Synthesis of 6-substituted 2(1H)-pyridon-3-yl C-2′- deoxyribonucleosides

Article abstract of DOI:10.1002/ejoc.201101662

Two approaches to the synthesis of the title 6-substituted 2(1H)-pyridon-3-yl C-2′-deoxyribonucleosides have been pursued. A protected 6-aminopyridine C-nucleoside intermediate was converted into the N-oxide followed by Ac₂O-mediated rearrangement and final deprotection to give 6-acetylamino-2-oxo(1H)-pyridin-3-yl deoxyribonucleoside. Due to the unusually high stability of the N-acetyl group, the full deprotection was unsuccessful. In the second approach, 6-chloro-2-pyridone was converted into phosphorodiamidate, which underwent ortho-magnesiation and iodination to give the 3-iododerivative. It was then used in a Heck coupling with a sugar glycal and the resulting product deprotected to give 6-chloro-2-oxo(1H)-pyridin- 3-yl deoxyribonucleoside, which was either directly or after reprotection converted into 6-methyl-, 6-amino-, and 6-unsubstituted pyridone C-nucleosides. The final nucleosides were very unstable and easily epimerized and/or oxidized, which limits (but not excludes) their further use in chemical biology.

Full text of DOI:10.1002/ejoc.201101662

FULL PAPER
DOI: 10.1002/ejoc.201101662
Synthesis of 6-Substituted 2(1H)-Pyridon-3-yl C-2Ј-Deoxyribonucleosides
[a]
[a]
[a]
[a]
ˇ
Hubert Chapuis, Tomás Kubelka, Nicolas Joubert, Radek Pohl, and
Michal Hocek*[a,b]
Keywords: C-Nucleosides / Nitrogen heterocycles / Magnesiation / Heck reaction / DNA
Two approaches to the synthesis of the title 6-substituted
which underwent ortho-magnesiation and iodination to give
2(1H)-pyridon-3-yl C-2Ј-deoxyribonucleosides have been
the 3-iododerivative. It was then used in a Heck coupling
pursued. A protected 6-aminopyridine C-nucleoside interme- with a sugar glycal and the resulting product deprotected
diate was converted into the N-oxide followed by Ac2O-me-
diated rearrangement and final deprotection to give 6-acet-
ylamino-2-oxo(1H)-pyridin-3-yl deoxyribonucleoside. Due to
the unusually high stability of the N-acetyl group, the full
deprotection was unsuccessful. In the second approach, 6-
chloro-2-pyridone was converted into phosphorodiamidate,
to give 6-chloro-2-oxo(1H)-pyridin-3-yl deoxyribonucleoside,
which was either directly or after reprotection converted into
6-methyl-, 6-amino-, and 6-unsubstituted pyridone C-nucleo-
sides. The final nucleosides were very unstable and easily
epimerized and/or oxidized, which limits (but not excludes)
their further use in chemical biology.
common intermediate. In most of the previous cases, this
method was applied[6,7] for the synthesis of substituted heta-
ryl C-nucleosides lacking the minor-groove functionality.
Therefore, we set up to develop the synthesis of the title 6-
substituted 2-oxo(1H)-pyridin-3-yl deoxyribonucleosides as
direct 1-carba-analogues of natural deoxycytidine or thymi-
dine nucleosides with a retained minor-groove oxo group
but with an altered H-bonding pattern with the comple-
mentary nucleobase (Figure 1). This class of 2Ј-deoxyribo
was assumed by Benner et al.[9] to be configurationally un-
stable and oxidizable, and therefore, they were replaced[9]
Introduction
C-Nucleosides are an important class of stable analogues
of natural nucleosides with diverse biological activities and
applications in chemical biology.[1] Hetaryl-C-2Ј-deoxy-
ribonucleosides have attracted prominent attention as can-
didates for novel base-pairs in the quest for extension of the
genetic alphabet[2] and some of their artificial base-pairs
were efficiently and selectively replicated by DNA polymer-
ases.[3] Particularly important is the presence of an H-ac-
ceptor group (typically oxo or methoxy) in the minor
groove,[3] which stabilizes the active site of the polymerase
and facilitates extension of the growing DNA chain. In ad-
dition, some pyridine C-nucleosides (as triphosphates or in-
corporated to oligonucleotides) have been used as probes
for studying the mechanism of DNA polymerases and
primases,[4] where again a significant effect of the minor-
groove H-bonding was confirmed.
There are numerous approaches[1,5] to the synthesis of C-
nucleosides, but none of them is general and many suffer
from moderate efficiency and/or stereoselectivity. We have
developed[6–8] a modular approach based on the synthesis
of halo-hetaryl C-nucleoside intermediates and their follow-
up functionalization by cross-couplings, aminations, and
other reactions to prepare a series of derivatives from each
[a] Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic
Gilead Sciences & IOCB Research Center
Flemingovo nam. 2, 16610 Prague 6, Czech Republic
Fax: +420-220-183-559
E-mail: hocek@uochb.cas.cz
Homepage: http://www.uochb.cas.cz/hocekgroup
[b] Department of Organic and Nuclear Chemistry,
Faculty of Science, Charles University in Prague
Hlavova 8, 12843 Prague 2, Czech Republic
Figure 1. Structures and H-bonding patterns of natural pyrimidine
and title pyridone C-nucleosides.
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H. Chapuis, T. Kubelka, N. Joubert, R. Pohl, M. Hocek
FULL PAPER
by the corresponding 5-aza- or 5-nitro-derivatives in their oxy group at the 2-position of the pyridine to give triacetyl
base-pairing studies. On the other hand, in the ribo-series, pyridone 8. Piccirilli et al.[10b] reported successful cleavage
several derivatives were prepared[10] and successfully incor- of analogous N-acetyl group from 1-deazacytidine-contain-
porated into RNA.
ing oligoribonucleotides by treatment with methanolic am-
monia in a sealed tube at 55 °C, but the product was only
confirmed by MALDI-MS. In our hands, the use of harsher
conditions led to the degradation of the rather labile nucleo-
side, and therefore, we were unable to prepare the desired
free 1-deaza-2Ј-deoxycytidine by this approach.
Results and Discussion
Two approaches were envisaged for the synthesis of the
desired title pyridone C-nucleosides (Scheme 1). The first
approach (A) was based on conversion of the known 6-
aminopyridine nucleoside into the protected N-oxide fol-
lowed by rearrangement and deprotection. The second ap-
proach (B) consisted in the ortho-lithiation of suitably acti-
vated 6-chloropyridone followed by iodination and Heck
coupling with a glycal.
Scheme 2. Attempted synthesis of the title nucleosides by ap-
proach A. Reagents and conditions: (i) Ac2O, Py, r.t., 16 h, 83%;
(ii) mCPBA, CH2Cl2, r.t., 18 h, 95%; (iii) Ac2O, 60 °C, 40 min,
72%; (iv) MeONa, MeOH, r.t. 2 h, 92%; (v) ZnBr2, CHCl3/MeOH,
r.t., 17 h, 84%.
Scheme 1. Retrosynthetic analysis of the two approaches to the syn-
thesis of the title nucleosides.
Approach A started by the synthesis of previously re-
ported[7] 6-aminopyridin-3-yl C-nucleoside 3 from chloro-
The second approach was envisaged based on the C-gly-
pyridine intermediate 1 by Pd-catalyzed Hartwig amin- cosidation of 6-halopyridin-2-one at the 3-position. An ob-
ation[11] with lithium bis(trimethylsilyl)amide followed by vious starting compound would be 6-chloro-3-iodo-2(1H)-
desilylation of the resulting aminopyridine nucleoside 2 pyridone, which surprisingly was not known in the litera-
(Scheme 2). Acetylation of 3 with Ac2O in pyridine gave ture. We attempted its synthesis through iodination of 6-
peracetylated derivative 4 in 83% yield, which was further chloropyridone (9) by using NIS,[13] but the reaction gave a
converted into N-oxide 5 by treatment with mCPBA in complex inseparable mixture of iodinated products. There-
dichloromethane in 95% yield. Rearrangement[10] of pyr- fore, we attempted the ortho-directed metalation concept.[14]
idineoxide 5 into acetoxypyridine 6 was performed by heat- After some unsuccessful attempts to ortho-lithiate the corre-
ing with Ac2O at 100 °C in 60% yield. Full deprotection sponding carbamates derived from 9, we turned our atten-
of peracetylated nucleoside 6 was attempted under diverse tion to the phosphorodiamidate directing group.[15] Pyr-
conditions to obtain the desired free 1-deaza-2Ј-deoxycytid- idone 9 was converted into phosphorodiamidate 10, which
ine. Classical deacylation procedures, that is, NaOMe in was then used for ortho-metalations (Scheme 3). The corre-
MeOH or methanolic ammonia cleaved all the acetyl sponding ortho-lithiation[16] of 10 with BuLi in the presence
groups except for the N6-amide to give N-acylated nucleo- of TMEDA did not work in our hands. However, Knochel
side 7. The unexpected stability of the acetyl group at the magnesiation[15] by treatment of 10 with (tmp)2Mg·LiCl
aminopyridine prompted us to try treatment with ZnBr2, (tmp = 2,2,6,6-tetramethylpiperidine) gave selectively the
which is known[12] to selectively cleave the acetyl group desired metalation of pyridine at the 3-position. The re-
from cytidine even in the presence of acetyl-protection in sulting organometallic intermediate 11 was immediately
the sugar part. However, this reaction only cleaved the acet- treated with an excess amount of iodine to obtain the de-
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Eur. J. Org. Chem. 2012, 1759–1767

Synthesis of 6-Substituted 2(1H)-Pyridon-3-yl C-2Ј-Deoxyribonucleosides
sired 3-iodo-6-chloropyridin-2-yl phosphorodiamidate 12 in
an acceptable 50% yield. The phosphorodiamidate protect-
ing group was cleaved by heating with 1 m NaOH in water/
dioxane to afford chloroiodopyridone 13 in 62% yield.
Scheme 3. Reagents and conditions: (i) ClP(O)[N(CH3)2]2, DMAP,
TEA, THF, 99%; (ii) (tmp)2Mg·2LiCl, THF, 0 °C; (iii) I2, THF,
–40 °C, 50% (from 10); (iv) NaOH, H2O/dioxane, 62%.
The next goal was the development and optimization of
the Heck coupling of deoxyriboglycal 14 with either iodop-
yridone 13 or iodopyridine phosphorodiamidate 12
(Scheme 4). Since any attempts to perform the Heck reac-
tion of chloroiodopyridone 13 with 14 under different con-
ditions using different catalysts failed, we further focused
on the couplings of phosphorodiamidate 12. Its Heck cou-
pling with glycal 14 proceeded smoothly with good conver-
sion (ca. 80%), but the product was a mixture of desired
silylated C-nucleoside 15 (20%) and desilylated oxonucleo-
side 16 (53%). Therefore, the crude mixture of 15 and 16
was directly treated with Et3N·3HF to quantitatively get
Scheme 4. Reagents and conditions: (i) Pd(OAc)2, AsPh3, Ag2CO3,
CHCl3, 70 °C, 12 h, mixture of 15 and 16 (ca. 80%); (ii) Et3N·3HF,
THF, r.t., 12 h, 98% from 15, 73% overall yield from 14; (iii) NaB-
H(OAc)3, acetonitrile, 0 °C, 57%; (iv) 1 m NaOH, 100 °C, 5 d, 40%;
(v) TBDMSCl, imidazole, DMF, r.t., 36 h, 80%; (vi) H2 (1 atm),
Pd/C, Et3N, THF/EtOH/H2O, r.t., 1.5 h, 99%.
pure oxo-derivative 16 (overall yield of 73% from 14). The was isolated in good 70% yield. Hartwig–Buchwald amin-
stereoselective reduction of 16 by NaBH(OAc)3 proceeded ation was performed by using LiN(TMS)2 in the presence
uneventfully giving rise to 2Ј-deoxyribonucleoside interme- of Pd2(dba)3 and 2-(dicyclohexylphosphanyl)biphenyl in
diate 17 in 57% isolated yield. Several methods of either THF at 60 °C to quantitatively convert chloropyridine 19
basic or acidic hydrolysis[15] were tried to remove the O- into aminopyridine nucleoside 22. The Morvan group re-
phosphorodiamidate group, but under mild conditions, the ported[17] the cleavage of phosphoramidates or phosphoro-
reaction did not proceed, and under harsh conditions, it led diamidates by prolonged treatment with Et3N·3HF, and
to decomposition of the labile C-nucleoside system. The we tried to use this reagent for complete deprotection of
best result was obtained by prolonged heating at reflux with silylated phosphorodiamidates 21 and 22. However, in the
1 m NaOH that gave 6-chloro-2-oxopyridin-3-yl C-deoxy- case of the deprotection of methylpyridine 21, desired free
ribonucleoside 18, as the first target derivative, in 40% iso- 6-methylpyridone C-nucleoside 23 was obtained only in a
lated yield (part of the material was decomposed). Chloro- low yield of 20% due to degradation. Limited stability of
pyridone C-nucleoside 18 was easily transformed into 6-un- nucleoside 23 was observed – it slowly epimerized and dark-
substituted pyridone nucleoside 20 in quantitative yield by ened even when stored at –20 °C. Treatment of aminopyr-
hydrogenolysis on Pd/C. For further cross-coupling studies, idine 22 with Et3N·3HF for 24 h led to almost full decom-
chloropyridine phosphorodiamidate nucleoside 17 was also position of the nucleoside and no desired aminopyridone
silylated to protected derivative 19 (80%).
C-nucleoside was isolated.
The silylated chloropyridine phosphorodiamidate inter-
Therefore, we tried an alternative approach based on sil-
mediate was then subjected to cross-coupling reactions with yl-only protection to avoid prolonged treatment of the very
trimethylaluminum and aminations (Scheme 5). The meth- stable phosphorodiamidate with Et3N·3HF. Chloropyr-
ylation of 19 by Me3Al in the presence of Pd(PPh3)4 in idone nucleoside 18 was trisilylated by using TBDMSCl at
THF at room temperature proceeded very slowly, but after both sugar OH groups and at the pyridone oxygen to give
5 d, desired 6-methylpyridine C-nucleoside intermediate 21 intermediate 24 (Scheme 6). This compound underwent Pd-
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H. Chapuis, T. Kubelka, N. Joubert, R. Pohl, M. Hocek
FULL PAPER
side] and its derivatives substituted at the 6-position by H,
Cl, or Me have been studied. The first approach based on
the rearrangement of aminopyridine N-oxide nucleoside
proved to be very laborious and, at the end, did not give
the desired target compound due to difficult deacetylation
of the aminopyridine. The second approach was based on
the ortho-magnesiation and iodination of the phosphorodi-
amidate of 6-chloropyridone and the Heck coupling of the
resulting 3-iodo-6-chloropyridin-2-yl phosphorodiamidate
12 with a glycal. Chloropyridine phosphorodiamidate inter-
mediate 17 was then converted into free chloropyridone nu-
cleoside 18 and 6-unsubstituted pyridone C-nucleoside 20,
which were reasonably stable. Pd-catalyzed cross-coupling
and amination of 19 gave the corresponding 6-methyl and
6-amino intermediates 21 and 22. However, their deprotec-
tion was difficult and gave only a low yield of 6-methylpyrid-
one C-deoxyribonucleoside 23. Because no desired amino-
pyridone nucleoside was isolated from deprotection of 22,
an analogous alternative approach through silyl-only pro-
tected intermediates was pursued. Unfortunately, target 1-
deaza-2Ј-deoxycytidine 26 was extremely unstable.
We can conclude that 6-substituted pyridone C-2Ј-deoxy-
ribonucleosides are extremely challenging compounds with
difficult synthesis and very limited stability. In particular,
the most desired 1-deaza-2Ј-deoxycytidine 26 is insuf-
ficiently stable for any biological testing or any other appli-
cations. The assumption of Benner et al.[9] that this com-
pound might be prone to oxidation and epimerization is
most likely true. On the other hand, our modular ap-
proach[6–8] consisting of the synthesis of a halogenated C-
nucleoside intermediate followed by cross-coupling and de-
protection can at least be applied for the synthesis of the
corresponding pyridone C-2Ј-deoxyribonucleosides substi-
tuted by H, Cl, or Me at the 6-position. These three com-
pounds will be phosphorylated and tested as substrates of
DNA polymerases.
Scheme 5. Reagents and conditions: (i) Me3Al, Pd(PPh3)4, THF,
r.t., 5 d, 70%; (ii) LiN(TMS)2, Pd2(dba)3, cyclohexyl johnPhos,
THF, 60 °C, 24 h, 98%; (iii) Et3N·3HF, THF, r.t., 24 h, 20% of 23;
degradation in case of reaction of 22.
catalyzed amination with LiN(TMS)2 in excellent yield to
give silylated aminopyridine nucleoside 25. Its desilylation
was achieved by treatment with Et3N·3HF at room tem-
perature for 12 h followed by immediate isolation of the
product by cation exchanger followed by semipreparative
RP-HPLC. Desired aminopyridone C-2Ј-deoxyribonucleo-
side 26 was found to be very unstable and degraded even
during isolation. These difficulties allowed us to obtain only
17% of this precious target derivative, which quickly de-
composed after characterization.
Experimental Section
1β-(6-Acetamidopyridin-3-yl)-1,2-dideoxy-3,5-di-O-acetyl-D-ribofur-
anose (4): Compound 3 (212 mg, 1 mmol) was dissolved in a mix-
ture of acetic anhydride (1.9 mL, 20 mmol) and pyridine (4.4 mL)
and stirred for 16 h. Then the reaction mixture was cooled down
(ice bath), MeOH (6.6 mL) was added, the reaction mixture was
stirred for 15 min, and then the solvents were evaporated and co-
evaporated with toluene (3ϫ). Then water (300 mL) and EtOAc
(50 mL) were added, and the aqueous phase was extracted with
EtOAc (3ϫ50 mL). The organic phase was dried with MgSO4, fil-
tered, and concentrated. The crude product was chromatographed
on silica gel (chloroform to 5% methanol in chloroform) to give
pure 4 (281 mg, 83%) as a colorless oil. MS (EI+): m/z = 336
[M]+. HRMS (EI): calcd. for C16H20N2O6 [M]+ 336.1321; found
Scheme 6. Reagents and conditions: (i) TBDMSCl (10 equiv.),
DMAP, Py, r.t., 24 h, 37%; (ii) LiN(TMS)2, Pd2(dba)3, cyclohexyl
JohnPhos, THF, 60 °C, 24 h, 90%; (iii) Et3N·3HF, THF, r.t., 12 h,
ca. 17%, very unstable compound that decomposed during isola-
tion.
336.1328. 1H NMR (500 MHz, CDCl3): δ = 2.05 (ddd, J2Јb,1Ј
=
11.0 Hz, J2Јb,3Ј = 6.2 Hz, Jgem = 13.8 Hz, 1 H, 2Ј-Hb), 2.10 and
2.13 (2 s, 6 H, 2 CH3COO), 2.21 (s, 3 H, CH3CON), 2.35 (ddd,
J2Јa,1Ј = 5.1 Hz, J2Јa,3Ј = 1.1 Hz, Jgem = 13.8 Hz, 1 H, 2Ј-Ha), 4.24
(ddd, J4Ј,3Ј = 2.1 Hz, J4Ј,5Ј = 4.5 Hz, 3.7 Hz, 1 H, 4Ј-H), 4.26 (dd,
Conclusions
Two approaches to the synthesis of 1-deaza-2Ј-deoxycyt-
J5Јb,4Ј = 4.5 Hz, Jgem = 11.4 Hz, 1 H, 5Ј-Hb), 4.37 (dd, J5Јa,4Ј
=
idine [6-amino-2-oxo(1H)pyridin-3-yl 2Ј-deoxyribonucleo- 3.7 Hz, Jgem = 11.4 Hz, 1 H, 5Ј-Ha), 5.09 (dd, J1Ј,2Ј = 11.0, 5.1 Hz,
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Synthesis of 6-Substituted 2(1H)-Pyridon-3-yl C-2Ј-Deoxyribonucleosides
1 H, 1Ј-H), 5.24 (m, J3Ј,2Ј = 6.1, 1.1 Hz, J3Ј,4Ј = 2.1, J3Ј,1Ј = 0.6 Hz,
1 H, 3Ј-H), 7.69 (ddd, J4,3 = 8.6 Hz, J4,6 = 2.4 Hz, J4,1Ј = 0.6 Hz,
1 H, 4-H), 8.02 (br. s, 1 H, NH), 8.19 (br. d, J3,4 = 8.6 Hz, 1 H, 3-
H), 8.24 (dt, J6,4 = 2.4 Hz, J6,3 = J6,1Ј = 0.6 Hz, 1 H, 6-H) ppm.
13C NMR (125.7 MHz, CDCl3): δ = 20.83 and 21.05 (CH3COO),
24.74 (CH3CON), 41.07 (CH2-2Ј), 64.30 (CH2-5Ј), 76.49 (CH-3Ј),
78.24 (CH-1Ј), 82.75 (CH-4Ј), 113.61 (CH-3), 131.93 (C-5), 136.21
(CH-4), 145.71 (CH-6), 151.10 (C-2), 168.56 (CON), 170.51 and
2), 170.46 and 170.62 (COO) ppm. IR (CHCl ): ν = 3420, 1767,
˜
3
1741, 1707, 1613, 1586, 1512, 1434, 1370, 1234, 1058, 1031,
606 cm–1.
1β-(6-Acetamido-2-hydroxypyridin-3-yl)-1,2-dideoxy-D-ribofuranose
(7): Compound 6 (91 mg, 0.23 mmol) was dissolved in MeOH
(3 mL), then MeONa (63 mg, 1.15 mmol) was added, and the reac-
tion mixture was stirred for 2 h. Then the solvents were evaporated,
and the crude product was absorbed on silica gel and chromato-
graphed (chloroform to 30% methanol in chloroform) to give 7
(57 mg, 92%) as a white foam. MS (ESI+): m/z = 291 [M + 23].
HRMS (ESI): calcd. for C12H16O5N2Na [M] 291.0951; found
170.64 (COO) ppm. IR (CHCl ): ν = 3419, 3354, 1740, 1702, 1606,
˜
3
1588, 1511, 1434, 1407, 1369, 1237, 1055, 1026, 948, 606 cm–1.
1β-(2-Acetamidopyridin-1-oxide-5-yl)-1,2-dideoxy-3,5-di-O-acetyl-
291.0952. 1H NMR (500 MHz, CD3OD): δ = 2.00 (ddd, Jgem
=
D
-ribofuranose (5): Compound 4 (147 mg, 0.44 mmol) was dis-
solved in dichloromethane (8.8 mL) and then mCPBA (151 mg,
0.66 mmol) was added, and the reaction mixture was stirred for
18 h. Then the reaction mixture was poured into a saturated
Na2S2O3 solution (200 mL), and the aqueous phase was extracted
with dichloromethane (3 ϫ 60 mL). The organic phases were
washed with saturated Na2S2O3 solution (2ϫ30 mL), dried with
MgSO4, filtered, and concentrated to obtain crude product 5
(146 mg, 95%) as a colorless oil, which was used directly for the
next step without further purification. MS (ESI): m/z = 375 [M +
23], 353 [M + 1]. HRMS (ESI): calcd. for C16H21N2O7 [M + H]
13.1 Hz, J2Јa,1Ј = 10.2 Hz, J2Јa,3Ј = 6.0 Hz, 1 H, 2Ј-Ha), 2.16 (s, 3 H,
CH3), 2.23 (ddd, Jgem = 13.1 Hz, J2Јb,1Ј = 5.8, Hz J2Јb,3Ј = 1.9 Hz, 1
H, 2Ј-Hb), 3.63 (dd, Jgem = 11.8 Hz, J5Јa,4Ј = 4.5 Hz, 1 H, 5Ј-Ha),
3.68 (dd, Jgem = 11.8 Hz, J5Јb,4Ј = 4.1 Hz, 1 H, 5Ј-Hb), 3.92 (td,
J4Ј,5Јa = J4Ј,5Јb = 4.3 Hz, J4Ј,3Ј = 2.5 Hz, 1 H, 4Ј-H), 4.30 (br. dt,
J3Ј,2Јa = 6.0 Hz, J3Ј,4Ј = J3Ј,2Јb = 2.2 Hz, 1 H, 3Ј-H), 5.12 (br. dd,
J1Ј,2Јa = 10.2 Hz, J1Ј,2Јb = 5.8 Hz, 1 H, 1Ј-H), 6.00 (br. m, 1 H, 5-
H), 7.69 (dd, J4,5 = 7.7 Hz, J4,1Ј = 0.8 Hz, 1 H, 4-H) ppm. 13C
NMR (125.7 MHz, CD3OD): δ = 23.82 (CH3), 41.99 (CH2-2Ј),
64.10 (CH2-5Ј), 74.59 (CH-3Ј), 77.86 (CH-1Ј), 88.85 (CH-4Ј), 94.16
(CH-5), 125.73 (C-3), 140.75 (CH-4), 144.46 (C-6), 161.73 (C-2),
1
353.1329; found 353.1343. H NMR (500 MHz, CDCl3): δ = 2.01
(ddd, Jgem = 13.7 Hz, J2Јb,1Ј = 10.8 Hz, J2Јb,3Ј = 6.2 Hz, 1 H, 2Ј-
Hb), 2.10 and 2.12 (2 s, 2 ϫ 3 H, CH3COO), 2.31 (s, 3 H,
173.81 (CO) ppm. IR (CHCl ): ν = 3236, 2926, 1647, 1577, 1475,
˜
3
1373, 1274, 1221, 1166, 1084, 1035, 997, 937 cm–1.
CH3CON), 2.39 (ddd, Jgem = 13.7 Hz, J2Јa,1Ј = 5.2 Hz, J2Јa,3Ј
1.1 Hz, 1 H, 2Ј-Ha), 4.24–4.36 (m, 3 H, 4Ј,5Ј-H), 5.05 (dd, J1Ј,2Ј
=
=
1β-[6-Acetamido-2-oxo(1H)pyridin-3-yl]-1,2-dideoxy-3,5-di-O-acet-
yl-D-ribofuranose (8): Compound 6 (25 mg, 0.06 mmol) was dis-
10.8, 5.2 Hz, 1 H, 1Ј-H), 5.22 (m, J3Ј,2Ј = 6.2, 1.1 Hz, J3Ј,4Ј = 1.9,
J3Ј,1Ј = 0.6 Hz, 1 H, 3Ј-H), 7.28 (ddd, J4,3 = 8.7 Hz, J4,6 = 2.0 Hz,
1 H, 4-H), 8.30 (ddd, J6,4 = 2.0 Hz, J6,1Ј = 0.6 Hz, J6,3 = 0.4 Hz, 1
H, 6-H), 8.41 (dd, J3,4 = 8.7 Hz, J3,6 = 0.4 Hz, 1 H, 3-H), 9.95 (br.
s, 1 H, NH) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 20.82 and
21.00 (CH3COO), 24.94 (CH3CON), 40.94 (CH2-2Ј), 64.10 (CH2-
5Ј), 76.08 (CH-3Ј), 77.24 (CH-1Ј), 82.97 (CH-4Ј), 114.32 (CH-3),
125.65 (CH-4), 132.57 (C-5), 134.74 (CH-6), 143.28 (C-2), 168.77
solved in a mixture of CHCl3/MeOH (1:1, 2 mL), then ZnBr2
(30 mg, 0.12 mmol) was added, and the reaction mixture was
stirred at room temperature for 17 h. Then the solvents were evapo-
rated, and the crude product was chromatographed on silica gel
(chloroform to 2% methanol in chloroform) to give pure 8 (11 mg,
84%) as a colorless oil. MS (ESI): m/z = 375 [M + 23], 353 [M +
1]. HRMS (ESI): calcd. for C16H21N2O7 [M + H] 353.1343; found
353.1346. 1H NMR (500 MHz, CDCl3): δ = 1.92 (ddd, Jgem
=
(CON), 170.40 and 170.55 (COO) ppm. IR (CHCl ): ν = 3288,
˜
3
13.7 Hz, J2Јb,1Ј = 10.6 Hz, J2Јb,3Ј = 6.3 Hz, 1 H, 2Ј-Hb), 2.07 and
2.08 (2 s, 2ϫ3 H, CH3COO), 2.20 (s, 3 H, CH3CON), 2.49 (ddd,
Jgem = 13.7 Hz, J2Јa,1Ј = 5.3 Hz, J2Јa,3Ј = 1.4 Hz, 1 H, 2Ј-Ha), 4.18
(ddd, J4Ј,5Ј = 4.9, 4.0 Hz, J4Ј,3Ј = 2.3 Hz, 1 H, 4Ј-H), 4.22 (dd, Jgem
= 11.4 Hz, J5Јb,4Ј = 4.9 Hz, 1 H, 5Ј-Hb), 4.36 (dd, Jgem = 11.4 Hz,
J5Јa,4Ј = 4.0 Hz, 1 H, 5Ј-Ha), 5.16 (br. dd, J1Ј,2Ј = 10.6, 5.3 Hz, 1
1742, 1617, 1576, 1528, 1476, 1398, 1382, 1366, 1314, 1283, 1101,
1029, 829, 588 cm–1.
1β-(6-Acetamido-2-acetoxypyridin-3-yl)-1,2-dideoxy-3,5-di-O-acet-
yl-D-ribofuranose (6): Compound 5 (371 mg, 1.1 mmol) was dis-
solved in acetic anhydride (15 mL) and then heated at 60 °C for
40 min. Then the reaction mixture was cooled down (ice bath),
MeOH (15 mL) was added, and the reaction mixture was stirred
for 15 min. The solvents were then evaporated and co-evaporated
with MeOH (3ϫ). Then the crude product was absorbed on silica
gel and chromatographed (chloroform to 1% methanol in chloro-
form) to give pure 6 (298 mg, 72%) as a colorless oil. MS (EI+):
m/z = 394 [M]. HRMS (EI): calcd. for C18H22N2O8 [M] 394.1376;
H, 1Ј-H), 5.18 (dddd, J3Ј,2Ј = 6.3, 1.4 Hz, J3Ј,4Ј = 2.3 Hz, J3Ј,1Ј
=
0.6 Hz, 1 H, 3Ј-H), 6.22 (br. d, J5,4 = 7.8 Hz, 1 H, 3-H), 7.54 (dd,
J4,3 = 7.8 Hz, J4,1Ј = 0.9 Hz, 1 H, 4-H), 9.93 (br. s, 1 H, NH) ppm.
13C NMR (125.7 MHz, CDCl3): δ = 20.89 and 21.07 (CH3COO),
24.35 (CH3CON), 38.66 (CH2-2Ј), 64.24 (CH2-5Ј), 75.78 (CH-1Ј),
76.41 (CH-3Ј), 82.80 (CH-4Ј), 93.80 (CH-5), 124.00 (C-3), 138.34
(CH-4), 142.71 (C-6), 160.07 (C-2), 170.66 and 170.82 (COO),
1
found 394.1369. H NMR (500 MHz, CDCl3): δ = 1.97 (ddd, Jgem
171.15 (CON) ppm. IR (CHCl ): ν = 3431, 3242, 1739, 1698, 1611,
˜
3
= 13.8 Hz, J2Јb,1Ј = 10.7 Hz, J2Јb,3Ј = 6.4 Hz, 1 H, 2Ј-Hb), 2.08 and
2.12 (2 s, 2ϫ3 H, CH3COO), 2.18 (s, 3 H, CH3CON), 2.32 (ddd,
Jgem = 13.8 Hz, J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј = 1.3 Hz, 1 H, 2Ј-Ha), 2.24
(s, 3 H, CH3COO-2), 4.21 (ddd, J4Ј,5Ј = 4.6, 3.8 Hz, J4Ј,3Ј = 2.3 Hz,
1580, 1552, 1514, 1434, 1379, 1370, 1322, 1245, 1054, 605 cm–1.
6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}pyridine (10): Com-
pound 9 (2.52 g, 19.5 mmol) and DMAP (259 mg, 2.12 mmol) were
1 H, 4Ј-H), 4.26 (dd, Jgem = 11.7 Hz, J5Јb,4Ј = 4.6 Hz, 1 H, 5Ј-Hb), dissolved in freshly distilled THF (20 mL). Subsequently,
4.38 (dd, Jgem = 11.7 Hz, J5Јa,4Ј = 3.8 Hz, 1 H, 5Ј-Ha), 5.10 (ddq, N,N,NЈ,NЈ-tetramethylphosphorodiamidic chloride (3.9 mL,
J1Ј,2Ј = 10.7, 5.4 Hz, J1Ј,3Ј = J1Ј,4Ј = J1Ј,4 = 0.6 Hz, 1 H, 1Ј-H), 5.21 26.9 mmol) and triethylamine (3.4 mL, 24.4 mmol) were added.
(dddd, J3Ј,2Ј = 6.4, 1.3 Hz, J3Ј,4Ј = 2.3 Hz, J3Ј,1Ј = 0.6 Hz, 1 H, 3Ј-
H), 7.89 (br. s, 1 H, NH), 7.93 (dt, J4,3 = 8.4 Hz, J4,NH = J4,1Ј
0.6 Hz, 1 H, 4-H), 8.15 (br. d, J5,4 = 8.4 Hz, 1 H, 3-H) ppm. 13C
The reaction mixture was then stirred at room temperature for 24 h
and then quenched by pouring onto a saturated ammonium chlor-
ide solution. The compound was extracted with EtOAc
=
NMR (125.7 MHz, CDCl3): δ = 20.80, 21.01 and 21.02 (CH3COO), (3ϫ100 mL), dried with MgSO4, filtered, and concentrated under
24.60 (CH3CON), 39.89 (CH2-2Ј), 64.12 (CH2-5Ј), 74.70 (CH-1Ј), reduced pressure. Product 10 (5.10 g, 99%) was obtained as a color-
76.23 (CH-3Ј), 82.58 (CH-4Ј), 112.33 (CH-5), 123.44 (C-3), 139.20 less oil, which spontaneously crystallized after a few days at 4 °C
(CH-4), 149.43 (C-6), 152.63 (C-2), 168.51 (CON), 168.60 (COO-
to give a brown solid. Rf (dichloromethane/methanol = 90:10) =
Eur. J. Org. Chem. 2012, 1759–1767
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1763

H. Chapuis, T. Kubelka, N. Joubert, R. Pohl, M. Hocek
FULL PAPER
0.53. M.p. 69–75 °C. HRMS (ESI+): calcd. for C9H16ClN3O2P [M
20%) and 16 (34 mg, 53%) in an overall 73% yield. Data for 15:
+ H]: calcd. 264.06632; found 264.06615. 1H NMR (499.8 MHz, R f ( e t hy l a c e t at e ) = 0 . 4 5 . H R M S ( E S I + ) : c a l c d . fo r
CDCl3): δ = 2.68 (d, JH,P = 10.4 Hz, 12 H, CH3), 7.01 (dt, J3,4
=
C20H36ClN3O5PSi [M + H] 492.1850; found 492.1848. HRMS
(ESI+): calcd. for C20H35ClN3O5NaPSi [M + Na] 514.1670; found
514.1668. H NMR (400 MHz, CDCl3): δ = 0.06, 0.20, 0.22 (3 s,
8.0 Hz, J3,5 = JH,P = 0.7 Hz, 1 H, 3-H), 7.05 (dt, J5,4 = 7.7 Hz, J5,3
= JH,P = 0.7 Hz, 1 H, 5-H), 7.58 (ddd, J4,3 = 8.0 Hz, J4,5 = 7.7 Hz,
JH,P = 0.6 Hz, 1 H, 4-H) ppm. 13C NMR (125.7 MHz, CDCl3): δ
1
3ϫ2 H, CH3-Si), 0.93 [s, 9 H, (CH3)3C], 2.78 (2 d, JH,P = 10.8 Hz,
= 36.54 (d, JC,P = 4.0 Hz, CH3), 111.94 (d, JC,P = 4.0 Hz, CH-3), 2ϫ6 H, CH3-N), 3.65 (dd, 2J = 12.0 Hz, 3J = 4.4 Hz, 1 H, 5Ј-Ha),
2
3
120.14 (CH-5), 141.49 (CH-4), 148.90 (C-6), 157.34 (d, JC,P
=
3.76 (dd, J = 12.0 Hz, J = 3.2 Hz, 1 H, 5Ј-Hb), 4.60–4.63 (m, 1
4.4 Hz, C-2) ppm. 31P NMR (202.3 MHz, CDCl3): δ = 16.54 ppm. H, 4Ј-H), 4.96 (t, J = J = 1.6 Hz, 1 H, 2Ј-H), 5.98 (dd, JH1Ј-H2’
4
2
3
4
3
IR (CHCl ): ν = 3091, 3059, 2816, 1581, 1570, 1484, 1457, 1433, = 3.4 Hz, JH1Ј-H4’ = 1.4 Hz, 1 H, 1Ј-H), 7.10 (d, J = 8.0 Hz, 1 H,
˜
3
1413, 1309, 1272, 1232, 1180, 1071, 997, 953, 684 cm–1.
3-H), 7.83 (d, J = 8.0 Hz, 1 H, 4-H) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = –4.94 (CH3-Si), 18.02 [(CH3)3C], 25.54 [(CH3)3C],
36.85 (CH3-N), 63.39 (CH2-5Ј), 78.36 (CH-1Ј), 83.49 (CH-4Ј),
100.02 (CH-2Ј), 120.50 (CH-3), 126.60 (C-5), 139.45 (CH-4),
147.62 (C-6), 151.70 (C-2), 154.55 (C-3Ј) ppm.
3
6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}-3-iodopyridine
(12): Compound 10 (1.5 g, 5.68 mmol) was dissolved in freshly dis-
tilled THF (50 mL). The solution was cooled down to 0 °C and
then a solution of freshly prepared tmp2Mg·2LiCl was added
(0.67 m, 42 mL, 28.14 mmol). The solution was then cooled down
to –40 °C. A solution of I2 in freshly distilled THF (3.3 m, 17 mL,
56.1 mmol) was prepared and added to the reaction mixture at
–40 °C. The reaction proceeded instantaneously and was immedi-
ately quenched with sat. aq. Na2S2O3 (100 mL). The product was
extracted with Et2O (3ϫ100 mL), dried with MgSO4, filtered, and
the solvents were evaporated in vacuo. After purification by flash
chromatography (dichloromethane/methanol, 90:10), 12 (1.1 g,
50%) was obtained as a brownish oil. Rf (dichloromethane/meth-
anol = 90:10) = 0.50. MS (ESI+): m/z = 390 [M + H], 412 [M +
Na], 800.4 [2M + Na]. HRMS (ESI+): calcd. for C9H15ClN3O2IP
[M + H] 389.96296; found 389.96303. 1H NMR (499.8 MHz,
1β-(6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2,3-trideoxy-3-oxo-D-ribofuranose (16): To a dried flask contain-
ing a solution of 15 (689 mg, 1.40 mmol) in dry THF (3.6 mL) at
0 °C under an atmosphere of argon was added Et3N·HF (588 μL,
3.61 mmol). After the disappearance of 15 (typically 5 min, checked
by TLC), the reaction mixture was filtered through a small pad of
silica gel (2 cm) and eluted with EtOAc. The solvents were removed
under vacuum, and the crude product was purified by flash
chromatography (hexane/diethyl ether = 4:1 to diethyl ether/meth-
anol = 9:1). Compound 16 (525 mg, 99%) was then obtained as a
yellowish oil. Alternatively, the same compound was obtained in
73% overall yield by the same desilylation of the crude reaction
mixture after the Heck reaction. Data for 16: Rf (ether/methanol =
90:10) = 0.51. [α]2D0 = +63.9 (c = 0.072, CHCl3). HRMS (ESI+):
calcd. for C14H22ClN3O5P [M + H] 378.0986; found 378.0983.
HRMS (ESI+): calcd. for C14H21ClN3O5NaP [M + Na] 400.0800;
found 400.0800. 1H NMR (600.1 MHz, CDCl3): δ = 2.41 (dd, Jgem
CDCl3): δ = 2.74 (d, JH,P = 10.7 Hz, 12 H, CH3), 6.80 (d, J5,4
8.0 Hz, 1 H, 5-H), 7.93 (dd, J4,5 = 8.0 Hz, JH,P = 1.0 Hz, 1 H, 4-
H) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 36.78 (d, JC,P
=
=
4.0 Hz, CH3), 78.94 (d, JC,P = 7.4 Hz, C-3), 121.26 (CH-5), 148.96
(C-6), 150.41 (CH-4), 157.76 (d, JC,P = 5.3 Hz, C-2) ppm. 31P
= 18.0 Hz, J2Јb,1Ј = 10.8 Hz, 1 H, 2Ј-Hb), 2.74, 2.75 (2 d, JH,P
=
NMR (202.3 MHz, CDCl ): δ = 17.75 ppm. IR (CHCl ): ν = 2817,
˜
3
3
10.6 Hz, 2ϫ6 H, CH3), 2.95 (dd, Jgem = 18.0 Hz, J2Јa,1Ј = 6.1 Hz,
1 H, 2Ј-Ha), 3.88 (dd, Jgem = 12.2 Hz, J5Јb,4Ј = 3.6 Hz, 1 H, 5Ј-Hb),
3.93 (dd, Jgem = 12.2 Hz, J5Јa,4Ј = 3.0 Hz, 1 H, 5Ј-Ha), 4.02 (dd,
J4Ј,5Ј = 3.6, 3.0 Hz, 1 H, 4Ј-H), 5.35 (dd, J1Ј,2Ј = 10.8, 6.1 Hz, 1 H,
1Ј-H), 7.14 (d, J5,4 = 7.9 Hz, 1 H, 5-H), 7.96 (dt, J4,5 = 7.9 Hz, J4,1Ј
= JH,P = 1.0 Hz, 1 H, 4-H) ppm. 13C NMR (150.9 MHz, CDCl3):
δ = 36.72, 36.75 (d, JC,P = 4.2 Hz, CH3), 44.01 (CH2-2Ј), 61.31
(CH2-5Ј), 71.08 (CH-1Ј), 82.35 (CH-4Ј), 120.57 (CH-5), 124.19 (d,
1673, 1630, 1559, 1535, 1483, 1457, 1421, 1401, 1310, 1266, 1231,
1180, 1070, 1004, 995, 946, 684 cm–1.
6-Chloro-3-iodo-2-oxo(1H)pyridine (13): Compound 12 (184 mg,
0.472 mmol) was dissolved in a mixture of 1 m NaOH (3 mL) and
dioxane (5 mL). The reaction mixture was heated to 100 °C for
12 h. Then the mixture was neutralized to pH 7 by addition of 1 m
HCl and extracted with ethyl acetate (3ϫ 20 mL). The organic
phases were collected and dried with sodium sulfate, and the sol-
vents were evaporated to dryness to yield 12 (74 mg, 62%) as a
black oil. Rf (dichloromethane/methanol = 95:5) = 0.10. MS (ESI–
): m/z = 254.0 [M – H]. HRMS (ESI–): calcd. for C5H2ClNOI [M –
H] 253.8875; found 253.8878. HRMS (EI): calcd. for C5H3ClNOI
[M] 254.8948; found 254.8960. 1H NMR (499.8 MHz, CDCl3): δ =
6.51 (d, J = 8.8 Hz, 1 H, 5-H), 7.94 (d, J = 8.8 Hz, 1 H, 4-H) ppm.
JC,P = 5.5 Hz, C-3), 139.06 (CH-4), 148.05 (C-6), 154.20 (d, JC,P
=
6.3 Hz, C-2), 212.97 (C-3Ј) ppm. 31P NMR (202.3 MHz, CDCl3):
δ = 17.47 ppm.
1β-(6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2-dideoxy-D-ribofuranose (17): NaBH(OAc)3 (1.18 g, 5.58 mmol)
was added to a dried flask containing 16 (173 mg, 0.558 mmol)
dissolved in dry acetonitrile (6 mL) at 0 °C. The reaction was in-
stantaneous. It was then quenched by the addition of methanol
(6 mL). After evaporation under reduced pressure a white solid was
obtained, which was further purified by flash chromatography on
silica gel (dichloromethane to dichloromethane/methanol = 90:10).
Pure 17 (120 mg, 57%) was then obtained as a colorless oil. Rf
(dichloromethane/methanol = 95:5) = 0.33. [α]2D0 = +34.1 (c =
0.122, CHCl3). HRMS (ESI+): calcd. for C14H24ClN3O5P [M +
H] 380.1142; found 380.1140. 1H NMR [499.8 MHz, D2O, ref. (di-
oxane) = 3.75 ppm]: δ = 1.98 (ddd, Jgem = 13.6 Hz, J2Јb,1Ј = 10.4 Hz,
IR (CHCl ): ν = 3533, 3300–2300 (br. NH), 1722, 1667, 1650, 1586,
˜
3
1570, 1461, 1440 cm–1.
1β-(6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2-dideoxy-2,3-didehydro-3-O-(tert-butyldimethylsilyl)-D-ribofur-
anose (15): Freshly distilled chloroform (1.3 mL) was added to an
argon purged dry flask containing Pd(OAc)2 (9 mg, 0.04 mmol)
and AsPh3 (23 mg, 0.0752 mmol), and the mixture was stirred at
room temperature for 30 min. Then a solution containing 12
(147 mg, 0.377 mmol) and glycal 14 (39 mg, 0.170 mmol) in freshly
distilled chloroform (1.3 mL) was added. After the final addition
of Ag2CO3 (64 mg, 0.232 mmol), the mixture was heated to 70 °C
for 12 h. The reaction mixture was then cooled down and silica
gel (500 mg) was added before evaporation of the solvents. Then
purification by flash chromatography (hexane/diethyl ether = 4:1
to diethyl ether/methanol = 9:1) gave yellowish oils of 15 (17 mg,
J2Јb,3Ј = 5.8 Hz, 1 H, 2Ј-Hb), 2.40 (ddd, Jgem = 13.6 Hz, J2Јa,1Ј
5.6 Hz, J2Јa,3Ј = 1.9 Hz, 1 H, 2Ј-Ha), 2.738, 2.740 (2 d, JH,P
=
=
2
3
10.7 Hz, 2ϫ6 H, CH3-N), 3.70 (dd, J = 12.2 Hz, J = 5.8 Hz, 1
2
3
H, 5Ј-Ha), 3.76 (dd, J = 12.2 Hz, J = 4.5 Hz, 1 H, 5Ј-Hb), 4.06
(ddd, J4Ј,5Ј = 5.8 and 4.5 Hz, J4Ј,3Ј = 2.5 Hz, 1 H, 4Ј-H), 4.40 (ddd,
J3Ј,2Ј = 5.8 and 1.9 Hz, J3Ј,4Ј = 2.5 Hz, 1 H, 3Ј-H), 5.37 (dd, J1Ј,2Ј
1764
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1759–1767

Synthesis of 6-Substituted 2(1H)-Pyridon-3-yl C-2Ј-Deoxyribonucleosides
= 10.4 and 5.6 Hz, 1 H, 1Ј-H), 7.33 (d, 3J = 8.0 Hz, 1 H, 3-H), 7.99
13C NMR (150.9 MHz, D2O): δ = 42.44 (CH2-2Ј), 64.87 (CH2-5Ј),
75.53 (CH-3Ј), 78.33 (CH-1Ј), 89.43 (CH-4Ј), 111.22 (CH-5), 131.48
3
(dt, J = 8.0 Hz, J4,1Ј = J4,P = 0.8 Hz, 1 H, 4-H) ppm. 13C NMR
[125.7 MHz, D2O, ref. (dioxane) = 69.3 ppm]: δ = 38.60, 38.62
[(CH3)2-NP], 43.80 (CH2-2Ј), 64.78 (CH2-5Ј), 75.38 (CH-3Ј), 76.89
(CH-1Ј), 89.64 (CH-4Ј), 123.93 (CH-5), 127.58 (C-3), 142.07 (CH-
4), 149.60 (C-6), 156.15 (C-2) ppm. 31P NMR [202.3 MHz, D2O,
(C-3), 137.81 (C-6), 141.86 (CH-4), 165.89 (C-2) ppm.
1β-[2-Oxo(1H)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose (20): To a
solution of nucleoside 18 (112 mg, 0.46 mmol) in THF/EtOH/H2O
(10:10:1, 10 mL) at room temperature were added 10 % Pd/C
(66 mg, 0.0893 mmol) and NEt3 (0.26 mL). The flask was filled
with H2 (1 atm) and stirred at room temperature. After the reaction
was complete (1.5 h, checked by TLC), Pd was filtered off. After
evaporation of the filtrate, 20 (95 mg, 99%) was obtained as a yel-
ref. (H PO ) = 0 ppm]: δ = 19.60 ppm. IR (CHCl ): ν = 3611, 3371,
˜
3
4
3
2817, 1588, 1573, 1483, 1436, 1309, 1255, 1230, 1205, 1180, 1078,
1053, 1003, 948, 684, 538 cm–1.
1β-(6-Chloro-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2-dideoxy-3,5-bis[O-(tert-butyldimethylsilyl)]-D-ribofuranose (19):
lowish oil. Rf (dichloromethane/methanol = 90:10) = 0.33. [α]2D0
=
To a dried flask containing a solution of 17 (230 mg, 0.605 mmol)
in dry DMF (28 mL) under an atmosphere of argon was added
imidazole (497 mg, 7.31 mmol) and then TBDMSCl (692 mg,
4.58 mmol). The resulting solution was stirred for 36 h at room
temperature under an atmosphere of argon. The DMF was then
evaporated under vacuum and co-evaporated with toluene. The re-
sulting dark raw oil was then directly chromatographed on silica
gel (hexane/EtOAc = 4:1 to EtOAc). This allowed us to obtain pure
nucleoside 19 (294 mg, 80%) as a yellowish oil. Rf (hexane/ethyl
acetate = 70:30) = 0.37. [α]2D0 = +23.5 (c = 0.034, CHCl3). HRMS
(ESI+): calcd. for C26H52ClN3O5PSi2 [M + H] 608.2866; found
608.2866. HRMS (ESI+): calcd for C26H51ClN3O5NaPSi2 [M +
+19.5 (c = 0.041, H2O). HRMS (ESI+): calcd. for C10H13NO4Na
[M + Na] 234.0737; found 234.0737. H NMR (600.1 MHz, D2O):
δ = 2.05 (ddd, Jgem = 13.7 Hz, J2Јb,1Ј = 10.2 Hz, J2Јb,3Ј = 6.0 Hz, 1
1
H, 2Ј-Hb), 2.34 (ddd, Jgem = 13.7 Hz, J2Јa,1Ј = 5.9 Hz, J2Јa,3Ј
=
2.1 Hz, 1 H, 2Ј-Ha), 3.69 (dd, Jgem = 12.1 Hz, J5Јb,4Ј = 5.3 Hz, 1 H,
5Ј-Hb), 3.75 (dd, Jgem = 12.1 Hz, J5Јa,4Ј = 4.1 Hz, 1 H, 5Ј-Ha), 4.05
(ddd, J4Ј,5Ј = 5.3, 4.1 Hz, J4Ј,3Ј = 2.1 Hz, 1 H, 4Ј-H), 4.40 (dt, J3Ј,2Ј
= 6.0, 2.1 Hz, J3Ј,4Ј = 2.1 Hz, 1 H, 3Ј-H), 5.23 (dd, J1Ј,2Ј = 10.2,
5.9 Hz, 1 H, 1Ј-H), 6.59 (dd, J5,4 = 7.1 Hz, J5,6 = 6.5 Hz, 1 H, 5-
H), 7.50 (dd, J6,5 = 6.5 Hz, J6,4 = 2.0 Hz, 1 H, 6-H), 7.84 (dd, J4,5
= 7.1 Hz, J4,6 = 2.0 Hz, 1 H, 4-H) ppm. 13C NMR (150.9 MHz,
D2O): δ = 42.49 (CH2-2Ј), 64.92 (CH2-5Ј), 75.63 (CH-3Ј), 78.64
(CH-1Ј), 89.43 (CH-4Ј), 111.55 (CH-5), 133.28 (C-3), 136.73 (CH-
1
Na] 630.2686; found 630.2683. H NMR [499.8 MHz, CDCl3, ref.
(dioxane) = 3.75 ppm]: δ = 0.06, 0.07 (2 s, 2ϫ6 H, CH3-Si), 0.88,
6), 141.87 (CH-4), 165.43 (C-2) ppm. IR (KBr): ν = 3431, 1645,
˜
1631, 1610, 1567, 1084, 1049, 775 cm–1.
0.89 [2 s, 2ϫ9 H, (CH3)3C], 1.72 (ddd, Jgem = 12.7 Hz, J2Јb,1Ј
=
10.1 Hz, J2Јb,3Ј = 5.3 Hz, 1 H, 2Ј-Hb), 2.31 (ddd, Jgem = 12.7 Hz,
J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј = 1.9 Hz, 1 H, 2Ј-Ha), 2.76, 2.77 [2 d, JH,P
1β-(6-Methyl-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
1,2-dideoxy-3,5-bis[O-(tert-butyldimethylsilyl)]-D-ribofuranose (21):
A solution of Me3Al (3 mmol) in THF was added dropwise to a
vigorously stirred solution of 19 (428 mg, 0.70 mmol) and Pd(PPh3)
= 10.6 Hz, 2ϫ6 H, (CH3)2N-P], 3.63 (dd, Jgem = 10.7 Hz, J5Јb,4Ј
=
5.4 Hz, 1 H, 5Ј-Hb), 3.75 (dd, Jgem = 10.7 Hz, J5Јa,4Ј = 3.5 Hz, 1
H, 5Ј-Ha), 3.95 (ddd, J4Ј,5Ј = 5.4, 3.5 Hz, J4Ј,3Ј = 1.9 Hz, 1 H, 4Ј-
H), 4.38 (dtd, J3Ј,2Ј = 5.3, 1.9 Hz, J3Ј,4Ј = 1.9 Hz, JH,P = 0.6 Hz, 1
(144 mg, 0.125 mmol) in freshly distilled THF (22 mL). The mix-
4
ture was stirred at room temperature for 5 d and then worked up
with dichloromethane and water. The organic phases were col-
lected, dried with MgSO4, filtered, and concentrated in vacuo. The
crude material was chromatographed on silica gel (ethyl acetate/
hexane = 50:50 to ethyl acetate/hexane = 70:30) to give 21 (290 mg,
70%) as a colorless oil. Rf (ethyl acetate) = 0.37. [α]2D0 = +30.6 (c
= 0.157, CHCl3). HRMS (ESI+): calcd. for C27H55N3O5PSi2 [M +
H, 3Ј-H), 5.34 (ddq, J1Ј,2Ј = 10.1, 5.4 Hz, J1Ј,3Ј = J1Ј,4Ј = JH,P
=
0.6 Hz, 1 H, 1Ј-H), 7.06 (d, J5,4 = 7.9 Hz, 1 H, 5-H), 7.89 (ddd, J4,5
= 7.9 Hz, JH,P = 1.4 Hz, J4,1Ј = 0.6 Hz, 1 H, 4-H) ppm. 13C NMR
[125.7 MHz, CDCl3, ref. (dioxane) = 69.3 ppm]: δ = –5.50, –5.43,
–4.74, –4.72 (CH3-Si), 17.93, 18.31 [(CH3)3C], 25.72, 25.88 [(CH3)3-
C], 36.70, 36.77 [d, JC,P = 3.8 Hz, (CH3)2N-P], 42.92 (CH2-2Ј),
63.59 (CH2-5Ј), 74.11 (CH-1Ј), 74.21 (CH-3Ј), 87.87 (CH-4Ј),
120.08 (CH-5), 126.28 (d, JC,P = 5.9 Hz, C-3), 138.37 (CH-4),
146.85 (C-6), 153.83 (d, JC,P = 6.2 Hz, C-2) ppm. 31P NMR
[202.3 MHz, CDCl3, ref. (H3PO4): δ = 0 ppm]: 17.10 ppm. IR
1
H] 588.3412; found 588.3413. H NMR (600.1 MHz, CDCl3): δ =
0.06, 0.07 (2 s, 12 H, CH3Si), 0.88, 0.89 [2 s, 2ϫ9 H, (CH3)3C],
1.71 (ddd, Jgem = 12.8 Hz, J2Јb,1Ј = 10.2 Hz, J2Јb,3Ј = 5.3 Hz, 1 H,
2Ј-Hb), 2.29 (ddd, Jgem = 12.8 Hz, J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј = 1.9 Hz,
1 H, 2Ј-Ha), 2.44 (s, 3 H, CH3-6), 2.74, 2.76 (2 d, JH,P = 10.5 Hz,
2ϫ6 H, CH3N), 3.60 (dd, Jgem = 10.6 Hz, J5Јb,4Ј = 5.7 Hz, 1 H, 5Ј-
Hb), 3.75 (dd, Jgem = 10.6 Hz, J5Јa,4Ј = 3.7 Hz, 1 H, 5Ј-Ha), 3.94
(ddd, J4Ј,5Ј = 5.7, 3.7 Hz, J4Ј,3Ј = 2.0 Hz, 1 H, 4Ј-H), 4.38 (m, J3Ј,2Ј
(CHCl ): ν = 2956, 2819, 1588, 1574, 1471, 1463, 1438, 1388, 1362,
˜
3
1309, 1257, 1233, 1179, 1085, 1004, 947, 838, 682, 537 cm–1.
1β-[6-Chloro-2-oxo(1H)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose
(18): A solution of nucleoside 17 (440 mg, 1.16 mmol) in 1 m
NaOH (25 mL) was heated to reflux for 5.5 d (monitoring of the
conversion by TLC). Then the reaction was quenched with formic
acid (1 mL). The water was evaporated with the help of ethanol
and toluene co-evaporation. Column chromatography using a RP-
Biotage purification system (water/MeOH) afforded pure 18
(114 mg, 40%) as a colorless oil. Rf (dichloromethane/methanol =
95:5) = 0.33. [α]2D0 = +37.0 (c = 0.054, H2O). MS (ESI–): m/z =
244.2 [M – H]. MS (ESI+): m/z = 246.1 [M + H], 268.1 [M + Na].
HRMS (ESI+): calcd. for C10H13ClNO4 [M + H] 246.05276; found
4
= 5.3, 1.9 Hz, J3Ј,4Ј = 2.0, J = 0.5 Hz, 1 H, 3Ј-H), 5.36 (dd, J1Ј,2Ј
= 10.2, 5.4 Hz, 1 H, 1Ј-H), 6.88 (d, J5,4 = 7.7 Hz, 1 H, 5-H), 7.77
(dt, J4,5 = 7.7 Hz, J4,1Ј = JH,P = 1.0 Hz, 1 H, 4-H) ppm. 13C NMR
(150.9 MHz, CDCl3): δ = –5.49, –5.42, –4.74, –4.72 (CH3Si), 17.94,
18.31 [C(CH3)3], 23.80 (CH3-6), 25.74, 25.89 [(CH3)3C], 36.77,
36.85 (d, JC,P = 3.8 Hz, CH3N), 42.91 (CH2-2Ј), 63.69 (CH2-5Ј),
74.28 (CH-3Ј), 74.40 (CH-1Ј), 87.67 (CH-4Ј), 119.27 (CH-5), 123.73
(d, JC,P = 6.3 Hz, C-3), 136.01 (CH-4), 154.15 (d, JC,P = 6.2 Hz,
C-2), 155.32 (C-6) ppm. 31P NMR (202.3 MHz, CDCl3): δ =
246.05295. 1H NMR (600.1 MHz, D2O): δ = 2.03 (ddd, Jgem
13.6 Hz, J2Јb,1Ј = 10.2 Hz, J2Јb,3Ј = 6.0 Hz, 1 H, 2Ј-Hb), 2.33 (ddd,
Jgem = 13.6 Hz, J2Јa,1Ј = 6.0 Hz, J2Јa,3Ј = 2.2 Hz, 1 H, 2Ј-Ha), 3.68
=
16.71 ppm. IR (CHCl ): ν = 3053, 2956, 2814, 1608, 1576, 1485,
˜
3
1471, 1464, 1455, 1438, 1410, 1390, 1361, 1307, 1265, 1252, 1232,
1187, 1091, 1071, 1000, 992, 966, 940, 839, 705 cm–1.
(dd, Jgem = 12.1 Hz, J5Јb,4Ј = 5.3 Hz, 1 H, 5Ј-Hb), 3.73 (dd, Jgem
=
12.1 Hz, J5Јa,4Ј = 4.3 Hz, 1 H, 5Ј-Ha), 4.04 (ddd, J4Ј,5Ј = 5.3, 4.3 Hz, 1β-(6-Amino-2-{[bis(dimethylamino)phosphoryl]oxy}-pyridin-3-yl)-
J4Ј,3Ј = 2.2 Hz, 1 H, 4Ј-H), 4.38 (dt, J3Ј,2Ј = 6.0, 2.2 Hz, J3Ј,4Ј 1,2-dideoxy-3,5-bis[O-(tert-butyldimethylsilyl)]- -ribofuranose (22):
2.2 Hz, 1 H, 3Ј-H), 5.18 (dd, J1Ј,2Ј = 10.2, 6.0 Hz, 1 H, 1Ј-H), 6.61 LiN(SiMe3)2 (1 m in THF, 0.31 mL, 0.31 mmol) was added to a
(d, J5,4 = 7.7 Hz, 1 H, 5-H), 7.73 (d, J4,5 = 7.7 Hz, 1 H, 4-H) ppm. flame-dried argon-purged flask containing 19 (88 mg, 0.145 mmol),
=
D
Eur. J. Org. Chem. 2012, 1759–1767
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1765

H. Chapuis, T. Kubelka, N. Joubert, R. Pohl, M. Hocek
FULL PAPER
2-(dicyclohexylphosphanyl)biphenyl (17 mg, 0.0485 mmol), and
Pd2(dba)3 (16 mg, 0.0175 mmol), and the mixture was stirred at
60 °C for 24 h. The reaction was then quenched by the addition of
Et2O and 5 drops of 2 m HCl and worked up. After drying with
MgSO4, filtration, and evaporation in vacuo, the raw material was
purified by flash chromatography (ethyl acetate/hexane = 60:40 to
ethyl acetate/methanol = 80:20). After evaporation of the corre-
sponding fractions, 22 (83 mg, 98%) was obtained as a yellowish
oil [contaminated by trace amounts of (2-biphenyl)dicyclohex-
ylphosphane oxide]. Rf (ethyl acetate/methanol = 90:10) = 0.61.
HRMS (ESI+): calcd. for C26H53N4O5PSi2 [M + H] 589.3365;
found 589.3363. HRMS (ESI+): calcd. for C26H52N4NaO5PSi2 [M
Et2O/NEt3 = 4:1:0.05) to obtain nucleoside 24 (55 mg, 37%) as a
colorless oil. [α]2D0 = +22.7 (c = 0.607, CHCl3). HRMS (ESI+):
calcd. for C28H55NO4ClSi3 [M + H] 588.31219; found 588.31246.
1H NMR (400 MHz, CDCl3): δ = 0.07, 0.07 (2 s, 12 H, CH3Si),
0.33, 0.37 (2 s, 2ϫ3 H, CH3Si), 0.89, 0.90, 0.99 [3 s, 3ϫ9 H, (CH3)3-
C], 1.63 (ddd, Jgem = 12.6 Hz, J2Јb,1Ј = 10.0 Hz, J2Јb,3Ј = 5.2 Hz, 1
H, 2Ј-Hb), 2.28 (ddd, Jgem = 12.6 Hz, J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј
=
2.0 Hz, 1 H, 2Ј-Ha), 3.60 (dd, Jgem = 10.8 Hz, J5Јb,4Ј = 5.6 Hz, 1 H,
5Ј-Hb), 3.76 (dd, Jgem = 10.4 Hz, J5Јa,4Ј = 3.6 Hz, 1 H, 5Ј-Ha), 3.94
(ddd, J4Ј,5bЈ = 5.6 Hz, J4Ј,5aЈ = 3.6 Hz, J4Ј,3Ј = 2.0 Hz, 1 H, 4Ј-H),
4.37 (m, 1 H, 3Ј-H), 5.27 (dd, J1Ј,2Ј = 10.0, 5.4 Hz, 1 H, 1Ј-H), 6.85
(d, J5,4 = 7.6 Hz, 1 H, 5-H), 7.74 (dd, J4,5 = 7.4 Hz, J4,1Ј = 0.8 Hz,
1 H, 4-H) ppm. 13C NMR (150.9 MHz, CDCl3): δ = –5.75, –5.62,
–5.39, –5.13, 4.99, –4.59 (CH3Si), 18.06, 18.08, 18.11 [C(CH3)3],
23.68, 22.30, 21.86 [(CH3)3C], 45.61 (CH2-2Ј), 65.98 (CH2-5Ј),
66.39 (CH-1Ј), 66.88 (CH-3Ј), 79.81 (CH-4Ј), 117.73 (CH-5), 129.30
(C-3), 138.15 (CH-4), 150.72 (C-6), 153.49 (C-2) ppm. IR (CHCl3):
1
+ Na] 611.3184; found 611.3184. H NMR (400 MHz, CDCl3): δ
= 0.06, 0.07, 0.07 (3 s, 12 H, CH3Si), 0.88, 0.90 [2 s, 2ϫ9 H, (CH3)3-
C], 1.72 (ddd, Jgem = 12.4 Hz, J2Јb,1Ј = 10.4 Hz, J2Јb,3Ј = 5.2 Hz, 1
H, 2Ј-Hb), 2.17 (ddd, Jgem = 12.4 Hz, J2Јa,1Ј = 4.8 Hz, J2Јa,3Ј
=
0.8 Hz, 1 H, 2Ј-Ha), 2.74, 2.75 (2 d, JH,P = 10.6 Hz, 2 ϫ 6 H,
CH3N), 3.60 (dd, Jgem = 10.6 Hz, J5Јb,4Ј = 5.8 Hz, 1 H, 5Ј-Hb), 3.74
ν = 3060, 2957, 1720, 1656, 1642, 1600, 1585, 1573, 1493, 1472,
˜
(dd, Jgem = 10.6 Hz, J5Јa,4Ј = 3.6 Hz, 1 H, 5Ј-Ha), 3.91 (ddd, J4Ј,5Ј 1464, 1434, 1410, 1396, 1392, 1362, 1259, 1098, 1086, 939, 838,
= 5.8, 3.6 Hz, J4Ј,3Ј = 1.6 Hz, 1 H, 4Ј-H), 4.37 (m, 1 H, 3Ј-H), 5.31 684, 401 cm–1.
(dd, J1Ј,2Ј = 10.4, 4.8 Hz, 1 H, 1Ј-H), 6.26 (d, J5,4 = 8.2 Hz, 1 H,
1β-{6-Amino-2-[(tert-butyldimethylsilyl)oxy]pyridin-3-yl}-1,2-dide-
5-H), 7.65 (d, J4,5 = 8.2 Hz, 1 H, 4-H) ppm.
oxy-3,5-bis[O-(tert-butyldimethylsilyl)]-
D-ribofuranose (25): LiN-
1β-[6-Methyl-2-oxo(1H)pyridin-3-yl]-1,2-dideoxy-
D-ribofuranose (SiMe3)2 (1 m in THF, 0.25 mL, 0.25 mmol) was added to a flame-
(23): NEt3·3HF (5 mL) was added to a solution of 21 (310 mg,
0.527 mmol) in dry THF (20 mL). After 20 h and TLC monitoring
of the reaction, the mixture was poured onto the top of an Am-
berlite IRA-96 small pad inside a glass column. The sample was
passed through and the glassware and the resin were washed with
THF. The fractions containing the compound (checked by TLC)
were collected and the solvents were evaporated. The yellowish resi-
due obtained was redissolved in water, filtered, and submitted to
RP-HPLC. Gradient: 0% B during 5 min; 0% B to 100% B in
25 min; 100% B during 5 min. Pure 23 (24 mg, 20%) was obtained
as a colorless oil. Rf (dichloromethane/methanol = 80:20) = 0.33.
HPLC (Phenomenex RP C18 stationary phase, 250ϫ21 mm; Luna
dried argon-purged flask containing 24 (65 mg, 0.11 mmol), 2-(di-
cyclohexylphosphanyl)biphenyl (18 mg, 0.05 mmol), Pd2(dba)3
(14 mg, 0.015 mmol), and THF (1 mL), and the mixture was stirred
at 60 °C for 24 h. The reaction was then quenched by the addition
of Et2O (20 mL) and 2 m HCl (3 drops) and worked up. After dry-
ing with MgSO4, filtration, and evaporation in vacuo, the raw ma-
terial was purified by flash chromatography (hexane). After evapo-
ration of the corresponding fractions, 25 (57 mg, 90%) was ob-
tained as a colorless oil. HRMS (ESI+): calcd. for C28H57N2O4Si3
[M + H] 569.36206; found 569.36205. 1H NMR (400 MHz,
CDCl3): δ = 0.08, 0.09 (2 s, 12 H, CH3Si), 0.29, 0.34 (2 s, 2ϫ3 H,
CH3Si), 0.90, 0.90, 0.98 [3 s, 3ϫ9 H, (CH3)3C], 1.64 (ddd, Jgem
=
10 μm particles; flow rate = 10 mL min–1; λ = 306 nm): tR
=
12.8 Hz, J2Јb,1Ј = 9.8 Hz, J2Јb,3Ј = 5.6 Hz, 1 H, 2Ј-Hb), 2.24 (ddd,
Jgem = 12.8 Hz, J2Јa,1Ј = 5.4 Hz, J2Јa,3Ј = 1.6 Hz, 1 H, 2Ј-Ha), 3.60
(dd, Jgem = 10.4 Hz, J5Јb,4Ј = 6.0 Hz, 1 H, 5Ј-Hb), 3.76 (dd, Jgem =
20.6 min. HRMS (ESI+): calcd. for C11H16NO4 [M + H] 226.1074;
1
found 226.4073. H NMR (600.1 MHz, D2O): δ = 2.10 (ddd, Jgem
= 13.6 Hz, J2Јb,1Ј = 10.3 Hz, J2Јb,3Ј = 5.9 Hz, 1 H, 2Ј-Hb), 2.31 (ddd, 10.4 Hz, J5Јa,4Ј = 3.6 Hz, 1 H, 5Ј-Ha), 3.92 (m, 1 H, 4Ј-H), 4.37 (m,
Jgem = 13.6 Hz, J2Јa,1Ј = 5.9 Hz, J2Јa,3Ј = 2.0 Hz, 1 H, 2Ј-Ha), 2.34
(s, 3 H, CH3), 3.71 (dd, Jgem = 12.2 Hz, J5Јb,4Ј = 5.2 Hz, 1 H, 5Ј-
Hb), 3.76 (dd, Jgem = 12.2 Hz, J5Јa,4Ј = 4.2 Hz, 1 H, 5Ј-Ha), 4.06
(ddd, J4Ј,5Ј = 5.2, 4.2 Hz, J4Ј,3Ј = 2.0 Hz, 1 H, 4Ј-H), 4.42 (dt, J3Ј,2Ј
= 5.9, 2.0 Hz, J3Ј,4Ј = 2.0 Hz, 1 H, 3Ј-H), 5.22 (dd, J1Ј,2Ј = 10.3,
5.9 Hz, 1 H, 1Ј-H), 6.41 (d, J5,4 = 7.4 Hz, 1 H, 5-H), 7.73 (d, J4,5
= 7.7 Hz, 1 H, 4-H) ppm. 13C NMR (150.9 MHz, D2O): δ = 20.66
(CH3), 42.47 (CH2-2Ј), 64.96 (CH2-5Ј), 75.74 (CH-3Ј), 78.76 (CH-
1Ј), 89.42 (CH-4Ј), 110.85 (CH-5), 129.03 (C-3), 142.58 (CH-4),
148.52 (C-6), 165.29 (C-2) ppm.
1 H, 3Ј-H), 5.31 (dd, J1Ј,2Ј = 9.8, 5.4 Hz, 1 H, 1Ј-H), 6.35 (d, J5,4
= 7.4 Hz, 1 H, 5-H), 7.58 (d, J4,5 = 7.4 Hz, 1 H, 4-H) ppm.
1β-[6-Amino-2-oxo(1H)pyridin-3-yl]-1,2-dideoxy-D-ribofuranose
(26): NEt3·3HF (0.17 mL) was added dropwise to a solution of 25
(29 mg, 0.051 mmol) in dry THF (5 mL). After stirring for 12 h
(TLC monitoring), the mixture was poured onto the top of an Am-
berlite IRA-96 small pad inside a glass column and eluted with
THF and then water. The fractions containing the compound were
quickly evaporated under reduced pressure with a bath temperature
not higher than 30 °C (higher temperature caused decomposition)
to remove the THF. The aqueous residue was then dried in a Speed-
vac. The oily residue was then dissolved in water and submitted to
RP-HPLC. Gradient: 0% B during 15 min; 0% B to 100% B in
30 min; 100% B during 5 min; with A: water HPLC grade; B: meth-
anol HPLC grade. After purification, the fractions containing the
compound are evaporated in a Speedvac and pure 26 (17%) was
obtained as an amorphous solid that quickly turned brown and
decomposed. Rf (reverse phase, acetonitrile/water = 20:80) = 0.26.
HPLC (Phenomenex RP C18 stationary phase, 250ϫ21 mm; Luna
1β-{6-Chloro-2-[(tert-butyldimethylsilyl)oxy]pyridin-3-yl}-1,2-dide-
oxy-3,5-bis[O-(tert-butyldimethylsilyl)]-D-ribofuranose (24): Com-
pound 18 (62 mg, 0.25 mmol) was twice co-evaporated with water
and pyridine and then dissolved in dry pyridine (1.2 mL) under
an atmosphere of argon. Then, DMAP (15 mg, 0.123 mmol) and
TBDMSCl (379 mg, 2.51 mmol) were added in three portions. The
resulting solution was stirred for 24 h at room temperature under
an atmosphere of argon. Then the pyridine was evaporated under
vacuum, and the residue was co-evaporated with toluene. The re-
sulting dark raw oil was dissolved in dichloromethane (50 mL) and
washed with water (50 mL). The water phase was extracted with
more dichloromethane (50 mL), and the collected organic phases
were dried with MgSO4, filtered, and concentrated in vacuo. The
yellowish residue was purified by flash chromatography (hexane/
10 μm particles; flow rate = 10 mLmin–1; λ = 306 nm): tR
17.6 min. HRMS (ESI+): calcd. for C10H15N2O4 [M
=
H]
+
227.10263; found 227.10284. HRMS (ESI–): calcd. for C10H13N2O4
[M + H] 225.08808; found 225.08742. 1H NMR (600.1 MHz, D2O):
δ = 1.99–2.07 (m, 1 H, 2Ј-Hb), 2.31–2.36 (m, 1 H, 2Ј-Ha), 3.69–
1766
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1759–1767

Synthesis of 6-Substituted 2(1H)-Pyridon-3-yl C-2Ј-Deoxyribonucleosides
[5] Recent examples: a) I. Singh, O. Seitz, Org. Lett. 2006, 8, 4319–
3.72 (m, 2 H, 5Ј-H), 4.03–4.05 (m, 1 H, 4Ј-H), 4.38 (dt, J3Ј,2Ј = 7.2,
2.4 Hz, J3Ј,4Ј = 2.4 Hz, 1 H, 3Ј-H), 5.19 (dd, J1Ј,2Ј = 7.8, 12 Hz, 1
H, 1Ј-H), 6.61 (d, J5,4 = 9.0 Hz, 1 H, 5-H), 7.74 (dd, J4,5 = 9.0 Hz,
J4,1Ј = 0.9 Hz, 1 H, 4-H) ppm.
4322; b) S. Hainke, I. Singh, J. Hemmings, O. Seitz, J. Org.
Chem. 2007, 72, 881–8819; c) P. Redpath, S. Macdonald, M. E.
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This work was supported by the Academy of Sciences of the Czech
Republic (Z4 055 905), by the Grant Agency of the Academy of
Sciences of the Czech Republic (IAA400550902) and by Gilead Sci-
ences, Inc.
Eur. J. Org. Chem. 2008, 1689–1704; c) N. Joubert, M. Urban,
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M. Hocek, J. Org. Chem. 2008, 73, 3798–3806; f) M. Stefko,
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Received: November 18, 2011
Published Online: February 2, 2012
Eur. J. Org. Chem. 2012, 1759–1767
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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