conforma-
tions.7 Since the conformation of the five-membered ring
is believed to play a critical role in modulating biological
Carbocyclic nucleosides in that the furanose oxygen is activity, the behavior of nucleosides with a cyclopentane
replaced by a methylene unit have attracted considerable moiety sometimes differs significantly from that of their
interest due to their wide range of biological activity.1 natural counterparts.8
Recently, carbocyclic nucleoside analogues like carbovir
A number of strategies have been designed for the prepa-
12 and the structurally related abacavir 2 (ZiagenTM)3 were
ration of carbocyclic nucleosides.9 The strategies can be
found to be potent inhibitors of HIV reverse transcriptase.
subdivided into two categories: i) the linear approach
involves initial synthesis of a functionalized cyclopentyl-
amine and a step-wise synthesis of the heterocyclic base
Moreover, the guanine derivative entecavir 3 (Bara-
cludeTM)4 was approved by the FDA in early 2005 for the
treatment of chronic HBV infections, a common co-infec-
and ii) the convergent approach, here, the appropriate
tion in people with HIV.
heterocycle is coupled directly to a functionalized
carbocyclic moiety, leading to a variety of carbocyclic
nucleosides starting from one common cyclopentane
precursor.
NH
O
N
N
N
N
N
N
NH
NH2
Recently, we published a new convergent route to
carbocyclic nucleoside analogues starting from enantio-
merically pure (1S,2R)-2-benzyloxymethylcyclopent-3-
enol (5).10 In the key step cyclopentanol 6 is condensed
with a N3-protected pyrimidine nucleobase using a
modified Mitsunobu protocol (Scheme 1).11
HO
HO
N
NH2
Carbovir 1
Abacavir 2
O
O
N
Br
N
N
HN
NH
NH2
BnO
BnO
HO
HO
O
N
Mitsunobu
reaction
ref. 10
OH
OH
OBn
ent-6
OH
OH
yield ca. 90%
ent-5
Entecavir 3
carba-BVdU 4
O
O
N
Figure 1 Examples of antiviral active carbocyclic nucleoside
analogues.
HN
HN
O
N
O
BnO
BnO
+
Beside carbocyclic purine analogues, an example of a bio-
active pyrimidine analogue is carba-BVdU 4 which
shows significant anti-HSV-1 activity.5
OBn
OBn
ent-8 (O2; 34%)
ent-7 (N1; 66%)
Scheme 1 Mitsunobu reaction conditions: (a) PPh3, DIAD,
N3-benzoylthymine 8, THF, –40 °C to r.t., 16 h (b) 1% NaOH in
MeOH, r.t., 12 h.
SYNLETT 2005, No. 20, pp 3145–3147
1
9
.1
2
.2
0
0
5
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922746; Art ID: G30405ST
© Georg Thieme Verlag Stuttgart · New York

3146
O. R. Ludek, C. Meier
LETTER
Table 1 Alkylation of N3-Benzoylthymine 9 with Alcohols 10a–h
in THF
This strategy can also be used for the synthesis of
carbocyclic a-, iso- and 3¢-epi-nucleosides.12 Unfortu-
nately, the nucleobases react as ambident nucleophiles
(Figure 2), leading to mixtures of isomers [N1-(7)/O2-(8)
isomers for pyrimidines, N7/N9-isomers for purines].
Alcohol 10
13C NMR
Yield N1/O2
shift (ppm)a (%)b alkylation (%)c
1-Pentanol (10a)
61.1
63.3
64.3
65.8
68.4
68.6
72.1
89
92
90
94
87
90
92
90
100:0
100:0
95:5
O
O
O
O
Benzylalcohol (10b)
Cyclohex-2-enol (10c)
2-Pentanol (10d)
R
R
N
N
O
N
O
N
80:20
79:21
73:27
66:34
60:40
1-Phenylethanol (10e)
Cyclohexanol (10f)
Cyclopentanol (10g)
O-alkylation (hard)
N-alkylation (soft)
Figure 2
Alkylation of ambident pyrimidine nucleobases.
In order to maximize reaction yields and to minimize pu-
rification, reaction conditions leading predominantly to
one isomer are needed. In our attempts to develop a con-
venient synthesis for carbocyclic nucleoside analogues,
we investigated in detail the influence of the alcohol on
the Mitsunobu coupling reaction with pyrimidine bases.
2,2,2-Trichloroethanol (10h) 75.1
a Chemical shift is given for the ipso-carbon atom of the alcohol.
b Yield of both isolated products.
c Determined by 1H NMR spectroscopy
After isolation of the isomeric mixtures, the product ratio
was correlated with the 13C chemical shifts of the respec-
tive carbon in DMSO-d6. Interestingly, the primary alco-
hols with a ‘soft’ carbon atom, e.g. 1-pentanol (10a) and
benzyl alcohol (10b), exclusively led to the N1-product.
As expected, with increasing ‘hardness’ of the carbon
atom, more of the O2-isomer was formed.
The regioselectivity of the alkylation of an ambident nu-
cleophile in a given aprotic solvent clearly depends on the
substrate and can be correlated to the HSAB-principle
(hard soft acid base) by Pearson.13 In the ambident nucleo-
phile N3-benzoylthymine the O2-atom represents a ‘hard’
alkylation site, while the N1-atom is a ‘soft’ nucleophilic
center. The hardness of the carbon connected to the hy-
droxyl group in an alcohol depends upon their respective
chemical environment, i.e. from the substituents or the
structure (e.g. strain) in the molecule. According to the
HSAB-principle it can be predicted, that the harder the
carbon atom, the more O2-alkylation should occur. To
measure the hardness of this carbon atom, its 13C NMR
chemical shift can be taken as an estimate. A ‘hard’ car-
bon atom is hardly polarizable, i.e. the electron density at
the nucleus is low, therefore the 13C absorption appears at
low magnetic fields and vice versa.
The results obtained can be used to predict the product
ratio of a Mitsunobu condensation with N3-benzoylthym-
ine 9 with any given alcohol by measuring the 13C chem-
ical shift of the carbon atom. This method has been
applied to (1S,3S,4R)-3-benzyloxy-4-benzyloxymethyl-
cyclopentanol (6),10 a precursor for carbocyclic 2¢-deoxy-
nucleoside analogues. The chemical shift of C-1 is 69.5
ppm in DMSO-d6. Therefore, a product distribution of
approximately 70% of N1-product to 30% of O2-isomer
was expected (Scheme 1).
To investigate the electronic influence of the alcohol on
the alkylation under the conditions of the Mitsunobu reac-
tion, N3-benzoylthymine 9 was condensed with alcohols
10a–h in THF (Scheme 2) leading to the N1-products
11a–h and the O2-compounds 12a–h (Table 1). THF was
used because it is the commonly used solvent for
Mitsunobu reactions. To avoid possible steric effects
caused by bulky substituents, only simple alcohols were
chosen as model compounds.
To prove this prediction, the alkylation reaction was per-
formed analogously to the above procedure in THF. After
chromatography of the crude product, a mixture of 66%
N1-7 and 34% O2-isomer 8 was isolated. This is surpris-
ingly close to the predicted distribution because one
should keep in mind that cyclopentanol 6 has two substit-
uents on the ring while none of the model compounds
were substituted. Consequently, the method seems to give
reasonable predictions for the isomeric ratio for carbo-
cyclic nucleosides.
O
O
Further work is currently in progress in our laboratories to
fine-tune the parameters of the Mitsunobu condensation
in the synthesis of carbocyclic nucleosides. Our aim is to
find optimized general reaction conditions for the syn-
thesis of either carbocylic pyrimidine or purine nucleo-
sides.
O
O
O
HN
HN
N
a, b
+
O
N
R
O
N
N
H
R
12a–h
11a–h
9
Scheme 2 (a) PPh3, DIAD, alcohol 10a–h (see Table 1, THF,
–40 °C to r.t., 16 h (b) 1% NaOH in MeOH, r.t., 12 h.
Synlett 2005, No. 20, 3145–3147 © Thieme Stuttgart · New York

LETTER
Tuning of Mitsunobu Couplings in Carbocyclic Nucleoside Synthesis
3147
General Procedure
(6) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and
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J. J. Am. Chem. Soc. 1998, 120, 2780.
(8) Béres, J.; Sági, G.; Tömösközi, I.; Gruber, L.; Baitz-Gács,
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(9) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48,
571. (b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50,
10611. (c) Crimmins, M. T. Tetrahedron 1998, 54, 9229.
(10) (a) Ludek, O. R.; Meier, C. Synthesis 2003, 13, 2101.
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2005, submitted
DIAD (545 mL, 2.80 mmol) was added slowly to a suspension of
PPh3 (787 mg, 3.00 mmol) in anhydrous THF (11 mL). The mixture
was stirred for 0.5 h at 0 °C. This preformed complex was slowly
added to a suspension of the N3-Bz-thymine 9 (506 mg, 2.2 mmol)
and alcohol 10 (1.00 mmol) in anhydrous THF (6.0 mL) at –40 °C
under nitrogen. The reaction was slowly warmed to r.t. and stirred
overnight. The solvent was removed from the reaction mixture and
a NaOH solution in MeOH (1%; 15 mL) was added and stirred over-
night at r.t. to cleave the N3-benzoyl protecting group. The solution
was neutralized by the addition of 1 M HCl and then concentrated.
The crude product was purified by silica gel chromatography
(hexanes–EtOAc, 1:2) to yield N1-products 11a–h and the O2-iso-
mers 12a–h as colorless solids. The product ratio was determined
by 1H NMR spectroscopy by integration of the H-1¢ protons.
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Synlett 2005, No. 20, 3145–3147 © Thieme Stuttgart · New York