A practical synthesis of xylo- and arabinofuranoside precursors by diastereoselective reduction using Corey-Bakshi-Shibata catalyst

Article abstract of DOI:10.1080/15257770.2017.1414240

The Corey-Bakshi-Shibata (CBS) catalyst provides an efficient mechanism to reduce ketones and achieve desired enantiopure alcohols. Herein, the diastereoselective reduction of C-2′ and C-3′-keto ribofuranoside derivatives to the corresponding arabino- and xylofuranosides in greater than 95% diastereomeric excess is reported. The stereo-directed substitution with an azido group as well as the synthesis of prodrugs cytarabine and vidarabine are also described. The reported strategy offers superior diastereoselectivity, shorter reaction times, and obviates cooling required with comparable protocols involving achiral reductants.

Full text of DOI:10.1080/15257770.2017.1414240

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
A practical synthesis of xylo- and
arabinofuranoside precursors by
diastereoselective reduction using Corey-Bakshi-
Shibata catalyst
Lynn M. Utley, Jessica Maldonado & Ahmed M. Awad
To cite this article: Lynn M. Utley, Jessica Maldonado & Ahmed M. Awad (2018): A
practical synthesis of xylo- and arabinofuranoside precursors by diastereoselective reduction
using Corey-Bakshi-Shibata catalyst, Nucleosides, Nucleotides and Nucleic Acids, DOI:
10.1080/15257770.2017.1414240
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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
, VOL. , NO. , –
https://doi.org/./..
A practical synthesis of xylo- and arabinofuranoside
precursors by diastereoselective reduction using
Corey-Bakshi-Shibata catalyst
Lynn M. Utley, Jessica Maldonado, and Ahmed M. Awad
Department of Chemistry, California State University Channel Islands, Camarillo, California, USA
ABSTRACT
ARTICLE HISTORY
Received  June 
Revised  November 
Accepted  December 
The Corey-Bakshi-Shibata (CBS) catalyst provides an efficient
mechanism to reduce ketones and achieve desired enantiopure
alcohols. Herein, the diastereoselective reduction of C-2ꢀ and
C-3ꢀ-keto ribofuranoside derivatives to the corresponding
arabino- and xylofuranosides in greater than 95% diastereomeric
excess is reported. The stereo-directed substitution with an azido
group as well as the synthesis of prodrugs cytarabine and vidara-
bine are also described. The reported strategy offers superior
diastereoselectivity, shorter reaction times, and obviates cooling
required with comparable protocols involving achiral reductants.
KEYWORDS
nucleoside analogues;
nucleoside drugs and
prodrugs; keto-nucleosides;
xylo- and
arabinofuranosides;
Corey-Bakshi-Shibata
catalyst; diastereoselective
reduction; oxazaborolidine
GRAPHICAL ABSTRACT
Introduction
With deliberate chemical modifications, nucleoside analogs elicit therapeutic effects
by inhibition of cancer cell growth and disruption of viral replication.[1,2] Several
CONTACT Ahmed M. Awad
ahmed.awad@csuci.edu
Channel Islands, One University Drive, Camarillo, CA , USA.
Department of Chemistry, California State University
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lncn.
©  Taylor & Francis Group, LLC

2
L. M. UTLEY ET AL.
Figure . Structures of important nucleoside drugs/prodrugs represent analogs that require specific
stereochemistry at the chiral C-ꢀ and C-ꢀ positions.
nucleoside drugs and prodrugs have been approved for cytotoxic therapy and for
treatment of hepatitis, HIV, and HSV (Figure 1). 3ꢀ-azidothymidine (AZT) was
the first antiretroviral treatment for HIV and is also used to treat several human
cancers.[3] Cytarabine (Ara-C) is an arabinofuranoside currently used for treat-
ment of acute myeloid leukemia.[4] Gemcitabine, another pyrimidine derivative, has
activity pertaining to several solid tumors including pancreatic, breast, lung, and
ovarian cancers.[5] Fludarabine is a purine analog used for treatment of malignant
blood disorders,[5] and most recently, uridine triacetate has been approved for treat-
ment of hereditary orotic aciduria (HOA) and as an antidote for certain types of
chemotherapy.[6] A nucleoside antibiotic, A201A, with potent antibacterial activi-
ties has also been reported.[7]
A key step in the synthesis of such analogs is to convert the 2ꢀ/3ꢀ-hydroxyl groups
on the ribose moiety into desired modifications with retention of the configuration.
Several approaches have been investigated, including the formation of anhydro
intermediate for pyrimidine nucleosides,[8] lyxo-epoxides which can be opened
selectively at the C-2ꢀ or C-3ꢀ,[9] modification of the D-xylose sugar prior to addition
of the nitrogenous base,[10] or reduction of 3ꢀ-oxime nucleoside to 3ꢀ-hydroxyamino
that are subject to a catalytic reduction to form 3ꢀ-amino analogs.[11]
The main goal of this work is to develop an efficient and economical route to
synthesize xylo- and arabinofuranosides from commercially available ribonu-
cleosides. These molecules may serve as effective precursors for achieving
desired stereochemistry at C-2ꢀ and C-3ꢀ positions during further synthesis of
important nucleoside analogs such as fluoro-, azido-, and amino derivatives.[12]

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Xylofuranosides have also been reported as excellent precursors for the synthesis of
potential nucleic acid therapeutics such as guanidine-linked DNA/RNA antisense
and antigene therapy[13], N3ꢀ→P5ꢀ phosphoramidates/thio-phosphoramidates,[14]
and xylonucleic acids (XyloNA).[15]
Results and discussion
The methodology in this study involves inversion of configuration at the 2ꢀ/3ꢀ-
positions of ribonucleosides by a two-step process, oxidation to keto-nucleoside
followed by diastereoselective reduction of the carbonyl group (Scheme 1). The oxi-
dation/reduction/substitution sequence has been described as an effective route for
stereocontrolled synthesis of nucleoside analogs.[16] Robins and co-workers showed
that stirring of protected keto-nucleosides with sodium triacetoxyborohydride (gen-
erated in situ from sodium borohydride and acetic acid) in acetic acid at low temper-
ature for 48 h resulted in hydride delivery at the α-face with high stereoselectivity.[17]
A similar reaction procedure has been applied to synthesize 3ꢀ-aminoacylamino-3ꢀ-
deoxyadenosine, an analog of the antibiotic puromycin.[18] However, the addition
and reaction of the keto-nucleoside were carried out at an external cooling bath
temperature of 8°C and the reaction was subject to mechanical stirring for 2.5 days.
The double inversion strategy to alter the stereochemistry of the 2ꢀ/3ꢀ-hydroxyl
groups was also reported to synthesize 2ꢀ-/3ꢀ-aspartyl or glutamyl adenosine.[19]
Dess–Martin periodinane was used as an oxidant for the conversion of both 2ꢀ- and
3ꢀ-hydroxyl groups of the ribose into keto-adenosine intermediates. The reduction
of the 3ꢀ-keto analog with excess NaBH(OAc)3, generated in situ at 0°C, provided the
ribo (minor) and xylo (major) diastereomers, as the hydride preferentially attacked
Scheme . Synthesis of xylofuranoside derivatives.

4
L. M. UTLEY ET AL.
the less sterically hindered α-face. The same method was described in the synthesis
of the nucleoside antibiotic 5ꢀ-O-[N-(salicyl)sulfamoyl]-adenosine (SAL-AMS) that
involves the incorporation of fluorine at the 2ꢀ and 3ꢀ positions.[20] Other optimized
protocols to a more efficient stereoselective reduction of keto-nucleosides involved
the use of commercial NaHB(OAc)3 in acetonitrile containing a minimal amount of
acetic acids. A much shorter reaction time (4 h) was reported, but the reaction pro-
ceeded at a very low temperature (−78°C to −18°C).[21] In addition, NaHB(OAc)3
is expensive and required greater quantity (2.4 equivalent) for complete conversion.
To facilitate the diastereoselective reduction of keto-nucleosides, we investi-
gated the use of Corey-Bakshi-Shibata oxazaborolidine (CBS) as a catalyst. CBS-
oxazaborolidine has been reported as a chiral catalyst that mediates the borane
reduction of ketones to secondary alcohols with excellent enantioselestivity.[22]
With one stereogenic center, CBS-oxazaborolidine exists as two enantiomers, (S)-
(−)-2-methyl-CBS-oxazaborolidine and (R)-(+)-2-methyl-CBS-oxazaborolidine.
The (S)-Me-CBS delivers a hydride ion to the Re face of the carbonyl, while the
(R)-Me-CBS delivers the hydride ion to the Si face, thus allowing for enantioen-
riched alcohol formation.[23] The CBS enantioselective reduction is practical, as the
preparation of the catalyst is quick, it is easy to handle, and inexpensive reagents
are involved.[24] It has been reported that ketones, which are susceptible to noncat-
alytic reduction by BH3, can be reduced to chiral alcohols by up to 90% ee using
electronically tuned-CBS catalyst with BH3.[25] We utilized the (R)-Me-CBS enan-
tiomer of the catalyst to reduce both 2ꢀ-keto and 3ꢀ-keto nucleosides. This catalytic
hydrogenation produced the corresponding arabino and xylo structures for both
pyrimidine and purine nucleosides in an excellent yield with high diastereoselec-
tivity (greater than 95:5 dr, Figure 2). In addition, the reduction was completed in
2 h at room temperature. These results suggest that our method to stereospecifically
Figure . Relative ratio of the H-NMR H-ꢀ signals for the diastereomeric crude mixture of A) com-
pound 9 and B) compound 15.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
reduce keto-nucleosides is more practical and convenient than the reported sodium
triacetoxyborohydride protocols.
As shown in Scheme 1, commercially available purine and pyrimidine nucle-
osides were converted to corresponding xylofuranoside analogs. Adenosine and
cytidine were first protected on the exocyclic amino group to produce N6-
benzoyladenosine and N4-benzoylcytidine, respectively, according to the described
method.[26] TBDMS protecting group was then selectively introduced to the C-
2ꢀ and C-5ꢀ hydroxyls of uridine, N4-benzoylcytidine, and N6-benzoyladenosine
to form 2ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)nucleoside derivatives 1, 4, and 7,
respectively.[27] The inversion of configuration at the 3ꢀ-position of these com-
pounds was accomplished by oxidation of the C-3ꢀ alcohol followed by CBS-
catalyzed enantioselective reduction of the formed ketones. Compounds 1, 4, and 7
were treated with 1.5 equivalents of chromium trioxide in a mixture of pyridine and
acetic anhydride to form the corresponding 3ꢀ-keto nucleoside derivatives 2, 5, and
8, respectively. Initially, the oxidation was carried out using 3.0 equiv of CrO3 and
6.0 equiv of Ac2O as previously reported.[11] However, a much higher reaction yield
(80% for 8 and >90% for 2 and 5) was obtained when the reagents were reduced
to 1.5 equiv of CrO3 and 2.0 equiv of Ac2O. This modified protocol minimized the
possibility of a chromium-nucleoside complex formation, and accordingly no need
to explore alternative oxidants such as Pfitzner–Moffatt or Dess–Martin periodi-
nane was proposed. We then examined the reduction of the formed carbonyl group
using CBS as a chiral catalyst. CBS has been reported as an efficient catalyst dur-
ing the synthesis of important biomolecules, including the formation of glycosyl
α-amino acids synthons by stereocontrolled reduction of glycosyl α-ketoesters,[28]
and the synthesis of steroidal glycosides, saundersiosides.[29] However, the catalyst
was not effective in the stereoselective preparation of all four isomers of β- and γ -
hydroxy α-amino acids,[30] in which enzymatic kinetic resolution was the method
of choice.[31] In our study, the enantioselective reduction of the 3ꢀ-keto derivatives 2,
5, and 8 was performed using the (R)-Me-CBS in a 10 mol% and 1 equivalent of BH3
in anhydrous THF as a solvent. The NMR data of crude mixtures showed that each
catalytic chiral reduction afforded the xylofuranose ribonucleosides 3, 6, and 9 with
a high level of diastereoselectivity (>95:5 dr, Figure 2A). High reaction yields were
obtained and pure compounds were confirmed by HRMS, 1H NMR, 13C NMR and
X-ray crystallography. Figure 3 represents the X-ray structure for compound 9 in
which the crystal structure revealed the β-D-xylo configuration. Moreover, to deter-
mine the minimum mol% of catalyst required for the diastereoselective reduction
of the carbonyl group, 5 mol% of the CBS catalyst was evaluated. The NMR data of
the crude product showed that 5 mol% can be used to catalyze the reduction, how-
ever, further purification was needed to remove the limited amount of unreacted
keto-ribonucleoside derivatives.
The resulting xylofuranosides provide precursor molecules for further modifica-
tion at C-3ꢀ to synthesize analogs that have potential applications in pharmacother-
apeutics. We demonstrated the conversion of the 3ꢀ-hydroxy group of compound 9
into an azide via the 3ꢀ-O-mesylate activation of the alcohol (Scheme 2). The silyl

6
L. M. UTLEY ET AL.
Figure . X-ray structure of N-benzoyl--[ꢀ,ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-xylofuranosyl]
adenine (9).
groups of the mesylated analog 10 were removed with tetrabutylammonium fluo-
ride (TBAF). The deprotected product 11 was subject to an SN2 nucleophilic attack
by azide group using NaN3 to form the desired azido derivative 12, which was con-
firmed by HRMS and its NMR analysis was in agreement with the reported data.[32]
This provides an alternative and efficient method to synthesize 3ꢀ-azido ribonucleo-
sides, especially with purine nucleosides in which the nucleophilic substitutions on
the secondary alcohols are stereochemically challenging.[27]
We applied the CBS-catalyzed diastereoselective reductive approach to produce
arabinoside precursors for the synthesis of nucleoside prodrugs vidarabine and
cytarabine (Scheme 3). Benzoyl group was used to protect the N6 and N4-amino
moieties of adenosine and cytidine, respectively. TBDMS was applied to block C-3ꢀ
and C-5ꢀ hydroxyls of the ribose sugar resulting in formation of N-benzoyl-3ꢀ,5ꢀ-
bis-O-(tert-butyldimethylsilyl)ribonucleosides 13 and 16. Oxidation of the latter
compounds with CrO3 in a mixture of pyridine and acetic anhydride afforded the
corresponding 2ꢀ-keto derivatives 14 and 17, respectively. When the oxidation was
conducted without protection of the amino group on the adenine moiety, it has
Scheme . Synthesis of N-benzoyl-ꢀ-azido-ꢀ-deoxyadenosine.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
Scheme . Synthesis of arabinofuranoside derivatives.
been reported that the 2ꢀ-keto adenosine derivative exists as an equilibrium mixture
of the ketone and its hydrate form. The DFT calculations suggested the origin of the
formation of the 2ꢀ-ketone hydrate via the internal hydrogen bond network, which
was not observed in the 3ꢀ-keto isomer.[19] The NMR and HRMS data indicated
that this has not been an issue in our case and no ketone hydrate was detected. The
electron-withdrawing benzoyl protective group might decrease the electron density
of the purine ring, thus reducing the tendency for H-bonding and prevent the for-
mation of the 2ꢀ,2ꢀ-diol. The diastereoselective hydrogenation of the carbonyl using
10 mol% (R)-Me-CBS and 1 equivalent of BH3ꢀTHF in anhydrous THF afforded the
arabinofuranose nucleosides 15 and 18 in a high level of diastereoselectivity (>95:5
dr, Figure 2B). Removal of the protecting groups from 15 produces the antiviral
nucleoside prodrug, vidarabine (Ara-A) which is used for treatment of HSV,[33]
while deprotection of 18 yields the cytotoxic nucleoside prodrug, cytarabine (Ara-
C) which is used as a chemotherapy agent in the treatment of acute leukemias.[34]
To examine the extent in which the diastereoselectivity is governed by the chiral
catalyst, the reduction of keto-ribonucleosides was carried out in absence of the cat-
alyst as well as by using the (S)-Me-CBS-oxazaborolidine enantiomer of the catalyst
(Table 1). In contrast to the R-CBS, under the same reaction conditions, reductions
in the absence of catalyst and by the S-CBS enantiomer were comparatively inef-
fective. While all reactions elicited the xylofuranoside in high diastereomeric ratio
(>95:5), only the R-CBS enantiomer produced a significantly high total yield. These
results indicate that although the hydride preferentially attacks the less sterically
hindered α-face of the keto substrate (>95% xylo formation), the stereocontrolled
reduction is accomplished and considerably accelerated by the chiral catalyst.

8
L. M. UTLEY ET AL.
Table . Borane reduction of keto-nucleosides 2 and 8 in absence of
CBS catalyst and with (R) or (S)-CBS enantiomers.
compound
CBS catalyst
yield (%)∗






—
R
S
—
R
S






∗all reactions produced the corresponding xylofuranoside in dr >:
Conclusion
In summary, we have developed an economical and efficient method for the diastere-
opure synthesis of arabino and xylofuranosides using the CBS chiral catalyst to
reduce the corresponding keto-ribonucleosides. Our method has proven successful
in both pyrimidine and purine nucleosides, providing a facile solution to achieve
desired stereochemistry in nucleoside drug/prodrug design that contributes to a
wide range of medicinal and biological applications. Moreover, this approach would
be particularly useful in the commercial scale manufacturing of nucleoside analogs,
in which the commercially available starting materials are considerably expensive.
Furthermore, we applied this method in the synthesis of current pharmaceuticals,
vidarabine and cytarabine. We believe that this method may serve biomedical sci-
ence as an efficient approach to synthesize nucleoside building blocks for antigene
and antisense therapeutics.
Experimental
General procedures
1H and 13C NMR spectra were recorded on a 500MHz Varian instrument using
CDCl3 or DMSO-d6 as solvents. Chemical shifts are reported in parts per million
(δ), and signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and coupling constants (J) are given in Hz. Thin layer chromatogra-
phy (TLC) was carried out on Silica Gel 60 F254 pre-coated plates and visualization
of the products was performed under UV light. Silica gel used for column chro-
matography was Scientific Silica Gel (particle size 0.035–0.070 mm). ESI mass spec-
tra were recorded on Micromass QTOF2 Quadrupole/Time of Flight Tandem mass
spectrometer with Turbo Ion Spray ionization source. X-ray Crystallography was
measured at 100K with Cu K-alpha radiation. The data collection and cell determi-
nation was done by Bruker Apex II software. Program Shelx were used for the struc-
ture determination and refinements. All reactions were performed under nitrogen
atmosphere using anhydrous solvents.
General procedure for oxidation of compounds (1), (4), and (7). Pyridine
(18.0 mmol) was added dropwise to a mixture of CrO3 (9.0 mmol) and molecular
˚
sieves 4 A beads (5 g) in CH2Cl2 (25 mL) at 0°C. After 30 min Ac2O (12.0 mmol)

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
was added and the mixture was stirred at 0°C for another 15 min. To this mixture
was added a solution of the protected nucleoside 1, 4, or 7 (6.0 mmol) in CH2Cl2
(15 mL) at room temperature. After the mixture was stirred at room temperature
for further 3 h, the reaction mixture was poured into EtOAc (250 mL) and stirred
for 40 min at room temperature. The mixture was filtered through Celite and the
filtrate was concentrated under reduced pressure to dryness. The crude was then
redissoved in EtOAc, washed with 5% NaHCO3, and dried over anhydrous Na2SO4.
The mixture was then concentrated under reduced pressure and purified by silica gel
column chromatography (30% ethyl acetate in hexanes for 2, and 40% ethyl acetate
in hexanes for 5 and 8) to afford pure compounds 2, 5, and 8, respectively.
1-[2ꢀ,5ꢀ-Bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuran-3ꢀ-ulosyl]uracil
(2) (94% yield) as a white foam. HRMS (ESI) m/z Calcd for C21H38N2O6NaSi2
(M+Na)+ 493.2166, found 493.2148. 1H NMR (500 MHz, CDCl3) 9.18 s, 1H (NH);
7.83 d, 1H, J = 7.8 (H-6); 6.26 d, 1H, J = 7.8 (H-1ꢀ); 5.8 d, 1H, J = 7.8 (H-5);
4.23 s, 1H (H-2ꢀ); 4.16 d, 1H, J = 7.8 (H-4ꢀ); 3.91–3.90 m, 2H, (H-5ꢀ); 0.89 s, 9H,
(SiC(CH3)3); 0.85 s, 9H (SiC(CH3)3); 0.09 s, 3H (SiCH3); 0.08 s, 3H (SiCH3); 0.05 s,
3H (SiCH3); −0.004 s, 3H (SiCH3); 13C NMR (500 MHz, CDCl3) 208.3, 162.7,
150.2, 139.0, 103.7, 84.8, 81.9, 62.8, 25.7, 25.4, 18.2, 18.1, −4.8, −5.4, −5.6, −5.8.
N4-Benzoyl-1-[2ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuran-3ꢀ-
ulosyl]cytosine (5) (92% yield) as a white foam. HRMS (ESI) m/z Calcd for
1
C28H43N3O6NaSi2 (M+Na)+ 596.2588, found 596.2566. H NMR (500 MHz,
CDCl3) 8.75 s, 1H (NH); 8.22 d, 1H J = 7.3 (H-6); 7.92–7.51 m, 6H (BzH and
H-5); 6.43 d, 1H J = 7.9 (H-1ꢀ); 4.28 br s, 1H (H-2ꢀ); 4.21 d, 1H J = 7.3 (H-4ꢀ);
3.98–3.92 m, 2H (H-5ꢀ); 0.91 s, 9H (SiC(CH3)3); 0.85 s, 9H (SiC(CH3)3); 0.11 s,
3H (SiCH3); 0.07 s, 3H (SiCH3); 0.04 s, 3H (SiCH3); 0.00 s, 3H (SiCH3); 13C NMR
(500 MHz, CDCl3) 208.4, 133.4, 129.1, 127.6, 86.3, 82.0, 78.7, 62.8, 25.8, 25.4, 18.2,
18.2, 0.0, −4.9, −5.4, −5.5, −5.7.
N6-Benzoyl-9-[2ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuran-3ꢀ-
ulosyl]adenine (8) (80% yield) as a pale yellow foam. HRMS (ESI) m/z Calcd for
1
C29H43N5O5NaSi2 (M+Na)+ 620.2700, found 620.2675. H NMR (500 MHz,
CDCl3) 9.12 s, 1H (NH); 8.82 s, 1H (H-8); 8.36 s, 1H (H-2); 8.05–7.52 m, 5H
(BzH); 6.23 d, 1H, J = 8.3 (H-1ꢀ); 4.94 d, 1H, J = 7.8 (H-2ꢀ); 4.33 br s, 1H (H-4ꢀ);
4.01–3.96 m, 2H (H-5ꢀ); 0.92 s, 9H (SiC(CH3)3); 0.72 s, 9H (SiC(CH3)3); 0.11 s, 3H
(SiCH3); 0.08 s, 3H (SiCH3); −0.01 s, 6H ((Si(CH3)2); 13C NMR (500 MHz, CDCl3)
208.2, 140.9, 132.8, 128.9, 127.9, 85.2, 82.5, 77.9, 62.4, 25.6, 23.8, 21.0, 18.3, 18.0,
14.2, −4.8, −5.5, −5.6.
General procedure for CBS reduction of compounds (2), (5), and (8). To a solution
of (R)-(+)-2-methyl-CBS-oxazaborolidine catalyst (0.019 g, 0.067 mmol) in THF
(0.5 mL) was added BH3, 1 M in THF (0.670 mL, 0.670 mmol). The resulting solu-
tion was stirred for 30 min. A solution of2, 5, or 8 (0.670 mmol) in THF (1.0 mL) was
then added dropwise over 30 min., and the resulting solution was stirred at room
temperature for 3 hours. The reaction was cooled on ice and quenched with 1 mL of
methanol. After concentration under reduced pressure, the residue was purified by

10
L. M. UTLEY ET AL.
silica gel column chromatography (25% ethyl acetate in hexanes for 3, and 40% ethyl
acetate in hexanes for 6 and 9) to afford pure compounds 3, 6, and 9, respectively.
1-[2ꢀ,5ꢀ-Bis-O-(tert-butyldimethylsilyl)-β-D-xylofuranosyl]uracil (3) (90% yield)
as a white foam. HRMS (ESI) m/z Calcd for C21H40N2O6NaSi2 (M+Na)+ 495.2323,
found 495.2310. 1H NMR (500 MHz, CDCl3) 8.86 s, 1H (NH); 7.90 d, 1H, J = 8.3
(H-6); 5.73 s, 1H (H-1ꢀ); 5.62 d, 1H, J = 8.3 (H-5); 4.45 d, 1H, J = 1.5 (OH-3ꢀ);
4.31–4.19 m, 2H, (H-5ꢀ); 4.20 br s, 1H (H-2ꢀ); 4.17 br s, 1H (H-3ꢀ); 4.15 br s, 1H
(H-4ꢀ); 0.92 s, 9H (SiC(CH3)3); 0.88 s, 9H (SiC(CH3)3); 0.16 s, 3H (SiCH3); 0.15 s,
3H (SiCH3); 0.14 s, 3H (SiCH3); 0.11 s, 3H (SiCH3); 13C NMR (500 MHz, CDCl3)
163.4, 150.2, 140.9, 101.0, 92.3, 81.9, 80.7, 78.4, 62.9, 25.7, 25.6, 18.0, 17.9, 0.0, −4.8,
−5.2, −5.6, −5.8.
N4-Benzoyl-1-[2ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-xylofuranosyl]cytosine
(6) (75% yield) as a white foam. HRMS (ESI) m/z Calcd for C28H45N3O6NaSi2
(M+Na)+ 598.2745, found 598.2716. 1H NMR (500 MHz, CDCl3) 9.36 s, 1H (NH);
8.30 d, 1H, J = 7.4 (H-6); 7.97–7.49 m, 5H (BzH); 7.43 d, 1H, J = 7.4 (H-5); 6.04 d,
1H, J = 8.8 (H-1ꢀ); 5.75 br s, 1H (OH-3ꢀ); 4.34 d, 1H, J = 3.4 (H-3ꢀ); 4.17 d, 1H,
J = 8.8 (H-2ꢀ); 4.09 br s, 1H (H-4ꢀ); 4.01–3.96 m, 2H (H-5ꢀ); 0.89 s, 9H (SiC(CH3)3);
0.88 s, 9H (SiC(CH3)3); 0.12 s, 3H (SiCH3); 0.07 s, 3H (SiCH3); 0.06 s, 3H (SiCH3);
0.04 s, 3H (SiCH3); 13C NMR (500 MHz, CDCl3) 153.9, 128.8, 127.2, 123.2, 100.9,
83.5, 81.9, 81.5, 81.1, 78.4, 75.0, 62.9, 62.7, 41.0, 25.8, 25.5, 25.4, 18.2, 18.1, 0.0,
−4.6, −5.3, −5.6, −5.8.
N6-Benzoyl-9-[2ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-xylofuranosyl]adenine
(9) (67% yield) as a pale yellow foam. HRMS (ESI) m/z Calcd for C29H45N5O5NaSi2
(M+Na)+ 622.2857, found 622.2827. 1H NMR (500 MHz, CDCl3): 9.03 s, 1H (NH);
8.80 s, 1H (H-8); 8.30 s, 1H (H-2); 8.30–7.54 m, 5H (BzH); 5.97 d, 1H, J = 0.90
(H-1ꢀ); 5.60 d, 1H, J = 6.3 (OH-3ꢀ); 4.50 br s, 1H (H-2ꢀ); 4.28 q, 1H, J = 3.9 (H-3ꢀ);
4.18 d, 1H, J = 3.9 (H-4ꢀ); 4.25–4.07 m, 2H (H-5ꢀ); 0.90 s, 9H (SiC(CH3)3); 0.90 s,
9H (SiC(CH3)3); 0.10 s, 3H (SiCH3); 0.09 s, 3H (SiCH3); 0.08 s, 3H (SiCH3);
−0.004 s, 3H (SiCH3); 13C NMR (500 MHz, CDCl3) 164.5, 152.3, 150.8, 149.7,
142.6, 132.8, 128.9, 127.8, 92.2, 83.1, 82.3, 78.2, 62.3, 26.0, 25.8, 25.6, 25.6, 18.3,
17.9, −4.8, −4.9, −5.4, −5.5.
N6-Benzoyl-9-[2ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-3ꢀ-O-mesyl-β-D-xylofura-
nosyl]adenine (10). To a solution of 9 (1.2 g, 2.0 mmol) in anhydrous methy-
lene chloride (20 mL) were added DMAP (0.12 g, 1.0 mmol) and Et3N (2.8 mL,
20 mmol). The mixture was cooled to 0°C for 15 min. MsCl (0.4 mL, 5.0 mmol) was
added dropwise and the mixture was stirred under N2 at 0°C for 3 h. The solvent was
removed under reduced pressure and the residue was dissolved in EtOAc, washed
with H2O and brine, dried over anhydrous Na2SO4 and concentrated in vacuum.
The crude mixture was purified by silica gel column chromatography (50% ethyl
acetate in hexanes) to afford compound 10 (1.2 g, 89%). HRMS (ESI) m/z Calcd for
C30H48SSi2N5O7 (M+H)+ 678.2813, found 678.2843. 1H NMR (500 MHz, CDCl3):
9.18 s, 1H (NH); 8.72 s, 1H (H-8); 8.27 s, 1H (H-2); 8.00–7.45 m, 5H (BzH); 6.20 d,
1H, J = 1.40 (H-1ꢀ); 4.95 t, 1H, J = 2.4 (H-3ꢀ); 4.84 t, 1H J = 2.0 (H-2ꢀ); 4.54 q, 1H,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
J = 3.9 (H-4ꢀ); 3.54–4.20 m, 2H, (H-5ꢀ); 2.94 s, 3H (SCH3); 0.90 s, 9H (SiC(CH3)3);
0.88 s, 9H (SiC(CH3)3); 0.11 s, 3H (SiCH3); 0.10 s, 3H (SiCH3); 0.09 s, 3H (SiCH3);
0.06 s, 3H (SiCH3); 13C NMR (500 MHz, CDCl3) 164.6, 152.8, 151.7, 149.4, 142.6,
140.8, 132.8, 132.7, 128.9, 127.8, 90.2, 83.1, 82.0, 81.2, 79.8, 78.2, 62.2, 60.2, 38.2,
31.5, 25.9, 25.8, 25.6, 25.5, 18.3, 17.8, −4.9, −5.0, −5.2, −5.3.
N6-Benzoyl-9-(3ꢀ-O-mesyl-β-D-xylofuranosyl)adenine (11). To a solution of 10
(1.00 g, 1.48 mmol) in anhydrous THF (10 mL), tetra-n-butylammonium fluoride
(1M in THF, 3.75 mL, 3.75 mmol) was added dropwise over 30 min at 0°C and the
mixture was stirred under N2 at room temperature for 4 h. The solvent was removed
under reduced pressure and the residue was re-suspended in EtOAc, washed with
H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The
crude mixture was purified by silica gel column chromatography (10% methanol in
ethyl acetate) to afford white crystals of pure compound 11 (0.42 g, 63%). HRMS
1
(ESI) m/z Calcd for C18H20O7N5S (M+H)+ 450.1083, found 450.1071. H NMR
(500 MHz, DMSO): 11.24 s, 1H (NH); 8.77 s, 1H (H-8); 8.52 s, 1H (H-2); 7.65–
7.52 m, 5H (BzH); 6.49 d, 1H, J = 4.9 (H-1ꢀ); 5.19 d, 1H, J = 4.9 (OH-2ꢀ); 5.15 t, 1H,
J = 4.9 (OH-5ꢀ); 4.90 t, 1H, J = 3.4 (H-3ꢀ); 4.55 d, 1H, J = 2.5 (H-2ꢀ); 4.44 q, 1H,
J = 4.8 (H-4ꢀ); 3.52–3.76 m, 2H, (H-5ꢀ); 3.27 s, 3H (SCH3); 13C NMR (500 MHz,
DMSO) 166.1, 152.3, 150.9, 142.7, 132.9, 128.9, 126.0, 88.4, 83.1, 81.8, 80.9, 77.8,
61.3, 59.5, 59.1, 58.2, 55.4, 38.1.
N6-Benzoyl-3ꢀ-azido-3ꢀ-deoxyadenosine (12). To a solution of 11 (0.25 g,
0.56 mmol) in anhydrous DMF (3 mL), sodium azide (0.29 g, 4.48 mmol) was added
and the reaction mixture was heated under N2 at 90°C for 24 h. After cooling to
room temperature, the mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude mixture was purified by silica gel column chromatog-
raphy (5% methanol in ethyl acetate) to afford compound 12 (0.19 g, 86%). HRMS
1
(ESI) m/z Calcd for C17H17O4N8 (M+H)+ 397.1373, found 397.1367. H NMR
(500 MHz, DMSO): 11.21 s, 1H (NH); 8.26 s, 1H (H-8); 8.11 s, 1H (H-2); 7.48–
7.99 m, 5H (BzH); 5.91 d, 1H, J = 4.9 (H-1ꢀ); 4.95 t, 1H, J = 5.4 (H-3ꢀ); 4.57 d, 1H,
J = 4.9 (H-2ꢀ); 4.28 q, 1H, J = 4.8 (H-4ꢀ); 3.62–3.70 m, 2H, (H-5ꢀ).
General procedure for oxidation of compounds (13) and (16). Pyridine (18.0 mmol)
˚
was added dropwise to a mixture of CrO3 (9.0 mmol) and molecular sieves 4 A
beads (5 g) in CH2Cl2 (25 mL) at 0°C. After 30 min Ac2O (12.0 mmol) was added
and the mixture was stirred at 0°C for another 15 min. To this mixture was added
a solution of the protected nucleoside 13 or 16 (6.0 mmol) in CH2Cl2 (15 mL) at
room temperature. After the mixture was stirred at room temperature for further
3 h, the reaction mixture was poured into EtOAc (250 mL) and stirred for 40 min at
room temperature. The mixture was filtered through Celite and the filtrate was con-
centrated under reduced pressure to dryness. The crude was redissoved in EtOAc,
washed with 5% NaHCO3, and dried over anhydrous Na2SO4. The mixture was then
concentrated under reduced pressure and purified by silica gel column chromatog-
raphy (40% ethyl acetate in hexanes for 14, and 30% ethyl acetate in hexanes for 17)
to afford pure compounds 14 and 17, respectively.

12
L. M. UTLEY ET AL.
N6-Benzoyl-9-[3ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuran-2ꢀ-
ulosyl]adenine (14) (74% yield) as a pale yellow foam. HRMS (ESI) m/z Calcd
1
for C29H43N5O5NaSi2 (M+Na)+ 620.2700, found 620.2675. H NMR (500 MHz,
CDCl3) 9.07 s, 1H (NH); 8.69 s, 1H (H-8); 8.05 s, 1H (H-2); 8.01–7.51 m, 5H
(BzH); 5.89 s, 1H (H-1ꢀ); 5.20 d, 1H, J = 8.8 (H-3ꢀ); 4.12–3.80 m, 3H (H-4ꢀ and
H-5ꢀ); 0.95 s, 9H (SiC(CH3)3); 0.82 s, 9H (SiC(CH3)3); 0.25 s, 3H (SiCH3); 0.21s,
3H (SiCH3); 0.02 s, 3H (SiCH3); −0.09 s, 3H (SiCH3); 13C NMR (500 MHz, CDCl3)
207.0, 152.9, 142.2, 132.8, 128.9, 127.9, 80.5, 80.1, 71.5, 61.0, 26.0, 25.7, 25.7, 25.6,
18.3, 18.2, −4.3, −5.2, −5.4, −5.5.
N4-Benzoyl-1-[3ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuran-2ꢀ-
ulosyl]cytosine (17) (86% yield) as a white foam. HRMS (ESI) m/z Calcd for
1
C28H43N3O6NaSi2 (M+Na)+ 596.2588, found 596.2564. H NMR (500 MHz,
CDCl3) 8.80 s, 1H (NH); 7.88 br s, 1H (H-6); 7.63–7.50 m, 5H (BzH); 7.49 s, 1H
(H-5); 5.25 s, 1H (H-1ꢀ); 4.79 d, 1H J = 7.8 (H-3ꢀ); 4.03–3.95 m, 3H (H-4ꢀ and H-5ꢀ);
0.92 s, 9H (SiC(CH3)3); 0.90 s, 9H (SiC(CH3)3); 0.20 s, 3H (SiCH3); 0.16 s, 3H
(SiCH3); 0.07 s, 6H (Si(CH3)2); 13C NMR (500 MHz, CDCl3) 205.8, 133.4, 133.2,
129.1, 127.5, 100.1, 89.8, 86.1, 82.7, 82.4, 71.0, 70.9, 63.1, 60.3, 26.0, 25.9, 25.7, 18.5,
18.4, 18.2, 18.0, −4.3, −5.2, −5.3, −5.5.
General procedure for CBS reduction of compounds (14) and (17). To a solution
of (R)-(+)-2-methyl-CBS-oxazaborolidine catalyst (0.019 g, 0.067 mmol) in THF
(0.5 mL) was added BH3, 1 M in THF (0.670 mL, 0.670 mmol). The resulting solu-
tion was stirred for 30 min. A solution of 14 or 17 (0.670 mmol) in THF (1.0 mL) was
then added dropwise over 30 min., and the resulting solution was stirred at room
temperature for 3 hours. The reaction was cooled on ice and quenched with 1 mL
of methanol. After concentration under reduced pressure, the residue was purified
by silica gel column chromatography (40% ethyl acetate in hexanes) to afford pure
compounds 15 and 18, respectively.
N6-Benzoyl-9-[3ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl]
adenine (15) (73% yield) as a pale yellow foam. HRMS (ESI) m/z Calcd for
1
C29H45N5O5NaSi2 (M+Na)+ 622.2857, found 622.2836. H NMR (500 MHz,
CDCl3): 9.12 s, 1H (NH); 8.80 s, 1H (H-8); 8.47 s, 1H (H-2); 8.04–7.50 m, 5H
(BzH); 6.45 d, 1H, J = 2.5 (H-1ꢀ); 4.80 d, 1H J = 10.3 (OH-2ꢀ); 4.35 br s, 1H (H-2ꢀ);
4.14–4.11 m, 2H (H-3ꢀ and H-4ꢀ); 4.00–3.82 m, 2H (H-5ꢀ); 0.95 s, 9H (SiC(CH3)3);
0.94 s, 9H (SiC(CH3)3); 0.16 s, 6H (Si(CH3)2); 0.15 s, 6H (Si(CH3)2); 13C NMR
(500 MHz, CDCl3) 164.6, 152.6, 151.7, 149.2, 142.8, 133.8, 132.7, 128.8, 127.9, 86.3,
85.5, 78.1, 76.3, 63.3, 25.9, 25.8, 18.4, 18.0, 0.0, −4.6, −4.9, −5.4, −5.7.
N4-Benzoyl-1-[3ꢀ,5ꢀ-bis-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl]
cytosine (18) (83% yield) as a white foam. HRMS (ESI) m/z Calcd for
1
C28H45N3O6NaSi2 (M+Na)+ 598.2745, found 598.2723. H NMR (500 MHz,
CDCl3) 9.26 s, 1H (NH); 7.81 d, 1H, J = 7.3 (H-6); 7.59–7.42 m, 6H (BzH and H-5);
6.20 d, 1H, J = 3.9 (H-1ꢀ); 4.34 br s, 1H (H-3ꢀ); 4.22 t, 1H, J = 9.8 (H-2ꢀ); 4.00 br s,
1H (H-4ꢀ); 3.98–3.80 m, 2H (H-5ꢀ); 0.95 s, 9H (SiC(CH3)3); 0.89 s, 9H (SiC(CH3)3);
0.016 s, 6H (Si(CH3)2); 0.13 s, 3H (SiCH3); 0.10 s, 3H (SiCH3); 13C NMR (500 MHz,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
13
CDCl3) 162.5, 145.9, 133.4, 133.1, 131.9, 128.9, 128.6, 128.3, 127.4, 127.3, 87.8, 85.5,
84.4, 77.4, 76.0, 62.4, 25.9, 25.7, 18.4, 18.0, −4.4, −5.0, −5.4, −5.5.
Conflicts of interest
The authors declare no conflict interest.
Acknowledgements
Financial support was provided by the Start-up and the Mini-Grant funding from CSU Channel
Islands. We thank Dr. James Pavlovich and Dr. Guang Wu at the University of California Santa
Barbara for assistance in obtaining Mass spectra and X-ray data.
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