Synthesis of a novel, optically active uridine analog containing a 1,4-dioxane sugar moiety. Synthesis of the corresponding dinucleotide

Article abstract of DOI:10.1080/15257770902865407

A new optically active uridine nucleoside analogue in which a substituted 1,4-dioxane ring functioned as the sugar analogue was prepared from L-tartaric acid. The nucleoside analogue was further converted into the corresponding protected dinucleotide.

Full text of DOI:10.1080/15257770902865407

This article was downloaded by: [New York University]
On: 03 June 2015, At: 11:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Nucleosides, Nucleotides and Nucleic
Acids
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lncn20
Synthesis of a Novel, Optically Active
Uridine Analog Containing a 1,4-
Dioxane Sugar Moiety. Synthesis of the
Corresponding Dinucleotide
Qiang Yu a & Per Carlsen a
a Department of Chemistry , Norwegian University of Science and
Technology, NTNU , Trondheim, Norway
Published online: 30 Mar 2009.
To cite this article: Qiang Yu & Per Carlsen (2009) Synthesis of a Novel, Optically Active Uridine
Analog Containing a 1,4-Dioxane Sugar Moiety. Synthesis of the Corresponding Dinucleotide,
Nucleosides, Nucleotides and Nucleic Acids, 28:3, 220-237, DOI: 10.1080/15257770902865407
To link to this article: http://dx.doi.org/10.1080/15257770902865407
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Nucleosides, Nucleotides and Nucleic Acids, 28:220–237, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770902865407
SYNTHESIS OF A NOVEL, OPTICALLY ACTIVE URIDINE ANALOG
CONTAINING A 1,4-DIOXANE SUGAR MOIETY. SYNTHESIS OF THE
CORRESPONDING DINUCLEOTIDE
Qiang Yu and Per Carlsen
Department of Chemistry, Norwegian University of Science and Technology, NTNU,
Trondheim, Norway
A new optically active uridine nucleoside analogue in which a substituted 1,4-dioxane ring
2
functioned as the sugar analogue was prepared from L-tartaric acid. The nucleoside analogue was
further converted into the corresponding protected dinucleotide.
Keywords Uridine analogs; 1,4-dioxane; nucleoside analogs; dinucleotide analogs;
optically active; heterocycle
INTRODUCTION
Nucleosides analogs have been a subject of considerable interest due
to their potential biologic activities. In the search for new antiviral and
antitumor agents, a number of nucleoside analogs have in recent years
been synthesized in with the sugar moiety was modified,[1] and examples
in which the sugar unit was replaced by a 1,4-dioxane group have been
reported, in attempts to develop novel therapeutics.[2] Some were reported
to have interesting biological activities.[2a,2b] Such an analogue may be
more potent and/or selective, due to their conformational properties.[2c]
Most of the reported nucleoside analogs with 1,4-dioxane groups replacing
the sugar in the natural nucleosides were substitutes so that formation of
polynucleotides was not possible. Few of the products described in these
publications were optically active.
We here report the synthesis a new optically active nucleoside ana-
log that consist of a 1,4-dioxane ring, substituted with uracil and a 1,2-
Received 24 June 2008; accepted 4 March 2009.
The authors wish to thank the Norwegian Research Council (NFR) for generous financial support.
Address correspondence to Per Carlsen, Department of Chemistry, Norwegian University of Science
and Technology, NTNU, N-7491, Trondheim, Norway. E-mail: per.carlsen@chem.ntnu.no
220

A Novel, Optically Active Uridine Analog
221
FIGURE 1 Optically active 1,4-dioxane uridine analogs, 1a and 1b.
dihydroxyethyl substituent (Figure 1). With the dihydroxyethyl substituent
is in the equatorial position, the uracil base is in either of the anomeric
positions, thus the dihydroxyethyl substituent and the uracil ring are of ei-
ther trans- or cis-configurations. This uridine analog was further elaborated
into the corresponding dinucleotide using the standard phosphoraimidite
procedure.[3] An additional objective was to establish if nucleoside 1 was a
suitable substrate for the preparation of new oligonucleotides.
RESULTS AND DISCUSSION
As the biologic activities of enantiomers are usually quite different, an
important objective in the work was to develop a synthetic procedure that
effortlessly produced either of the possible stereoisomers corresponding to
structure 1, that is, either of the four possible isomers of each anomer. The
chirality of the 1,4-dioxane system was introduced through the use of tartaric
acid, in this work exclusively L-tartaric acid, 2, (R,R-tartaric acid). All the
tartaric acid stereoisomers are inexpensive and readily available chiral pool
materials.
Initially (2R,3R)-dimethyl tartrate was converted into the corresponding
enantiomerically pure allyl ether 3 either by the reaction with allyl bromide
in the presence of silver oxide[4] or in a tin assisted reaction with dibutyltin
[6]
oxide.[5] Allylether 3 was next reduced to triol 4, either using LiAlH4 in
[7]
26% isolated yield, or as a viable alternative by reduction with NaBH4
which gave 4 in 88% yield. The latter product contained minor borate
impurities, but could be used in the subsequent steps without further
purification. Ozonolysis of 4 gave the corresponding aldehyde 5, which
however spontaneously converted into the corresponding hemiacetals 6 and
7 (Scheme 1). NMR and IR measurements indicated the presence of no free
aldehyde. Hemiacetal 6 was formed from 5 through ring closure with the
C-3 OH group (route a), while hemiacetals 7 were obtained through ring
closure with the C-1 OH group (route b). As expected separation of products
6 and 7 by chromatography was not successful. Assuming the hemiacetals
being in equilibrium, it was expected that upon subjecting the mixture to
acid catalyzed acetal formation with 2,2-dimethoxypropane, the more stable

222
Q. Yu and P. Carlsen
SCHEME 1 Synthesis of chiral 1,4-dioxane sugar analogs 8 from L-dimethyl tartrate.
5-membered acetal 8 would be formed as the exclusive product. Diol 6
may form a less favorable 7-membered acetal. As it turned out, the desired
product 8 was formed in mixture with unreacted 6. Product 8 was isolated
by flash chromatography, but obtained in merely 21% yield. That not all
the components in the equilibria shown in Scheme 1 were channeled into
acetal 8, may be ascribed to the kinetic stability of hemiacetal 6 under the
reaction conditions.
In order to obtain compound 8 in a better yield, the reaction sequence
was altered. Thus, triol 4 was reacted with 2,2-dimethoxypropane with p-
TsOH-catalysis to give the five-membered acetal 9 as the exclusive product,
without any signs of the alternative seven-membered acetal. Ozonolysis of
9 gave after flash chromatography the desired 1,4-dioxane derivative 8 as
the only product, isolated in 43% over-all yield from 3 (Scheme 2), as
an approximately 1:1 mixture of the anomers. The stereochemistry of all
stereogenic carbons were retained in all of these transformations, except
for the anomeric hemiacetal carbon generated in the reaction sequence.
SCHEME 2 Alternative synthesis of 1,4-dioxane sugar analog 8.

A Novel, Optically Active Uridine Analog
223
SCHEME 3 Synthesis of 1,4-dioxane uracil analogs 1a and 1b.
For the introduction of the nucleic base into the pseudo-sugar, com-
pound 8 was next acetylated with acetic anhydride in pyridine to give
the mixture of anomeric acetates, 10 (Figure 3), which was then reacted
in a TMSOTf-catalyzed reaction with silylated uracil[9] according to the
Vorbru¨ggen’s procedure.[8] This afforded nucleoside 11 (Figure 4), for
which the acetal deprotection was removed using catalytic amount of Am-
berlyst 15 in methanol. This gave the desired uridine analog anomers 1a and
1b, as an approximately 4:1 mixture as indicated by NMR (Scheme 3) and in
59% isolated yield from compound 8. Anomer, 1a (Figure 5), was isolated in
42% yield from the reaction mixture by recrystallization from acetonitrile.
The anomers were also readily separated by flash chromatography.
The structures of nucleoside analog 1a and 1b are shown in Figure 2,
and were elucidated by 1H- and 13C-NMR, by DEPT and the various 2D-NMR
FIGURE 2 Structures of anomers 1a and 1b.

224
Q. Yu and P. Carlsen
techniques, COSY, HSQC, HMBC, NOESY. In the 1H NMR spectrum of 1a,
a relatively large JFE2 value (10 Hz) was observed, which indicated that HF
occupied the axial position, uracil thus occupying the equatorial position.
The coupling constants JCD1 (11.2 Hz) and JCD2 (2.8 Hz) provided evidence
that HD1 was in the axial position and HD2 was equatorial, and HC was in an
axial position. The 2D-NOESY experiment of 1a showed a clear NOE effect
between HF and HD1. These data were in agreement with 1a being the trans-
1
compound. For diastereomer 1b, in the H-NMR the coupling constants
ꢁ
ꢁ
ꢁ
ꢁ
JF E1 and JF E2 were measured to 1.2 Hz and 3.7 Hz, respectively, indicating
ꢁ
HF to be in the equatorial position, hence the uracil group in the axial
position. 2D-NOESY experiment with 1b showed a clear NOE effect between
ꢁ
ꢁ
HG and HE1
.
In modern polynucleotide chemistry, building oligonucleotides is usu-
ally done using solid support methods and automated synthesis machines.
It was not planned here to prepare larger oligomers, but rather to elucidate
if the dioxane nucleoside analogs were capable of undergoing the necessary
transformations for such automated procedures. For this reason a batch pro-
cedure including the preparation of key intermediates and transformations
were studied. To prepare the uridine dinucleotide analog, the phospho-
ramidite procedure[3] was adopted because this is extensively used in the
solid phase synthesis of oligonucleotides. Uridine analog 1a was thus reacted
with 4, 4ꢁ-dimethoxyltrityl chloride in pyridine to afford primary hydroxyl
group protected compound 12 (Figure 6).[10] Compound 12 was next
treated with 2-cyanoethyl N,N -diisopropylphosphoramido chloride in the
presence of N,N -diisopropylethylamine in anhydrous dichloromethane[11]
at room temperature affording the desired intermediate 13 (Scheme 4
SCHEME 4 Synthesis of nucleoside phosphite analog 13.

A Novel, Optically Active Uridine Analog
225
SCHEME 5 Synthesis of uracil acetate analog 14.
and Figure 7). Interestingly, the two diastereomers generated due to the
presence of the phosphite stereogenic center, were separated by chromatog-
raphy on a silica gel column.
To obtain the other component required for the coupling scheme
towards the protected dinucleotide 16, intermediated 12 was first acylated
with acetic anhydride in pyridine to afford compound 15 (Figure 8) and the
trityl group was subsequently removed using dichloroacetic acid providing
the desired primary alcohol 14 (Scheme 5 and Figure 9).
The uracil dinucleotide 16 was then prepared by coupling 13 with 14 in
the presence of tetrazole in dry acetonitrile,[12] followed by iodine oxidation
of the phosphite moiety to the desired protected phosphate group. The
product was purification by flash chromatography on silica gel (Scheme
6). Dinucleotide 16 was formed as a diastereomeric mixture due to the
1
phosphate stereogenic center. This resulted in rather complex H-NMR
spectrum. The 31P NMR spectrum shows two strong signals at -1.83 and
-1.90 ppm together with two very small signals at 9.0 ppm and 8.3 ppm,
indicating the crude product to be of reasonable good purity. Compound
16 was further purified by column chromatography.
The synthesis was not extended beyond this point, as product 16 may
now function as substrate for further oligomerization reactions, or be
deprotected to give the parent uridine dinucleotide analog.
CONCLUSIONS
In conclusion, the uridine 1,4-dioxane nucleoside analog 1 was readily
prepared from tartaric acid. This compound was further converted into the
corresponding partially protected dinucleotide, hence demonstrating that

226
Q. Yu and P. Carlsen
SCHEME 6 Synthesis of the protected uracil dinucleotide analog 16.
the uridine nucleoside analog may be elaborated into larger oligomers using
established standard procedure.[13]
EXPERIMENTAL
NMR spectra were recorded on Bruker Avance DPX 300 or DPX 400
instruments (Bruker, Germany). Chemical shifts are reported in ppm using
TMS (0.0) as the internal standard in CDCl3 or relative to 2.50 ppm
1
1
for H and 39.99 ppm for 13C in [D6-DMSO] or 3.31 ppm for H and
49.15 ppm for 13C in CD3OD. Structural assignments were based on H,
1
13C, DEPT135 and 2D spetra, COSY, HSQC, HMBC, NOESY. EI-Mass,
and ESI spectra were recorded on a Finnigan MAT 95XL spectrometer
(Finnegan MAT AB, Sweden). IR spectra were obtained on a FT-IR Nexus
spectrometer (Thermo-Nicolet, USA) using a Smart Endurance reflection
cell. For ozonolysis was used an OZ-500 Ozone Generator produced by
Fischer Technology (Germany). Silica gel Kieselgel 60G (Merck) was used
for Flash Chromatography. The solvents were purified by standard methods.
(2R,3R)-Dimethyl 2-(allyloxy)-3-hydroxysuccinate, 3
This compound was prepared from dimethyl l-tartrate, 2, as described
earlier[14] either by reaction with allyl bromide and silver oxide,4 resulting

A Novel, Optically Active Uridine Analog
227
in variable yields between 20 and 84% or by a reaction involving dibutyltin
oxide5 resulting in a 70% overall yield. B.p. 90◦C at 10−3 torr. The spectro-
scopic properties were in agreement with those reported previously.[5]
(2S,3S)-3-(Allyloxy)butane-1,2,4-triol, 4
This product was obtained by reduction of 3 with either LiAlH4 or
NaBH4.
LiAlH4 reduction: To a suspension of LiAlH4 (3.72 g, 95%, 93 mmol) in
dry diethyl ether (50 mL) was drop wise added a solution of 3 (4.36 g, 20
mmol) in 4 mL of diethyl ether at 0–5◦C. The reaction mixture was refluxed
for 18 hours and then cooled in an ice bath. Then 5 mL of water was
added and the mixture stirred for 20 minutes, followed by addition of a 15%
NaOH solution (12 mL) and then 10 mL of water. The resulting mixture was
stirred and the granular salt formed, was separated by filtration, washed with
hot THF (200 mL), and the filtrate concentrated under reduced pressure.
The residue was purified by flash chromatography (CHCl3/CH3OH, 9:1
mixture) to give 0.83 g, 26% of the pure product 4.
NaBH4 reduction. Sodium borohydride (3.45 g, 93 mmol) in ethanol
(50mL) was stirred for half an hour and then dropwise added a solution of 3
(4.35 g, 20 mmol) in ethanol (15 mL). The resulting solution was refluxed
gently for 5 hours. The solution was cooled in an ice bath and added 10
mL of acetic acid. The mixture was stirred for 20 minutes and filtered.
The solid was washed with 2 × 50 ml ethanol. The combined organic phase
was concentrated under reduced pressure. The crude product was purified
by flash chromatography using a 19:1 mixture of CH2Cl2/MeOH as the
eluent yielding 2.88 g, 88% of the pure product, which exhibited the
1
following spectroscopic properties: H-NMR (CDCl3, 400 MHz): δ = 3.45
(q, 1H, CH-OAllyl), 3.66–3.74 (m, 3H, 1H from CH2-CHOH, 2H from
CH2-CH-OAll), 3.80 (dd, 1H from CH2-CHOH), 3.86 (q, 1H, CHOH),
4.03–4.20 (m, 2H, OCH2-CH=CH2), 4.32 (s, broad, 3H, OH), 5.18–5.38
(m, 2H, CH2 = CH), 5.86–5.96 (m, 1H, CH=CH2) ppm.13C-NMR (CDCl3,
100MHz): δ = 60.6, 63.3, 71.6, 71.8, 79.1, 117.8, 134.5 ppm. MS (EI) m/z:
145 (M+-OH), 131 (M+-CH2OH), 101 (OH-CH2 = O+CH2-CH=CH2), 61
(HOCH2CH=O+H). IR (neat): 3365, 2881, 1736, 1448 cm−1
.
(S)-2-(Allyloxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol, 9
A solution of 4 (6.20 g, 38 mmol), 2,2-dimethoxylpropane (4.00 g, 38.5
mmol) and pTsOH (223 mg, 1.2 mmol) in 100 mL acetone was stirred
overnight at room temperature. The solvent was then removed and the
residue was purified by flash chromatography using a 3:2 mixture of Et2O/n-
hexane as the eluent to provide product 9 as colorless oil (5.11 g, 85%).
Unreacted starting material 4 (1.05 g crude product) was recovered by

228
Q. Yu and P. Carlsen
continued elusion with a 19:1 mixture of CH2Cl2/MeOH. Product 9 exhib-
ited the following spectroscopic properties: 1H-NMR (CDCl3, 400MHz): δ =
1.37 (s, 3H, CH3), 1.44 (s, 1H, CH3), 2.48 (s, broad, 1H, OH), 3.49–3.53 (m,
1H, CH-OAll), 3.59 (dd, J = 10.8Hz, 12Hz, 1H, HOCH2-CHOAll), 3.73 (dd,
J = 4.2Hz, 12Hz, 1H, HOCH2-CHOAll), 3.81 (dd, J = 7.2Hz, 8.4Hz, 1H, C-
OCH2CHO-C), 4.03 (dd, J = 6.4Hz, 8.4Hz, 1H, C-OCH2CHO-C), 4.18–4.22
(m, 2H, OCH2-CH=CH2), 4.26–4.31 (m, 1H, C-OCH2CHO-C), 5.24–5.33
(m, 2H, CH2 = CH), 5.88–5.95 (m, 1H, CH=CH2) ppm.13C-NMR (CDCl3,
100MHz): δ 25.3, 26.4, 61.6, 65.4, 71.8, 76.4, 79.1, 109.4, 117.4, 134.7 ppm.
MS: (EI) m/z: 202(M+), 187 (M+-CH3), 171(M+-CH2OH), 101(C5H9O2+).
(2R,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyl-1,4
-dioxane, 8a, and (2S,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2-hydroxyl-1,4-dioxane, 8b
A solution of 9 (5.9 g, 29.2 mmol) in a mixed of methanol and
dichloromethane (1:4) (200 mL) was ozonized at −78◦C until a persistent
blue color, 1 hour 45 minutes. The ozonolysis mixture was then purged
until most of the blue color had disappeared and then added dimethyl
sulfide (2.2 g, 35.5 mmol) and stirred overnight. The resulting mixture
was concentrated under reduced pressure and the crude product purified
by flash chromatography using a 7:3 mixture of Et2O/n-hexane as the
eluent, yielding the product as a colorless oil (4.62 g, 78%). The anomeric
ration was approximately 1:1 as determined by NMR, however, the isomers
were not separated. The product exhibited the following spectroscopic
1
properties: H-NMR (CDCl3, 400 MHz): δ = 1.36 (s, 3H, CH3), 1.37(s,
3H, CH3), 1.43 (s, 3H, CH3), 1.44 (s, 3H, CH3), 3.30 (dd, 8.4Hz, 11.2Hz,
1H, OCH2CHOH-), 3.45 (dd, 11.6Hz, 2.8Hz, 1H, CHCH2CHOH-), 4.84
(d, 8.4Hz, 1H, anomeric proton), 4.98 (d, 3.6Hz, 1H, anomeric proton),
(3.55–3.66, m, 3H; 3.69–3.76, m, 1H; 3.78–3.84, m, 5H; 3.93–4.02, m, 3H;
4.05–4.16, m, 2H; the other protons). 13C-NMR (CDCl3, 100MHz): δ 25.2,
26.22, 26.25, 59.3, 65.0, 65.1, 65.7, 69.2, 70.0, 74.29, 74.6, 74.9, 75.5, 88.7,
91.8, 109.8 ppm.
(2S,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-acetyloxy-1,4
-dioxane, 10a, and (2R,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-
2-acetyloxy-1,4-dioxane, 10b
To a solution of 9 (1.0 g, 4.9 mmol) in 15mL of dry pyridine was added
acetic anhydride (0.62 g, 6 mmol) at 0–5◦C and the reaction mixture was
stirred for 6 hours. The solution was concentrated under reduced in vacuo
overnight, yielding the crude product in 87% yield as a sticky oily material,
which was used in the subsequent reaction step without further purification.

A Novel, Optically Active Uridine Analog
229
FIGURE 3 Structure 10a.
The anomeric ration 10a:10b (trans- cis- ratio) was determined to 4:1 by
NMR.
The product exhibited the following spectroscopic properties: NMR
spectrum of trans- compound 10a (Figure 3) was assigned the following
1
signals: H-NMR (CDCl3, 400MHz): δ = 1.36, 1.43 (s, 2×3H, (CH3)2C),
2.11 (s, 3H, CH3COO), 3.48 (dd, J = 8.0Hz, 11.4Hz, 1H, HB1), 3.63 (m, 1H,
HC), 3.69 (dd, J = 9.4Hz, 11.4Hz, 1H, HD1), 3.81 (dd, J = 6.8Hz, 8.0Hz,
1H, (CH3)2C-O-CH2), 3.89 (dd, J = 2.6Hz, 11.4Hz, 1H, HD2), 3.93 (dd,
2.8Hz, 11.4Hz, 1H, HB2), 4.00 (dd, 6.8Hz, 8.4Hz, 1H, (CH3)2C-O-CH2), 4.15
(m, 1H, (CH3)2C-O-CH-), 5.74 (dd, 2.8Hz, 8.4Hz, 1H, HA) ppm. 13C-NMR
(CDCl3, 100MHz): δ = 20.9, 25.2, 26.3, 65.2, 65.6, 66.9, 74.2, 74.2, 89.4,
109.7, 169.0 ppm.
The protons NMR spectrum of the corresponding cis- compound, 10b,
could not be fully assigned due to the peaks overlap with 10a. The carbons
NMR spectrum of the cis- compound was assigned the following signals: 13C-
NMR (CDCl3, 100MHz): δ = 21.1, 25.2, 26.2, 61.0, 64.9, 67.6, 74.9, 75.1,
88.4, 109.7, 169.8 ppm.
The mixture exhibited the following mass spectrum: MS (EI) m/z: 247
(M++1), 231(M+-CH3), 187(M+-OAc), 145 (C6H9O4). Elem. Anal. calcd.
for C13H18N2O6: C 53.65, H 7.37; found C, 53.84, H 7.45.
1-[(2R,5S)-5-[(4S)-(2,2-dimethyl-1,3-dioxolan-4-yl)]-1,4-dioxan
-2-yl]uracil, 11a, and 1-[(2S,5S)-5-[(4S)-(2,2-dimethyl-1,3-di-
oxolan-4-yl)]-1,4-dioxan-2-yl]uracil, 11b
A mixture of uracil (0.92 g, 8.2 mmol) in 40 mL of hexamethyldisilazane
(HMDS) was refluxed overnight. The resulting solution was concentrated
and the residue was dissolved in 15 mL of dichloroethane. The solution
was added 10 (0.48 g, 2 mmol) and the mixture was cooled to 0–5◦C and
added TMSOTf (0.37 mL, 2mmol). After 5 hours of stirring the mixture
was added 60 mL dichloromethane, which was washed twice with 15 mL of

230
Q. Yu and P. Carlsen
FIGURE 4 Structure 11a.
a saturated aqueous sodium bicarbonate solution. The aqueous phase was
extracted once with 50 mL chloroform, and the combined organic phase
was washed with 20 mL saturated solution of NaCl, dried over anhydrous
MgSO4 and filtered. The filtrate was concentrated under reduced pressure
to give product 11 as a light yellow solid (0.37 g, 63.7%).
The trans-cis-ratio of the diastereomers was determined to 4:1 (NMR).
The trans-compound 11a (Figure 4) was assigned the following NMR signals:
1H-NMR (CDCl3, 400MHz): δ = 1.35, 1.43 (s, 2×3H, HA and HB), 3.40 (dd,
10Hz, 11.2Hz, 1H, HG1), 3.78–3.89 (m, 2H, HC1+HF1), 3.94–4.06 (m, 3H,
HC2+ HG2+HF2), 4.10–4.17 (m, 2H, HD+ HE), 5.74–5.77 (m, 1H, HH), 5.76
(d, J = 8.4Hz, 1H, HJ), 7.41 (d, J = 8.4Hz, 1H, HI), 9.70 (s, 1H, HK) ppm.
13C-NMR (CDCl3, 100MHz): δ = 25.10, 26.2, 64.9, 68.1, 68.3, 74.3, 74.5,
78.5, 102.9, 109.9, 139.4, 150.0, 163.2 ppm. It was not possible to fully assign
the protons NMR spectrum of the cis-compound due to the overlap of the
peaks with those of 11a. The carbons NMR signals of the cis-compound
were assigned as follow: 13C-NMR (CDCl3, 100MHz): δ = 25.1, 26.1, 61.8,
64.9, 66.2, 74.37, 74.41, 75.4, 101.8, 110.0, 142.3, 151.1, 163.3 ppm. MS (EI)
m/z: 298(M+), 283 (M+-CH3), 187 (M+-uracil). IR (neat): 3197, 3098, 3065,
2986, 2937, 1688, 1452 cm−1. Elem. anal.: Calcd. for C13H18N2O6: C 52.34,
H 6.08, N 9.39; Found C, 52.43, H 6.41, N 9.23.
1-[(2R,5S)-5-[(1S)-1,2-dihydroxyethyl]-1,4-dioxan-2-yl]uracil, 1a,
and 1-[(2S,5S)-5-[(1S)-1,2-dihydroxyethyl]-1,4-dioxan-2-yl]
uracil, 1b
Compound 11 (0.35 g, 1.2 mmol) in 20 mL of methanol was refluxed
for 2.5 hours in the presence of 50 mg of Amberlyst-15. The hot solution
was filtered and the filtrate was cooled to room temperature. A white
solid precipitated and was isolated by filtration. The product was dried
in vacuo to give a pure trans-product 1a (101 mg, 42%). NMR analysis
of the concentrated crude product showed a 4:1 trans-cis-ratio (1a:1b =
4:1).

A Novel, Optically Active Uridine Analog
231
FIGURE 5 Structure 1a.
Product 1a (Figure 5) exhibited the following spectroscopic properties:
1H-NMR ([D6]DMSO, 400MHz): δ = 3.33 (dd, 12.8Hz, 16Hz, 1H, HA1),
3.39–3.45 (m, 2H, HA2 + HB), 3.58 (dd, 10Hz, 11.2Hz, 1H, HE2), 3.62 (dt,
2.8Hz, 2.8Hz, 11.2Hz, 1H, HC), 3.78 (dd, 11.2Hz, 11.6Hz, 1H, HD1), 3.83
(dd, 2.8Hz, 11.2Hz, 1H, HE1), 3.96 (dd, 2.8Hz, 11.6Hz, 1H, HD2), 4.61 (s,
br. 2H, -OH), 5.53 (dd, 2.8Hz, 10Hz, 1H, HF), 5.62 (dd, 2.4Hz, 8.0Hz, 1H,
HH), 7.69 (d, 8.0Hz, 1H, HG), 11.41 (d, 2.4Hz, 1H, NH) ppm.13C-NMR
([D6]DMSO, 100MHz) δ 61.9, 67.0, 68.3, 70.4, 74.6, 77.9, 101.9, 140.9,
150.1, 162.9 ppm. IR (neat): 3478.9, 3430.3, 3032.2, 1704.1, 1674 cm−1
.
MS (EI) m/z: 258(M+), 197(M+-(OHCHCH2OH)), 147(M+-uracil). HRMS
(ESI) m/z: for C10H14N2O6 [M+Na]+ calcd, 281.0750; found 281.0746.
Elem. anal.: Calcd, for C10H14N2O6: C 46.51, H 5.46, N 10.85; Found C
46.33, H 5.32, N 10.80. [α] 25 +41.5 (c = 0.248, DMSO).
D
1-[(2R,5S)-5-[(1S)-hydroxy-2-(4,4ꢁ-dimethoxytrityl)-ethyl-1-yl]-1,4-
dioxan-2-yl]uracil, 12
Compound 1a (286 mg, 1.11 mmol) in dry pyridine (18 mL) was added
4, 4-dimethoxytrityl chloride (0.41g, 1.15mmol) at room temperature under
nitrogen. The reaction mixture was stirred for 3 hours and the solution
then concentrated to half volume and then added 50 mL of ethyl acetate.
The resulting solution was washed with 3 × 10 mL of saturated NaHCO3
solution. The aqueous phase was extracted with 50 mL ethyl acetate. The
combined organic phase was dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by flash
chromatography using ethyl acetate as the eluent to afford product 12 as
a white solid (0.58 g, 93%).
The product 12 (Figure 6) exhibited the following spectroscopic prop-
1
erties: H-NMR (CDCl3, 400MHz): δ = 2.50 (d, 5.6Hz, 1H, OH), 3.17 (dd,
10Hz, 5.4Hz, 1H, HA1), 3.27 (dd, 10Hz, 5.6Hz, 1H, HA2), 3.37 (dd, 10.2Hz,
11.2Hz, 1H, HE2), 3.62–3.67 (m, 1H, HB), 3.71–3.75 (m, 1H, HC), 3.79 (s,
2×3H, OCH3), 3.78–3.84 (m, 1H, HD1), 3.94 (dd, 2.0Hz, 11.6Hz, 1H, HD2),

232
Q. Yu and P. Carlsen
FIGURE 6 Structure 12.
4.02 (dd, 2.8Hz, 11.2Hz, 1H, HE1), 5.69 (dd, 2.8Hz, 9.6Hz, 1H, HF), 5.74 (d,
8.4Hz, 1H, HH), 6.82–6.85, 7.16–7.33 (m, aromatic hydrogen), 7.41–7.43
(m, HG and aromatic hydrogen), 9.08 (s, 1H, NH) ppm. 13C-NMR (CDCl3,
100MHz): δ = 55.4, 60.6, 63.8, 68.4, 68.9, 70.1, 75.1, 78.7, 86.6, 102.9, 113.36,
113.41, 127.1, 128.1, 128.24, 129.3, 130.2, 135.9, 136.0, 139.6, 144.8, 150.0,
158.8, 163.0 ppm. IR (neat): 3427, 3201, 3061, 2999, 2836, 1687, 1508,
1247, 1031, 827, 756, 727, 702 cm−1. MS (EI) m/z: 560.2(M+), 304.1(trityl),
273.1, 227.1, 197(M+-(OHCHCH2OH)-trityl group). HRMS (ESI) m/z: for
C31H32N2O8 [M+Na]+ calcd, 583,2057; found 583.2050. Elem. anal.: calcd.
for C31H32N2O8: C 66.42, H 5.75, N 5.00; found C 66.42, H 5.94, N 4.50.
1-[(2R,5S)-5-[(1S)-O-[2-cyanoethoxy(diisopropylamino)
phosphino]-2-O-(4,4ꢁ-dimethoxy-trityl)-ethyl-1-yl]-1,4-dioxan-2-
yl]uracil, 13
Compound 12 (275 mg, 0.49 mmol) in 10 mL of dry dichloromethane
was added N,N -diisopropylethylamine (0.18 mL, 1.0 mmol) under nitrogen.
To this solution was added 2-cyanoethyl N,N -diisopropylphosphoramido
chloride (0.2 mL, 0.90 mmol). The reaction mixture was stirred for four
hours. The solution was then added 20 mL of dichloromethane and washed
with 2 × 5ml of a saturated NaHCO3 solution and then with 10 mL of
brine. The organic phase was dried over anhydrous Na2SO4, filtered and
the solvent evaporated. The residue was purified by flash chromatography
using a 9:1 mixture of ethyl ether and n-hexane as the eluent to afford
three fractions of 13a (70 mg, 17.7%) and 13b (110 mg, 27.8%) and a
mixture (60 mg, 15.2%) of 13a and 13b. Compounds 13a and 13b were
the diastereomers due to the stereogenic centre of phosphorus.
Compound 13a (Figure 7) exhibited the following spectroscopic prop-
1
erties: H-NMR (CDCl3, 400MHz): δ = 1.19 (d, 4Hz, 2×3H, HJ), 1.21 (d,
4Hz, 2×3H, HJ), 2.42 (t, 6.6Hz, 2H, HL), 3.09 (dd, 9.6Hz, 4.8Hz, HA), 3.34

A Novel, Optically Active Uridine Analog
233
FIGURE 7 Structure 13.
(dd, 11.2Hz, 10Hz, HE2), 3.41 (dd, 9.6Hz, 5.2Hz, HA), 3.59–3.67 (m, 1H,
HI), 3.66–3.73 (m, 2H, HK), 3.72–3.79 (m, 1H, HD), 3.79 (s, 3H, OCH3),
3.80 (s, 3H, OCH3), 3.81–3.86 (m, HC), 3.93–4.01 (m, 3H, HB, HD and
HE1), 5.65 (dd, 9.6Hz, 2.8Hz, 1H, HF), 5.74 (d, 8Hz, 1H, HH), 6.80–6.86
(m, 4H, Aromatic H), 7.42–7.46 (m, Aromatic H), 7.20–7.25 (Aromatic H
and HG), 8.85 (broad s 1H, HL) ppm. 13C-NMR (CDCl3, 100MHz): δ =
19.7, 19.8, 24.10, 24.16, 24.18, 24.22, 42.8, 42.9, 54.8, 57.7, 57.8, 62.1, 67.9,
68.1, 72.5, 74.7, 78.1, 85.9, 102.2, 112.2, 117.1, 126.4, 127.4, 127.7, 129.6,
135.3, 135.5, 139.1, 144.3, 149.2, 158.1, 162.2, 174.5 ppm. 31P (85% H3PO4):
151.7 ppm. Product 11b exhibited the following spectroscopic properties:
1H-NMR (CDCl3, 400MHz): δ = 1.10 (d, 6.8Hz, 2×3H, HJ), 1.17 (d, 6.8Hz,
2×3H, HJ), 2.64 (dt, 6.4Hz, 0.4Hz, 2H, HL), 3.15 (dd, 9.5Hz, 5.8Hz, HA),
3.28 (dd, 9.5Hz, 5.6Hz, HA), 3.40 (dd, 9.6Hz, 11.2Hz, HE), 3.52–3.62 (m,
1H, HI), 3.72–3.78 (m, 2H, HK), 3.79 (s, 2×3H, OCH3), 3.82–3.89 (m,
1H, HD), 3.90–3.95 (m, 1H, HB), 3.95 (dd, 11.2, 3.2Hz, HE1), 4.00–4.07
(m, 2H, HD and HC), 5.66 (dd, 9.6Hz, 2.8Hz, 1H, HF), 5.73 (d, 8.2Hz,
1H, HH), 6.80–6.85 (m, 4H, Aromatic H), 7.18–7.12 (m, 1H, Aromatic H)
7.25–7.30 (m, 2H, Aromatic H), 7.31–7.36 (m, 4H, Aromatic H), 7.43–7.46
(m, 2H, Aromatic H), 7.48 (d, 8.2Hz, 1H, HG), 8.71 (broad s, 1H, N-H)
ppm. 13C-NMR (CDCl3, 100MHz): δ = 20.67, 20.74, 24.72, 24.80, 24.88,
24.94, 55.4, 58.1, 58.3, 62.7, 62.8, 68.6, 68.9, 72.6, 72.8, 75.28, 75.3, 78.7,
86.5, 102.8, 113.3, 127.0, 128.0, 128.3, 130.2, 130.3, 136.1, 136.2, 140.0,
145.0, 150.0, 158.7, 162.9 ppm. 31P (85% H3PO4): 151.3 ppm. IR (neat):
3204, 3064, 2965, 2931, 2874, 1693, 1508, 1248, 1177, 1029, 757, 726, 702

234
Q. Yu and P. Carlsen
FIGURE 8 Structure 15.
cm−1. HRMS (ESI) m/z: Calcd. for C40H49N4O9P [M+H]+ 783.3135; found
783.3127. Elem. Anal.: Calcd. for C40H49N4O9P: C 63.15, H 6.49, N 7.36, P
4.07; found C, 63.03, H 6.52, N 7.25, P 3.96.
1-[(2R,5S)-5-[(1S)-acetyloxy-2-(4,4ꢁ-dimethoxytrityl)-ethyl-1-yl]-
1,4-dioxan-2-yl]uracil, 15
Compound 12 (940 mg, 1.7 mmol) in 10 mL of dry pyridine was
added acetic anhydride (360 ml, 3.4 mmol) at 0–5◦C under an atmosphere
of nitrogen. The mixture was stirred overnight. The mixture was the
concentrated under reduced pressure and the residue was purified by flash
chromatography using a 9:1 mixture of ethyl acetate and n-hexane as the
eluent to afford product 15 (988 mg, 98%).
The product 15 (Figure 8) exhibited the following spectroscopic prop-
1
erties: H-NMR (CDCl3, 400MHz): δ = 2.15 (s, 3H, CH3), 3.15 (dd, 10Hz,
5.2Hz, 1H, HA), 3.32 (dd, 10Hz, 5.6Hz, 1H), 3.34 (dd, 11.6Hz, 10Hz, 1H,
HE2), 3.61–3.78 (m, 1H, HD), 3.79 (s, 2×3H, OCH3), 3.89–3.95 (m, 2H, HC
and HD), 3.97 (dd, 11.4Hz, 3Hz, 1H, HE1), 5.07 (dd, 9.6Hz, 5.2Hz, 1H, HB),
5.69 (dd, 10Hz, 2.8Hz, 1H, HF), 5.75 (d, 8Hz, 1H, HH), 6.81–6.85 (m, 4H,
aromatic H), 7.20–7.22 (m, 1H, aromatic H), 7.27–7.32 (m, 6H, aromatic
H), 7.40–7.44 (m, 3H, aromatic H and HG), 9.42 (broad s, 1H, N-H) ppm.
13C-NMR (CDCl3, 100MHz) δ = 21.0, 55.2, 61.4, 68.3, 70.9, 73.4, 78.4, 86.3,
102.8, 113.2, 126.9, 127.91, 127.98, 129.9, 130.0, 135.5, 135.6, 139.4, 144.5,
149.5, 149.8, 158.6, 163.0, 170.3 ppm. IR (neat): 3188, 3060, 2934, 2837,
1692, 1508, 1244, 1030, 827, 757, 727, 703 cm−1. HRMS (ESI) m/z: Calcd.
for C33H34N2O9 [M+Na]+ 625.2162, Found 625.2152. Elem. Anal.: Calcd.
for C33H34N2O9: C 65.77, H 5.69, N 4.65; found C 65.35, H 5.76, N 4.73.

A Novel, Optically Active Uridine Analog
235
FIGURE 9 Structure 14.
1-[(2R,5S)-5-[(1S)-acetyloxy-2-hydroxylethyl-1-yl]-1,4-dioxan-2-
yl]uracil, 14
Compound 15 (849 mg, 1.4 mmol) in 25 mL of dry dichloromethane
was added 40 mL solution of dichloroacetic acid (2%, v/v) in
dichloromethane. The mixture was stirred for half an hour and quenched
with 25 mL of a saturated aqueous NaHCO3 solution. The separated aque-
ous phase was extracted with 3 × 40 mL dichloromethane. The combined
organic phase was dried over anhydrous Na2SO4, and the solution the
filtered and concentrated under reduced pressure. The crude product was
purified by flash chromatography, elution first with ethyl acetate then with
methanol, to afford product 14 as a white solid (234 mg, 55%).
The product 14 (Figure 9) exhibited the following spectroscopic prop-
erties: 1H-NMR (CD3OD, 400MHz): δ = 2.07 (s, 3H, CH3), 3.58 (dd, 11.4Hz,
9.8Hz, 1H, HE2), 3.70–3.74 (m, 1H, HB), 3.77–3.82 (m, 1H, HC), 3.92–3.98
(m, 2H, HE and HD1), 4.06 (dd, 11.6, 2.8Hz, 1H, HD2), 4.13 (dd, 11.2, 6.4Hz,
1H, HA), 4.16 (dd, 11.2Hz, 5.4Hz, 1H, HA), 5.69 (dd, 10Hz, 2.8Hz, 1H, HF),
5.70 (d, 8Hz, 1H, HH), 7.71 (d, 8Hz, 1H, HG) ppm. 13C-NMR (CD3OD,
100MHz): δ = 20.9, 66.4, 69.2, 69.4, 69.8, 76.0, 80.0, 103.1, 142.3, 151.9,
166.0, 172.8 ppm. IR (neat): 3477, 3190, 3110, 3074, 2996, 2879, 1697, 1268,
1105 cm−1. MS (EI): 230.3, 197(M+-(CH3COCHCH2OH)), 189(M+-uracil).
HRMS (ESI): Calcd. for C12H16N2O7 [M+Na]+ 323.0856, Found 323.0862.
Elem. Anal.: Calcd. for C12H16N2O7: C 48.00, H, 5.37, N, 9.33; found C,
47.51, H, 5.46, N, 9.85.
Dinucleotide Analog 16
Compound 14 (8 mg, 0.027 mmol) and compound 13 (30 mg, 0.039
mmol) with a magnetic stirring bar were dried in high vacuo over night. The
mixture was then added 6 mL of dry acetonitrile and 0.3 mL of 1-H tetrazole
(0.45 M in acetonitrile). The resulting solution was stirred for 15 hours and
then added a solution of iodine (1M in a mixture of THF, 2,6-lutidine and

236
Q. Yu and P. Carlsen
H2O (2:2:1) until a persistent orange color. The solution was quenched
with a saturated sodium thiosulfate solution, and then added 4 mL of a
saturated NaHCO3 solution and the phases separated. The aqueous phase
was extracted with dichloromethane 4 × 8 mL. The combined organic phase
was dried over anhydrous Na2SO4, filtered and then concentrated under
reduced pressure. The crude product was purified by flash chromatography
using gradient elution of the mixture of dichloromethane and methanol
(25:1, 15:1). The product, 16, was obtained as a white product, 16 mg,
62% yield. The product exhibited the following spectroscopic properties:
1H-NMR (CDCl3, 400MHz): δ = 2.09, 2.11 (s, CH3COO), 2.50–2.67 (m,
CH2CN), 2.71–2.75 (m, CH2CN), 3.14–3.25, 3,38–3.52, 4.04–4.10 (m, CH2-
CH-Uracil), 3.79, 3.80 (s, OCH3), 4.17–4.23 (m, OCH2CH2CN), 5.61–5.78
(m, CH=CH-CO in uracil and anomeric H), 6.81–6.86 (m, aromatic pro-
tons), 7.22–7.32 (aromatic protons and CH = CH-CO in uracil), 7.38–7.44
(aromatic protons and CH = CH-CO in uracil), 3.64–3.69, 3.72–3.81,
3.84–3.98, 4.21–4.33, 4.37–4.44, 4.52–4.67 (m, the other protons) ppm. 31P
NMR (CDCl3): -1.83, -1.90 ppm. HRMS (ESI): Calcd. for C46H50N5O17P
[M+Na]+ 998.2837, Found 998.2802.
REFERENCES
1. Ichikawa, Eiko; Kato, Kuniki Sugar-modified nucleosides in past 10 years, a review. Current Medicinal
Chemistry 2001, 8, 385–423.
2. a) Grate, J.W.; Frye, G.C. in Sensors Update, (Eds): Baltes, H.; Go¨pel, W.; Hesse, J., Wiley-VCH,
Weinheim, 1966, vol. 2, pp. 10–20. b) Szarek, W.A.; Pinto, B.M.; Iwakawa, M. Synthesis and biological
activity of nucleoside analogues involving modifications in the carbohydrate ring. Can. J. Chem.
1985, 63, 2149–2161. c) Hronowski, L.J.; Szarek, W.A. Synthesis and biological evaluation of novel
pyrimidine nucleoside analogues of 1,4-oxathiane, 1,4-dithiane, and 1,4-dioxane. J. Med. Chem. 1982,
25, 522–526. d) Prisbe, E.J. Synthesis and antiviral evaluation of 1,4-dioxane nucleoside analogueues
related to nucleoside dialdehydes. J. Med. Chem. 1986, 29, 2445–2450. e) Mitsuaki, M.; Naoko, K.;
Yamaizumi, Z.; Okamoto, Y.; Nagahara, K.; Takayanagi, H. Synthesis of a novel dioxane nucleoside
having two bases, 2(R)-(5-fluorouracil-1-yl)-5(R)-hydroxymethyl-3(R)-(uracil-1-yl)-1,4-dioxane and
its 2(S)-isomer, from uridine. Tetrahedron Lett. 1997, 38, 6841–6844. f) Szarek, W.A.; Vyas, D.M.;
Achmatowicz, B., Synthesis of nucleoside analogues of 1,4-oxathiane, 1,4-dothiane, and 1,4-dioxane.
J. Heterocycle. Chem. 1975, 12, 123–127. g) Van Aerschot, A.; Balzarini, J.; De Clercq, E.; Herdewijn,
P. Synthesis and antiviral activity of 1,4-dioxane, 1,4-oxathiane and morpholine nucleoside analogs.
Nucleosides Nucleotides 1991, 10, 591–592. h) Van Aerschot, A.; Janssen, G.; Herdewijn, P., Nucleoside
analogs with a 1,4-dioxane, 1,4-oxathiane or 1,4-oxazine ring structure as the carbohydrate fragment.
Bulletin des Societes Chimiques Belges 1990, 99, 769–777.
3. Sinha, N.D.; Biernat, J.; Mcmanus, J.; Ko¨ster, H., Polymer support oligonucleotide synthesis. XVIII:
Use of -cyanoethyl-N,N-dialkylamino-/N-morpholino phosphoramidite of deoxynucleosides for the
synthesis of DNA fragments simplifying deprotection and isolation of the final product. Nucleic Acids
Res. 1984, 12, 4539–4557.
4. Baskaran, S.; Aurich, H.G.; Biesemeier, F.; Harms, K. Cycloadducts from highly functionalized
nitrones and oximes as ligands in the enantioselective addition of diethylzinc to benzaldehyde.
J. Chem. Soc., Perkin Trans. 1 1998, 22, 3717–3724.
5. a) Nagashima, N.; Ohno, M. Selective monoalkylation of acyclic diols by means of dibutyltin oxide
and fluoride salts. Chem. Pharm. Bull. 1991, 39, 1972–1982. b) Nagashima, N.; Ohno, M. An efficient
O-monoalkylation of dimethyl L-tartrate via O-stannylene acetal with alkyl halides in the presence of
cesium fluoride. Chem. Lett. 1987, 1, 141–144.

A Novel, Optically Active Uridine Analog
237
6. a) Marshall, J.A.; Andersen, N.H.; Hochstetler, A.R. Reduction of malonic enolates with lithium
aluminum hydride. J. Org. Chem. 1967, 32, 113–118. b) Shi, M.; Jiang, J.; Feng, Y., Chiral C2-symmetric
2,3-disubstituted aziridine and 2,6-disubstituted piperidine as chiral ligands in the addition reaction
of diethylzinc with arylaldehydes. Tetrahedron: Asymmetry 2000, 11, 4923–4933. c) Marshall, J.A.;
Beaudion, S. Stereoselective Synthesis of Higher Sugars by Homologation of Carbohydrate-Derived
Enals with Nonracemic-(Silyloxy) Allylic Stannanes and Substrate-Directed Hydroxylation. J. Org.
Chem. 1994, 59, 6614–6619.
7. a) Albizati, K.F.; Babu, S. etc. A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid.
Tetrahedron Lett. 2001, 42, 6481–6485. b) Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Satoh, S.; Hirama,
M.; Ogasawara, K. Selective manipulation of hydroxy groups in (2S,3S)-threitol. Synthesis 1986, 10,
811–817.
8. a) Vorbru¨ggen, H.; Krolikiewicz, K. Nucleoside syntheses. XXII. Nucleoside synthesis with
trimethylsilyl triflate and perchlorate as catalysts. Chem. Ber. 1981, 114, 1234–1255. b) Vorbru¨ggen,
H.; Ho¨fle, G. Nucleoside syntheses. XXIII. On the mechanism of nucleoside synthesis. Chem. Ber.
1981, 114, 1256–1268.
9. Colacino, E.; Sindona, G.; Gosselin, G.; Mathe´, C. Synthesis and Biological Evaluation of Some 5-
Nitro- and 5-Amino Derivatives of 2ꢁ-Deoxycytidine, 2ꢁ,3ꢁ-Dideoxyuridine, and 2ꢁ,3ꢁ-Dideoxycytidine.
Nucleosides, Nucleotides Nucleic Acids, 2003, 22, 2013–2026.
10. Fisher, E.F.; Caruthers, M.H., Color coded triarylmethyl protecting groups useful for deoxypolynu-
cleotide synthesis. Nucleic Acids Res. 1983, 11, 1589–1599.
11. a) Stu¨tz, J.A.R.; Richert, C. Synthesis of a formamidine-protected 5ꢁ-amino-2ꢁ,5ꢁ-dideoxyguanosine
phosphoramidite and preparation of 5ꢁ-acylamidooligonucleotides. Tetrahedron Lett. 2004, 45,
509–513. b) Eisenfuhr, A.; Arora, P.S. A ribozyme with michaelase activity: synthesis of the substrate
precursors. Bioorg. Med. Chem. 2003, 11, 235–249.
12. Ferris, J.P.; Peyser, J.R. Rapid and efficient syntheses of phosphorylated dinucleotides. Nucleosides
Nucleotides, 1994, 13, 1087–1111.
13. Gait, M.J. Oligonucleotide Synthesis, A Practical Approach, IRL PRESS: Oxford, Washington DC, 1984.
14. Yu, Q.; Kaffarnik, S.; Carlsen, P. Synthesis of Optically Active 1,4-Dioxane Nucleotide Analogues,
Synth. Commun., 2008, 38, 4250–4264.