Influence of the N3-protection group on N1- vs. O2-alkylation in the Mitsunobu reaction

Article abstract of DOI:10.1002/ejoc.200500801

The influence of the N3-protection group of thymine on the regioselectivity of the N1- vs. O²-alkylation under Mitsunobu conditions is described. A series of N3-protected thymine derivatives 8a-f was prepared and coupled to cyclopentanol as mod

Full text of DOI:10.1002/ejoc.200500801

FULL PAPER
DOI: 10.1002/ejoc.200500801
Influence of the N3-Protection Group on N1- vs. O2-Alkylation in the
Mitsunobu Reaction[‡]
Olaf R. Ludek[a] and Chris Meier*[a]
Keywords: Carbocyclic nucleosides / Regioselectivity / Nucleoside analogues / Antiviral agents / Mitsunobu reaction
The influence of the N3-protection group of thymine on the
regioselectivity of the N1- vs. O2-alkylation under Mitsunobu
viously reported synthetic strategy to carbocyclic thymidine
(carba-dT). Moreover, the 2,6-dimethyl-Bz group led exclu-
conditions is described. A series of N3-protected thymine de- sively to the O2-analogue of carba-dT.
rivatives 8a–f was prepared and coupled to cyclopentanol as
model compound for carbocyclic nucleoside precursors. Fi-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
nally, the N3-BOM group was selected to improve our pre-
Germany, 2006)
Introduction
Analogues of naturally occurring nucleosides have at-
tracted considerable interest as antiviral and antitumor
agents.[2] A major drawback of this class of compounds is
often their low conversion into the ultimate bioactive nucleo-
side monophosphates (nucleotides) and their hydrolytic and
enzymatic instability of the glycosidic bond leading to a ra-
pid degradation of the nucleosides. To overcome these
limitations, several modifications have been made to the
structure of nucleosides, including the replacement of the
furanose oxygen atom by a methylene unit.[3] However, the
removal of the aminal oxygen atom abolishes the anomeric
and gauche effects, responsible for forcing the furane system
into two distinct conformations.[4] Since the conformation
of the five-membered ring is believed to play a critical role
in modulating biological activity, the behaviour of nucleo-
sides with a cyclopentane moiety sometimes differs signifi-
cantly from that of their natural counterparts.[5] Neverthe-
less, carbocyclic nucleoside analogues like carbovir (1)[6]
and the structurally related abacavir (2)[7] (ZiagenTM) were
found to be potent inhibitors of HIV reverse transcriptase.
Moreover, the guanine derivative entecavir (3)[8] (Bara-
cludeTM) was approved by the FDA in early 2005 for the
treatment of chronic HBV infections. Beside carbocyclic
purine analogues, carba-BVdU (4) is an example of a bioac-
tive pyrimidine analogue that showed significant anti-HSV-
1 activity (Figure 1).[9]
Figure 1. Examples of antivirally active and approved carbocyclic
nucleosides.
Carbocyclic nucleosides are synthetically the most chal-
lenging class of nucleosides, requiring multi-step syntheses
to introduce the required multiple stereogenic centers. A
number of strategies, which can be classified into two cat-
egories, have been used to obtain enantiomerically pure car-
bocyclic nucleosides.[10] The linear approach involves an ini-
tial synthesis of a functionalized cyclopentylamine. Then
the heterocyclic base is built in a step-wise manner. The
second strategy is the convergent approach. Here, the ap-
propriate heterocycle is coupled directly to a functionalized
carbocyclic moiety, leading to a variety of carbocyclic nu-
cleosides starting from one common cyclopentane precur-
sor.
[‡] Synthesis of Carbocyclic Pyrimidine Nucleosides, III. Part II:
Ref.[1]
[a] Institut für Organische Chemie, Universität Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: + 49-40-42838-2495
Recently, we published a new convergent route to carbo-
cyclic nucleoside analogues, starting from enantiomerically
pure (1S,2R)-2-(benzyloxymethyl)cyclopent-3-enol (5).[11,12]
E-mail: chris.meier@chemie.uni-hamburg.de
Eur. J. Org. Chem. 2006, 941–946
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
941

O. R. Ludek, C. Meier
FULL PAPER
Figure 2. Convergent synthesis of carbocyclic nucleosides starting from a chiral cyclopentanol.
After a stereoselective hydroboration as the key step, the
Here, we report on the effect of different N3-protecting
resulting chiral cyclopentanol 6α is condensed with an N3- groups on the regioselectivity of the coupling of the hetero-
protected pyrimidine nucleobase to yield the carbocylic nu- cycle to the alcohol.
cleoside 7 by a modified Mitsunobu protocol (Figure 2).
This strategy can also be used for the synthesis of carbo-
cyclic α-, iso- and 3Ј-epi-nucleosides.[13] However, the nu-
Results and Discussion
cleobases often react as ambident nucleophiles, leading to
mixtures of isomers (N1- and O2-regioisomers for pyrimi-
For the Mitsunobu coupling reaction the N3-position of
dines).[14] In order to maximize reaction yields, to control the pyrimidine base has to be protected. Usually the N-
the regioselective coupling and to minimize purification ef- benzoyl group is used for this purpose.[18] However, due to
forts, reaction conditions leading predominantly to one iso- the results obtained with different 5-substituents, we de-
mer are highly desirable. In this context we have studied the cided to investigate the influence of different protecting
effect of the alcohol on the coupling to the heterocycle as groups in the 3-position of the nucleobase on the product
well as solvent effects. The first study led to a method to ratio in more detail. Therefore, differently substituted N-
predict the regioselectivity for a given alcohol[1] and the sec- benzoyl groups were attached to the N3-position of thymine
ond study proved that CH3CN or DMF are the most suit- (8a–e). Additionally, we blocked the N3-position by alky-
able solvents to be used in order to furnish predominantly lation with
a
benzyloxymethyl (BOM) group (8f)
the N1-isomer.[15] From previous reactions it became clear (Scheme 1).
that the substituent in the 5-position of the protected nuc-
These reactions were carried out, according to the pro-
leobase has a major effect on the outcome of the Mitsu- cedure for the benzoylation of pyrimidines as described by
nobu coupling.[11,16] The 5-substituent obviously has an in- Cruickshank et al.[18] The intermediately formed N1,N3-di-
fluence on the relative nucleophilicity of both alkylation benzoylated compounds were not isolated. After evapora-
centers. Most probably this can be explained by differences tion of the solvent, the crude products were purified by sil-
in the electronic structure and differences in the solvation ica gel column chromatography (CH2Cl2/MeOH, 20:1),
cages.[17]
leading to a selective methanolysis at the N1-position. Ex-
Scheme 1. Synthesis of different N3-benzoylthymine derivatives 8. (a) Thymine, pyridine, CH3CN, room temp., 2 d; (b) chromatography
on silica gel (CH2Cl2/MeOH, 20:1).
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Influence of the N3-Protection Group on N1- vs. O2-Alkylation in the Mitsunobu Reaction
FULL PAPER
cept for (3,5-dinitrobenzoyl)thymine 8d, the yields of the tected thymine 9 was not isolated and the crude mixture
benzoylated thymine derivatives 8a–e are good to excellent was subsequently treated with sodium hydride in DMF and
(Table 1).
alkylated by slow addition of benzyl chloromethyl ether
(BOM-Cl). In the last step the Boc group was cleaved by
stirring a mixture of 10 in methanol with potassium car-
bonate as base. N3-(Benzyloxymethyl)thymine (8f) (BOM-
T) was obtained in an overall yield of 64%.
Table 1. Selective acylation on N3 of thymine with benzoyl chlo-
rides.
Bz-thymine
Protection group
Yield [%]
Compounds 8a–f were then subjected to the coupling re-
action under modified Mitsunobu conditions in THF with
cyclopentanol as a model for the chiral cyclopentanols used
in carbocyclic nucleoside synthesis. The reaction with (3,5-
dinitrobenzoyl)thymine 8d was performed in CH3CN for
solubility reasons (Scheme 3).
8a
8b
8c
8d
8e
benzoyl
80
69
72
25
95
3,5-dimethylbenzoyl
2,6-dimethylbenzoyl
3,5-dinitrobenzoyl
4-chlorobenzoyl
The low yield of the 3,5-dinitro derivative 8d (Entry 4) is
due to the high instability of this compound. When purified
on silica gel, not only the N1-protecting group was cleaved
but also a partial loss of the second benzoyl group was ob-
served. This observation was confirmed by a stability test
of compound 8d in CH2Cl2/MeOH (20:1). After stirring for
20 min, TLC showed a noticeable amount of thymine and
methyl 3,5-dinitrobenzoate.
In addition to the N-acylated compounds 8a–e, one N3-
alkylated thymine derivative (8f) was prepared. Since our
reported strategy for carbocyclic nucleoside synthesis in-
volves the cleavage of benzyl ethers by hydrogenolysis in the
final step,[11–13,19] a protection group was attached, which
can be cleaved at the same time by catalytic hydrogenation.
Unfortunately, a benzyl group at the N3-atom of an uracil
derivative is extremely stable. Therefore, the benzyloxyme-
thyl (BOM) group was used,[20] that degrades to the nucleo-
base in a tandem reaction after hydrogenolysis of the benzyl
ether and spontaneous elimination of formaldehyde.
The synthesis of N3-BOM-thymine (8f) was first de-
scribed by Schmitt and Caperelli in poor chemical yields.[21]
To improve the yield, we applied the three-step one-pot
strategy developed by Jaime-Figeroa et al. for the synthesis
of N3-alkylated pyrimidines (Scheme 2).[22]
Scheme 3. Coupling of the N3-protected thymine with cyclopenta-
nol. (a) PPh3, DIAD, cyclopentanol, THF, –40 °C to room temp.,
16 h; (b) 1% NaOH in MeOH, room temp., 12 h.
Both isomers 11 and 12 were isolated and the product
1
ratio was determined by H NMR spectroscopy using the
integration of the 1Ј-H protons. The yields and obtained
product ratios of the couplings are summarized in Table 2.
Table 2. Alkylation of N3-protected thymines with cyclopentanol.
Pyrimidine
Solvent
Yield [%][a]
N1/O2 ratio [%][b]
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
THF
THF
THF
CH3CN
THF
THF
92
89
85
59
88
94
66:34
60:40
0:100
96:4
65:35
80:20
[a] Yield of both isolated products. [b] Determined by 1H NMR
spectroscopy.
As already seen in the case of 5-substituted pyrimidine
nucleobases, the product ratio of the coupling reaction can
also be strongly influenced by the protecting group in the
3-position of the heterocycle. For example the 3,5-dini-
trobenzoyl group (8d) led almost exclusively to the forma-
tion of the N1-isomer while the 2,6-dimethylbenzoyl group
(8c) led highly selectively to the O2-product. Unfortunately,
the yield of the coupling reaction with 8d is considerably
lower than with the other derivatives. However, N3-benzyl-
oxymethyl (BOM) protected thymine 8f is a good alterna-
tive, leading to high overall yields and an improved N1-
selectivity. Benzoylated derivatives 8b and 8e gave regio-
selectivities comparable to prototype 8a. A surprising effect
can be seen from the two dimethylated Bz groups. While
2,6-dimethylbenzoyl-protected thymine led exclusively to
Scheme 2. Synthesis of N3-(benzyloxymethyl)thymine. (a) Di-tert-
butyl dicarbonate, DMAP, CH3CN, room temp., 4 h; (b) NaH,
BOM-Cl, DMF, room temp., 1 h; (c) K2CO3, MeOH, room temp.,
2 h.
Thus, thymine was selectively protected by the Boc group O2-alkylation, the 3,5-dimethylbenzoyl counterpart showed
at the N1-atom by reaction with di-tert-butyl dicarbonate a strong preference for the N1-product. Although the
(Boc2O) in acetonitrile with DMAP as a catalyst. N1-Pro- reason for this detrimental effect remains unclear, this offers
Eur. J. Org. Chem. 2006, 941–946
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O. R. Ludek, C. Meier
FULL PAPER
Scheme 4. Application of the N3-BOM method to the synthesis of carba-dT. (a) PPh3, DIAD, N3-(benzyloxymethyl)thymine (8f),
CH3CN, –40 °C to room temp., 16 h.
an elegant and selective access to the O2-analogues of car-
bocyclic pyrimidine nucleosides.
ton-decoupled mode. Mass spectra were obtained with a VG Ana-
lytical VG/70-250 F spectrometer (FAB, m-nitrobenzyl alcohol as
matrix).
To verify and use the above observations, enantiomer-
ically pure (1S,3S,4R)-3-(benzyloxy)-4-(benzyloxymethyl)-
cyclopentanol (6α), a precursor for carbocyclic 2Ј-deoxynu-
cleoside analogues, was condensed to N3-(benzyloxymeth-
yl)thymine (8f) in CH3CN according to our modified Mit-
sunobu protocol (Scheme 4).
General Procedure for the Benzoylation of Thymine: A stirred sus-
pension of thymine (1.0 equiv.) in CH3CN and pyridine (4.5 equiv.)
was slowly treated with benzoyl chloride (2.1 equiv.) at 0 °C under
nitrogen and stirred at room temperature for 2 d. Methanol was
added to the mixture (0.1 mL/mmol of benzoyl chloride) and stir-
ring was continued at room temperature for 1 h. Volatiles were
evaporated in vacuo and the crude was reconcentrated three times
from toluene. The residue was purified on silica gel (CH2Cl2/
MeOH, 20:1) to yield the N3-benzoylated thymine derivatives 8b–
e as colourless solids.
The products were isolated as a mixture of N1/O2-iso-
mers in a 85:15 ratio The ratio is noticeably better than the
ratio observed when N-Bz-thymine was used (66:34 in
THF). Consequently, N3-BOM-thymine should be used as
nucleophile, when alkylation at the N1-position of thymine
is wanted. The fully blocked intermediate 13 was depro-
tected in one step by hydrogenolysis in ethanol leading to
enantiomerically pure carba-dT (14), a useful starting mate-
rial for 3Ј-modified carbocyclic nucleosides.[12] The second
important result from our study is that by using (2,6-di-
methylbenzoyl)thymine O2-analogues of carbocyclic pyr-
imidine nucleosides are exclusively available. Thus, with the
help of the protecting group the reaction can be fine-tuned
to yield the N1- or the O2-analogues.
N3-(3,5-Dimethylbenzoyl)thymine (8b): The reaction was carried
out according to the described general procedure with thymine
(1.00 g, 7.93 mmol) in anhydrous CH3CN (12 mL), pyridine
(4.0 mL), 3,5-dimethylbenzoyl chloride (2.90 g, 17.4 mmol) and
MeOH (1.5 mL). Yield: 1.40 g (69%); m.p. 250–252 °C; Rf (TLC)
= 0.30 (CH2Cl2/MeOH, 30:1). 1H NMR (400 MHz, [D6]DMSO):
4
δ = 11.35 (br. s, 1 H, NH); 7.57 (s, 2 H, CH-arom.-o); 7.55 (q, J
= 1.0 Hz, 1 H, 6-H); 7.43 (s, 1 H, CH-arom.-p); 2.38 (s, 6 H, 3,5-
4
CH3); 1.85 (d, J = 1.0 Hz, 3 H, 7-H) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 170.6 (Ph–CO); 163.3 (C-4); 150.3 (C-2); 139.2
(6-C); 139.0 (C-1 arom.); 137.1 (C-4 arom.); 131.9 (C-3 arom.);
128.1 (C-2 arom.); 108.2 (C-5); 20.9 (3-CH3); 12.1 (C-7) ppm. IR
(KBr): ν = 3215, 3170, 2960, 2925, 1740, 1715, 1650, 1485, 1410,
˜
Experimental Section
1380, 1300, 1220, 1180, 1160, 1045, 860, 805, 780, 750, 725, 675,
575, 480 cm–1. MS-FAB: m/z calcd. for C14H15N2O3 [M + H]+
259.1; found 259.2.
General: All experiments involving water-sensitive compounds were
conducted under scrupulously dry conditions (nitrogen) using stan-
dard syringe, cannula and septum techniques. Solvents: THF was
distilled from sodium or potassium/benzophenone and stored over
molecular sieves. Dichloromethane and CH3CN were distilled from
CaH2 and stored over molecular sieves. Ethyl acetate, dichloro-
methane, and methanol employed in chromatography were distilled
before used. Chromatography: Chromatotron (Harrison Research
7924), silica gel 60Pf (Merck, “gipshaltig”). UV detection at
254 nm. TLC: analytical thin layer chromatography was performed
on Merck precoated aluminium plates 60 F254 with a 0.2-mm layer
of silica gel containing a fluorescence indicator; sugar-containing
compounds were visualized with the sugar spray reagent (0.5 mL of
4-methoxybenzaldehyde, 9 mL of ethanol, 0.5 mL of concentrated
sulfuric acid, and 0.1 mL of glacial acetic acid) by heating with a
fan or a hot plate. NMR spectra were recorded using Bruker WM
400 at 400 MHz or Bruker AMX 400 at 400 MHz (1H NMR);
Bruker WM 400 at 101 MHz or Bruker AMX 400 at 101 MHz (13C
NMR) (calibration was done in both cases with the solvent); all
1H and 13C NMR chemical shifts (δ) are quoted in parts per million
(ppm) downfield from tetramethylsilane, (CD3)(CD2H)SO being
set at δH = 2.49 ppm as a reference. The spectra were recorded at
room temperature, and all 13C NMR spectra were recorded in pro-
N3-(2,6-Dimethylbenzoyl)thymine (8c): The reaction was carried
out according to the described general procedure with thymine
(750 mg, 5.95 mmol) in anhydrous CH3CN (10 mL), pyridine
(3.0 mL), 2,6-dimethylbenzoyl chloride (2.20 g, 13.0 mmol) and
MeOH (1.0 mL). Yield: 1.11 g (72%); m.p. 183–185 °C; Rf (TLC)
= 0.29 (CH2Cl2/MeOH, 30:1). 1H NMR (400 MHz, [D6]DMSO):
4
δ = 11.60 (br. s, 1 H, NH); 8.22 (q, J = 1.0 Hz, 1 H, 6-H); 7.24 (t,
3J = 7.5 Hz, 1 H, CH-arom.-p); 7.09 (d, 3J = 7.5 Hz, 2 H, CH-
arom.-m); 2.17 (s, 6 H, 2-CH3); 1.94 (d, 4J = 1.0 Hz, 3 H, 7-H)
ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 169.5 (Ph–CO); 164.1
(C-4); 148.6 (C-2); 137.3 (C-1 arom.); 133.1 (C-6); 132.8 (C-2
arom.); 129.1 (C-4 arom.); 127.6 (C-3 arom.); 113.7 (C-5); 19.2 (2,6-
CH ); 12.5 (C-7) ppm. IR (KBr): ν = 3435, 3040, 2840, 1740, 1680,
˜
3
1460, 1420, 1385, 1345, 1270, 1205, 1105, 1080, 945, 890, 785, 760,
625, 585, 540, 430 cm–1. MS-FAB: m/z calcd. for C14H15N2O3 [M
+ H]+ 259.1; found 259.2.
N3-(3,5-Dinitrobenzoyl)thymine (8d): The reaction was carried out
according to the described general procedure with thymine (1.00 g,
7.93 mmol) in anhydrous CH3CN (12 mL), pyridine (4.0 mL), 3,5-
dinitrobenzoyl chloride (4.00 g, 17.4 mmol) and MeOH (1.5 mL).
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Influence of the N3-Protection Group on N1- vs. O2-Alkylation in the Mitsunobu Reaction
FULL PAPER
1
Yield: 650 mg (25%); Rf (TLC) = 0.32 (CH2Cl2/MeOH, 30:1). H
NMR (400 MHz, [D6]DMSO): δ = 11.40 (br. s, 1 H, NH); 8.99 (s,
(THF or CH3CN, 6.0 mL) at –40 °C under nitrogen. The reaction
mixture was slowly warmed to room temperature and stirred over-
night. The solvent was removed from the reaction mixture and an
NaOH solution in MeOH (1%, 15 mL) was added and the mixture
stirred at room temperature overnight. The solution was neutral-
ized by addition of 1  HCl and then concentrated. The crude
product was purified on silica gel (hexanes/EtOAc, 1:2) to yield the
product as a mixture of N1- (11) and O2-isomers (12) as a colour-
less syrup. For 8f the deprotection step was omitted.
4
1 H, CH-arom.); 8.91 (s, 2 H, CH-arom.); 7.54 (q, J = 1.2 Hz, 1
H, 6-H); 1.78 (d, 4J = 1.2 Hz, 3 H, 7-H) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 168.7 (Ph–CO); 164.0 (C-4); 150.3 (C-2); 149.4
(C-3 arom.); 139.6 (C-6); 134.5 (C-1 arom.); 129.7 (C-2 arom.);
124.3 (C-4 arom.); 108.5 (C-5); 12.1 (C-7) ppm.
N3-(4-Chlorobenzoyl)thymine (8e): The reaction was carried out ac-
cording to the described general procedure with thymine (2.00 g,
15.8 mmol) in anhydrous CH3CN (20 mL), pyridine (8.0 mL), 4-
chlorobenzoyl chloride (6.08 g, 34.8 mmol) and MeOH (3.5 mL).
Yield: 3.99 g (95%); m.p. 198–200 °C; Rf (TLC) = 0.35 (CH2Cl2/
Cyclopentylthymine 11: Rf (TLC) = 0.25 (hexanes/EtOAc, 1:2).
1HNMR (400 MHz, [D6]DMSO): δ = 11.20 (br. s, 1 H, NH); 7.56
(q, 4J = 1.2 Hz, 1 H, 6-H); 4.80–4.72 (m, 1 H, 1Ј-H); 2.00–1.90 (m,
1
4
MeOH, 30:1). H NMR (400 MHz, [D6]DMSO): δ = 11.28 (br. s,
2 H, 2Јa-H, 5Јa-H); 1.82 (d, J = 1.2 Hz, 3 H, 7-H); 1.80–1.55 (m,
1 H, NH); 7.96 (d, 3J = 7.5 Hz, 2 H, CH-arom.); 7.65 (d, 3J =
6 H, 2Јb-H-, 5Јb-H-, 3Ј-CH2, 4Ј-CH2) ppm. 13C NMR (101 MHz,
4
7.5 Hz, 2 H, CH-arom.); 7.54 (q, J = 1.0 Hz, 1 H, 6-H); 1.83 (d, [D6]DMSO): δ = 164.2 (C-4); 152.3 (C-2); 137.4 (C-6); 111.2 (C-5);
4J = 1.0 Hz, 3 H, 7-H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ 56.0 (C-1Ј); 32.9 (C-2Ј, C-5Ј); 25.3 (C-3Ј, C-4Ј); 12.8 (C-7) ppm. IR
= 169.8 (Ph–CO); 163.9 (C-4); 150.2 (C-2); 140.8 (C-4 arom.); 139.2 (KBr): ν = 3175, 3040, 2960, 2875, 1690, 1475, 1415, 1370, 1370,
˜
(C-6); 132.4 (C-2 arom., C-6 arom.); 130.6 (C-1 arom.); 129.9 (C- 1320, 1270, 1120, 920, 585, 425 cm–1. HRMS-FAB: m/z calcd. for
3 arom., C-5 arom.); 108.3 (C-5); 12.0 (C-7) ppm. IR (KBr): ν =
C10H15N2O2 [M + H]+ 195.1134; found 195.1131.
˜
3250, 3090, 1750, 1710, 1670, 1590, 1490, 1415, 1400, 1255, 1210,
1090, 970, 850, 835, 770, 480 cm–1. MS-FAB: m/z calcd. for
C12H10ClN2O3 [M + H]+ 265.038; found 265.038.
O2-Cyclopentylthymine (12): Rf (TLC) = 0.35 (hexanes/EtOAc, 1:2).
1HNMR (400 MHz, [D6]DMSO): δ = 12.10 (br. s, 1 H, NH); 7.60
(q, 4J = 1.0 Hz, 1 H, 6-H); 5.38–5.30 (m, 1 H, 1Ј-H); 2.00–1.90 (m,
4
N3-(Benzyloxymethyl)thymine (8f): To a suspension of thymine
2 H, 2Јa-H, 5Јa-H); 1.88 (d, J = 1.0 Hz, 3 H, 7-H); 1.80–1.55 (m,
(2.50 g, 19.8 mmol) and DMAP (25.0 mg) in anhydrous CH3CN 6 H, 2Јb-H, 5Јb-H, 3Ј-CH2, 4Ј-CH2) ppm. 13C NMR (101 MHz,
(100 mL) was added di-tert-butyl dicarbonate (Boc2O, 4.50 g,
20.6 mmol) at 0 °C under nitrogen. The mixture was warmed to
room temperature and stirred for 4 h, until conversion was com-
plete according to TLC. The solvent was evaporated under reduced
pressure and the residue was dissolved in DMF (100 mL) and co-
oled to 0 °C. Sodium hydride (1.15 g, 24.0 mmol, 50% in oil) was
added in portions and the mixture was stirred at 0 °C under nitro-
gen for 0.5 h. For the alkylation, benzyl chloromethyl ether (BOM-
Cl, 3.3 mL, 24 mmol) was added at 0 °C. The mixture was slowly
warmed to room temperature, stirred for 1 h and poured into ice-
cold water (200 mL). The aqueous phase was extracted with EtOAc
(3×100 mL) and the combined organic phases were dried with
Na2SO4 and concentrated. The crude mixture was dissolved in
methanol (200 mL) and K2CO3 (1.00 g, 7.24 mmol) was added. Af-
ter stirring at room temperature for 2 h, the reaction was complete
according to TLC. The solvent was evaporated in vacuo and the
residue was dissolved in CH2Cl2 (200 mL) and washed with satd.
aqueous NH4Cl solution. The organic phase was dried with
Na2SO4 and concentrated under reduced pressure. The crude mix-
ture was purified by chromatography on silica gel (CH2Cl2/MeOH,
20:1) to yield the title compound 8f (3.10 g, 64%) as a colourless
solid; m.p. 127 °C; Rf (TLC) = 0.35 (CH2Cl2/MeOH, 30:1). 1H
NMR (400 MHz, [D6]DMSO): δ = 11.25 (br. s, 1 H, NH); 7.45–
7.35 (m, 6 H, CH-arom., 6-H); 5.52 (s, 2 H, O–CH2–N); 4.70 (s, 2
[D6]DMSO): δ = 164.2 (C-4); 157.1 (C-2); 151.4 (C-6); 118.4 (C-5);
80.1 (C-1Ј); 33.7 (C-2Ј, C-5Ј); 24.9 (C-3Ј, C-4Ј); 12.9 (C-7) ppm. IR
(KBr): ν = 2960, 1650, 1580, 1500, 1380, 1330, 1160, 1040, 955,
˜
920, 770, 750, 590 cm–1. HRMS-FAB: m/z calcd. for C10H15N2O2
[M + H]+ 195.1134; found 195.1128.
1-(6Ј-Carba-2Ј-deoxy-β-D-erythro-pentofuranosyl)thymine (carba-
dT) (14): The reaction was carried out according to the general
procedure with triphenylphosphane (787 mg, 3.00 mmol) in anhy-
drous CH3CN (11 mL), DIAD (545 µL, 2.80 mmol), cyclopentanol
6α (312 mg, 1.00 mmol) and N3-BOM-thymine (8f) (542 mg,
2.20 mmol) in anhydrous CH3CN (6.0 mL). After removal of the
solvent, the crude mixture was purified on silica gel (hexanes/
EtOAc, 1:1) to yield the protected carbocyclic nucleoside 13
(405 mg, 75%) as a light yellow syrup; Rf (TLC) = 0.66 (hexanes/
EtOAc, 1:2). 1H NMR (400 MHz, CDCl3): δ = 7.33–7.20 (m, 15
H, CH-arom.); 6.97 (q, 4J = 1.0 Hz, 1 H, 6-H); 5.43 (s, 2 H, O–
CH2–N); 5.13–5.05 (m, 1 H, 1Ј-H); 4.64 (s, 2 H, CH2-benzyl); 4.48–
4.38 (m, 4 H, CH2-benzyl, CH2-benzyl-C); 3.95–3.90 (m, 1 H, 3Ј-
H); 3.52 (dd, 3J = 9.2 Hz, 4.3 Hz, 1 H, 5Јa-H); 3.47 (dd, 3J =
9.2 Hz, 4.7 Hz, 1 H, 5Јb-H); 2.36–2.30 (m, 1 H, 4Ј-H); 2.27–2.20
(m, 1 H, 6Јa-H); 2.13–2.08 (m, 1 H, 2Јa-H); 1.89–1.80 (m, 1 H, 2Јb-
H); 1.73 (d, 4J = 1.0 Hz, 3 H, 7-H); 1.57–1.52 (m, 1 H, 6Јb-H)
ppm. The benzylated nucleoside 13 was subsequently dissolved in
EtOH (25 mL) and Pd/C (10%, 50 mg) was added. This mixture
was stirred under hydrogen at room temperature until complete
conversion was observed by TLC. The reaction mixture was filtered
through Celite and washed with MeOH. The filtrate was concen-
trated and the residue was purified by chromatography on a chro-
matotron (CH2Cl2/MeOH gradient 0–20%) to yield the carbocyclic
nucleoside 14 (145 mg, 81%) as colourless foam. After lyophiliza-
tion (CH3CN/H2O, 1:1) the target compound 14 was obtained as
4
H, CH2-benzyl); 1.88 (d, J = 1.2 Hz, 3 H, 7-H) ppm. 13C NMR
(101 MHz, [D6]DMSO): δ = 164.2 (C-4); 151.8 (C-2); 138.5 (Cq
arom.); 137.5 (C-6); 128.5, 127.8, 127.7 (CH-arom.); 107.7 (C-5);
71.3 (O–CH –N); 69.8 (CH -benzyl); 12.7 (C-7) ppm. IR (KBr): ν
˜
2
2
= 3220, 3175, 3060, 2930, 1725, 1650, 1585, 1500, 1450, 1380, 1230,
1130, 1110, 1080, 950, 805, 770, 730, 710, 695, 560, 470, 430 cm–1.
MS-FAB: m/z calcd. for C13H15N2O3 [M + H]+ 247.1; found 247.2.
General Procedure for the Coupling of N3-Protected Pyrimidines to colourless solid; Rf (TLC) = 0.12 (CH2Cl2/MeOH, 9:1); [α]2D0 = +7.5
Cyclopentanols: To a suspension of triphenylphosphane (787 mg,
3.00 mmol) in dry solvent (THF or CH3CN, 11 mL), diisopropyl
azodicarboxylate (DIAD, 545 µL, 2.80 mmol) was added slowly
and the solution was stirred at 0 °C for 0.5 h. This preformed com-
plex was slowly added to a suspension of the protected thymine 8a–
f (2.2 mmol) and cyclopentanol (312 mg, 1.00 mmol) in dry solvent
(c = 0.37, H2O) {ref.[5] [α]2D0 = +8.9 (c = 1.0, methanol)}. 1H NMR
(400 MHz, [D6]DMSO): δ = 11.20 (s, 1 H, NH); 7.57 (q, 4J =
3
1.0 Hz, 1 H, 6-H); 5.02–4.96 (m, 1 H, 1Ј-H); 4.73 (d, J = 4.5 Hz,
3
1 H, 3Ј-OH); 4.61 (t, J = 5.2 Hz, 1 H, 5Ј-OH); 4.03–3.98 (m, 1 H,
3
3Ј-H); 3.53 (ddd, 1 H, 2J = 10.6 Hz, J = 5.5 Hz, 5.2 Hz, 1 H, 5Јa-
H); 3.43 (ddd, 2J = 10.6 Hz, 3J = 5.7 Hz, 5.2 Hz, 1 H, 5Јb-H); 2.11–
Eur. J. Org. Chem. 2006, 941–946
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
945

O. R. Ludek, C. Meier
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Received: October 14, 2005
Published Online: December 13, 2005
946
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 941–946