A new synthesis of 2-chloro-2'-deoxyadenosine (Cladribine), CdA)

Article abstract of DOI:10.1080/15257770.2011.587701

A new efficient route for the synthesis of 2-chloro-2';-deoxyadenosine (Cladribine), CdA) has been developed. The key step of this method was selective deprotection of the acetyl group at the 2' position; the 3', 5' acetyl groups were not affected. This can be accomplished efficiently with hydroxylamine hydrochloride and sodium acetate in pyridine. The 2' hydroxyl group was removed by the Barton-McCombie reaction. Using this strategy, CdA was prepared in five steps and 31.0% yields. Copyright Taylor and Francis Group, LLC.

Full text of DOI:10.1080/15257770.2011.587701

This article was downloaded by: [University of Saskatchewan Library]
On: 11 July 2012, At: 01:56
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
A New Synthesis of 2-chloro-2′-
deoxyadenosine (Cladribine), CdA)
Shaohong Xu a , Peng Yao a , Gairong Chen a & Hui Wang a
a Department of Chemistry and Chemical Engineering, Xinxiang
University, Xinxiang City, Henan Province, P. R. China
Version of record first published: 20 Jul 2011
To cite this article: Shaohong Xu, Peng Yao, Gairong Chen & Hui Wang (2011): A New Synthesis of
2-chloro-2′-deoxyadenosine (Cladribine), CdA), Nucleosides, Nucleotides and Nucleic Acids, 30:5,
353-359
To link to this article: http://dx.doi.org/10.1080/15257770.2011.587701
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
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.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Nucleosides, Nucleotides and Nucleic Acids, 30:353–359, 2011
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2011.587701
A NEW SYNTHESIS OF 2-CHLORO-2ꢀ-DEOXYADENOSINE
(CLADRIBINE), CDA)
Shaohong Xu, Peng Yao, Gairong Chen, and Hui Wang
Department of Chemistry and Chemical Engineering, Xinxiang University, Xinxiang City,
Henan Province, P. R. China
A new efficient route for the synthesis of 2-chloro-2 ꢁ;-deoxyadenosine (Cladribine), CdA) has
2
been developed. The key step of this method was selective deprotection of the acetyl group at the
2 ꢁ position; the 3 ꢁ, 5 ꢁ acetyl groups were not affected. This can be accomplished efficiently with
hydroxylamine hydrochloride and sodium acetate in pyridine. The 2 ꢁ hydroxyl group was removed
by the Barton-McCombie reaction. Using this strategy, CdA was prepared in five steps and 31.0%
yields.
Keywords 2-chloro-2ꢁ-deoxyadenosine (Cladribine), CdA); new synthesis; Barton-
McCombie reaction
The deaminase-resistant drug Cladribine (2-chloro-2ꢁ-deoxyadenosine,
CdA), a close analogue of 2ꢁ-deoxyadenosine, is used for treatment of pa-
tients with hairy cell leukemia.[1] The potential of CdA as a chemotherapeutic
agent against lymphoid neoplasms was proposed by Carson et al.[2] CdA also
has been used for treatment of other neoplasms including acuteleukemia,[3]
chronic myelogenous leukemia,[4] cutaneous T-cell lymphoma,[5] and non-
Hodgkin’s lymphoma.[6]
The first commonly used synthetic sequence to synthesize CdA is a
purine-sugar coupling procedure. CdA was first prepared by Venner in
Fischer-Helferich synthesis of 2ꢁ-deoxyuncleosides in 1960; it was an interme-
diate for synthesis of both 2ꢁ-deoxyguanosine and 2ꢁ-deoxyinosine.[7] Ikehara
and Tada also synthesized 2ꢁ-deoxyguanosine with CdA as an intermediate
(obtained by the desulfurization of 8,2ꢁ-anhydro-9-(β-D-arabinofuranosyl)-2-
chloro-8-thioadenine).[8] Direct glycosylation of 2-deoxyfuranose derivatives
invariably gives anomeric mixtures, and both N7 and N9 can be glycosylated
to give regioisomers. Robins et al. solved this problem via direct glycosylation
Received 5 March 2011; accepted 9 May 2011.
The authors are grateful to the Key Science and Technology Program of Henan Province, China
(0624070006) and Scientific Research Program of Xinxiang City, China (09J049) for their support.
Address correspondence to Gairong Chen, Department of Chemistry and Chemical Engineering,
Xinxiang University, Xinxiang City, Henan Province, 453003, P. R. China. E-mail: xxcgr@163.com
353

354
S. Xu et al.
of 2-deoxy chlorosugar with 6-(lipophilic substituents substituted-imidazol-
1-yl)purine sodium salts.[9] However, an additional step must be added to
synthesize 6-(lipophilic substituents substituted-imidazol-1-yl) purines. The
glycosylation of purine salt with 2-deoxy chlorosugar derivative was also re-
ported by Gupta,[10] Kaminski,[11] and Alonso.[12]
The second major method for the preparation of CdA is the modification
of natural nucleosides. Chen prepared CdA in eight steps from guanosine
(2.8% overall yield).[13] Robins reported on a concise synthesis of CdA from
2ꢁ-deoxyguanosine (64–75% overall) by conversion of the 6-oxo group to
Cl or arylsulfonyloxy, diazotization/chloro-dediazoniation at C2, and am-
monolysis at C6 with concomitant deprotection of the sugar moiety in four
steps.[14]
A third method for the synthesis of CdA uses enzymatic glycosyl transfer.
Mikhailopulo et al. reported an enzymatic synthesis by direct transfer of
the 2-deoxyfuranose moiety of thymidine to 2-chloroadenine using a trans-
N-deoxyribosylase.[15a] Barai et al.[15b] described a similar glycosyl transfer
from 2ꢁ-deoxyguanosine to CdA with a large excess of 2ꢁ-deoxyguanosine,
which gave a low yield (<27%) based on 2ꢁ-deoxyguanosine.
Thus, there is a great need for cost-effective methods to prepare CdA.
We recently developed a new and efficient synthesis of CdA from 2-
chloroadenosine (Scheme 1) using regioselective 2ꢁ-O-deacylation of 2ꢁ,3ꢁ,5ꢁ-
O-triacetyl-2-chloroadenosine. The 2ꢁ; deoxygenation was performed by a
Barton-McCombie reaction. CdA was obtained in a 31.0% yield in five steps
after deprotection of the 3ꢁ,5ꢁ acetyl groups; we avoided the separation of
mixtures with fusion and sodium salt glycosylation procedures and employed
the transformation of pure β isomer. We believe that as the preparation
methods of 2-chloroadenosine are improved, the presented method can be
competitive. We herein describe this new method.
SCHEME 1 Synthesis of CdA from 2-chloroadenosine.
Deoxygenation of the 2ꢁ hydroxyl group directly starting from 2-
chloroadenosine is the most convenient route to afford CdA. In fact,
Robins[16] reported on protection of the 3ꢁ and 5ꢁ hydroxyl groups of
nucleoside with 1,3-dichloro-1,1,3,3-tetraisopropyl-1,3-disiloxane (TPDSCl)
followed by the functionalization of the 2ꢁ hydroxyl group with phe-
noxythiocarbonyl chloride (PTC-Cl). Free radical-mediated reductive 2ꢁ

2-Chloro-2 ꢁ-deoxyadenosine (Cladribine), CDA)
355
C O bond cleavage of these 3ꢁ,5ꢁ-O-TPDS-2ꢁ-O-PTC-nucleoside derivatives
with tributyltin hydride (Bu3SnH), followed by removal of the silyl pro-
tecting group with tetrabutylammonium fluoride(Bu4NF), provided the 2ꢁ-
deoxyribonucleosides. However, TPDSCl is so expensive that it is not practi-
cal for large-scale synthesis.
Regioselective 2ꢁ-O-deacylation of fully acylated nucleosides is especially
appealing as the reagents used are inexpensive. Since Yoshiharu Ishido[17] re-
ported on deprotection of triacetyl nucleoside selectively in 2ꢁ position using
acetic acid and hydrazine hydrate, this method has been applied commonly
in nucleoside synthesis.[18] However, the removal of other acetyl groups can-
not be avoided, which leads to a lower yield and viscous work-up procedure.
Rather than hydrazine hydrate, suitable deacylation agents include hydrox-
ylamine and soluble carboxylate salts thereof, such as hydroxylammonium
acetate. The hydroxylammonium acetate may be generated by mixing a sus-
pension of hydroxylamine hydrochloride and sodium acetate in solvent.[17]
Bearing this in mind, we wondered if we could selectively deprotect 2ꢁ
acetyl group and remove the 2ꢁ hydroxyl group to synthesize CdA. To ini-
tiate our study, we carried out the deacylation reaction based on Ishido’s
conditions. A solution of 2ꢁ,3ꢁ,5ꢁ-O-triacetyl-2-chloroadenosine (3, 0.21 g,
0.50 mmol) in the pyridine (5 mL) was treated with hydrazine hydrate
(0.03 mL, 0.60 mmol) at room temperature for 12 hours, giving a com-
plex mixture by HPLC. We speculated that the acetyl group was too active
at room temperature, or hydrazine hydrate’s basicity was so strong that it
can deprotect not only 2ꢁ acetyl group but also 3ꢁ and 5ꢁ. When the tem-
perature was decreased to 0◦C, HPLC showed that main peak was up to
49%. When we replaced hydrazine hydrate by equivalent hydroxylamine hy-
drochloride and sodium acetate at 0◦C, we were pleased to find that the
main peak was up to 82% and 3 was 5%. The reaction was quenched by
1 mL acetone and concentrated in vacuum. The resultant crude residue was
then suspended in methanol, but only little solid precipitated. We reasoned
that the polarity of methanol was quite high, so we employed ethanol as a
cosolvent. The best results were obtained when we used methanol/ethanol
(1:6 v/v) as crystallization solvent. The solid was filtrated after stirring for
6 hours. The HPLC purity was up to 95% and the isolated yield was up to
73%. It is notable that when the reaction was enlarged to 10 mmol, 20 mmol,
or 40 mmol scale, no significant change of the purity and yield was observed.
The filtrate of previous work up containing 2ꢁ,3ꢁ,5ꢁ-O-triacetyl-
2-chloroadenosine, 2ꢁ,3ꢁ, -O-diacetyl-2-chloroadenosine, 5ꢁ-O-acetyl-2-
chloroadenosine, and other impurities can be concentrated in vacum and
acetylated with acetic anhydride to form more 2.
After obtaining 3ꢁ,5ꢁ-O-diacetyl-2-chloroadenosine, the deoxygenation
reaction was carried out to get the final product. The 2ꢁ hydroxyl group was
esterificated with PTC-Cl and then removed by treatment with Bu3SnH and

356
S. Xu et al.
α, αꢁ-azobisisobutyronitrile (AIBN). Removal of the 3ꢁ and 5ꢁ acetyl groups
provided CdA as a white solid.
In conclusion, we have described a new, efficient, and reproducible
synthetic route to synthesize Cladribine from industrially available 2-
chloroadenosine. This synthetic route makes use of hydroxylamine hy-
drochloride and sodium acetate in pyridine to selectively deprotect 2ꢁ acetyl
group of 2ꢁ,3ꢁ,5ꢁ-O-triacetyl-2-chloroadenosine, and the 2ꢁ hydroxyl group was
removed by the free radical-mediated Barton-McCombie reaction. The more
detailed study of this selective deprotection to synthesis other 2ꢁ modified
nucleoside is on progress in our laboratory.
EXPERIMENTAL
1H and 13C NMR spectra were determined on a Bruker AC 400 spectro-
meter (Bruker, Billerica, MA, USA) as DMSO-d6 solutions. Chemical shifts
were expressed in parts per million (δ) downfield from the internal standard
tetramethylsilane and were reported as s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), and dd (doublet of doublets) and coupling con-
stants J were given in Hz. The high-resolution mass spectra (HRMS) were
performed on a JEOL HX 110A spectrometer (JEOL, Tokyo, Japan).
2ꢀ,3ꢀ,5ꢀ-O-triacetyl-2-chloroadenosine 3
Acetic anhydride (2.20 mL, 23.27 mmol) was added slowly to a mag-
netically stirred suspension of 2-chloroadenosine (2, 2.00 g, 6.63 mmol),
4-dimethylaminopyridine (DMAP, 0.06 g, 0.49 mmol), and triethylamine
(TEA, 3.70 mL, 25.59 mmol) in acetonitrile (5 mL). The mixture was stirred
magnetically and heated to 50◦C. Within 3–5 minutes the mixture became
clear; stirring was continued for 30 minutes, at which time, thin layer chro-
matography (TLC; silica gel plates eluted with 9 : 1 chloroform : methanol
Rf 0.52) showed no starting material. We then added 2 mL methanol to
quench reaction and evaporated solvent; the residue was suspended in
5 mL ethanol to give 2 as a white powder (2.78 g, 6.49 mmol, 94% based on
2-chloroadenosine).
1H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.90 (brs, 2H), 6.16 (d,
J = 8 Hz, 1H), 5.92-5.85 (m, 1H), 5.59 (t, J = 5.2 Hz, 1H), 4.41-4.36 (m,
2H), 4.29-4.24 (m, 1H), 2.12 (s, 3H), 2.05 (s, 3H), 2.02 (s, 3H).
3ꢀ, 5ꢀ-O-triacetyl-2-chloroadenosine 4
A suspension of hydroxylamine hydrochloride (0.20 g, 2.81 mmol) and
anhydrous sodium acetate (0.23 g, 2.34 mmol) in pyridine (10 mL) was
stirred at 0◦C for 30 minutes. 2ꢁ,3ꢁ,5ꢁ-O-triacetyl-2-chloroadenosine (3, 1.00
g, 2.34 mmol) was added in one portion to the magnetically stirred suspen-
sion. The mixture soon became clear, at which time it was stirred at 0◦C for

2-Chloro-2 ꢁ-deoxyadenosine (Cladribine), CDA)
357
17 hours. The solution was analyzed by HPLC indicating that the main
peak was up to 82% and 3 was 5%. The reaction was quenched with ace-
tone (1 mL), coevaporated with toluene (3 × 5 mL), and added 5 mL
methanol/ethanol (1 : 6 v/v). The mixture was stirred for 2 hours at –5◦C
to afford 4 as a white solid (0.66 g, 1.71 mmol, 73% based on previous 3, no
more purification).
1H NMR (400 MHz, d6-DMSO) δ 8.39 (s, 1H), 7.89 (brs, 2H), 5.94 (dd,
J = 6 Hz, 2H), 5.28 (dd, J = 3.6 Hz, 1H), 4.94 (dd, J = 6 Hz, 1H), 4.31-4.22
(m, 2H), 2.13 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, d6-DMSO) δ 170.6,
170.1, 157.3, 157.7, 150.9, 140.5, 118.6, 87.6, 79.9, 72.7, 71.4, 63.7, 62.4, 25.9;
HRMS (FAB) Calcd for C14H17ClN5O6: 385.0789 (MH+), Found 385.0781.
2ꢀ-O-[phenoxy(thiocarbonyl)-3ꢀ,5ꢀ-O-triacetyl-2-chloroadenosine 5
PTC-Cl (0.43 mL, 3.03 mmol) was added to a solution of 4 (1.00 g, 2.59
mmol) and DMAP (0.69 g, 5.63 mmol) in dry acetonitrile (10 mL) under
argon. The solution was stirred for 2 hours at room temperature and the
solvent was evaporated in vacuum. The residue was partitioned between
AcOEt (10 mL) and H2O (5 mL). The organic phase and the aqueous
phase were separated, and the aqueous phase was extracted with AcOEt (3 ×
5 mL). The combined organic phase were dried over Na2SO4 and evaporated
in vacuum. The residue was dissolved in 5 mL ethanol and 5 precipitated
as a white solid (1.08 g, 2.07 mmol, 80% based on previous 4; there was no
further purification).
1 H NMR (400 MHz, d6-DMSO) δ 8.40 (s, 1H), 7.96 (brs, 2H), 7.47-7.45
(m, 2H), 7.33-7.31(m, 1H), 7.17 (d, J = 7.6 Hz, 2H), 6.38-6.41 (m, 2H), 5.82
(t, J = 5.6 Hz, 1H), 4.45 (dd, J = 3.2 Hz), 4.42-4.20 (m, 1H), 2.14 (s, 3H),
2.02 (s, 3H); 13C NMR (100 MHz, d6-DMSO) δ 1936.7, 170.2, 170.4, 156.3,
153.4, 153.2, 149.8, 140.1, 130.1, 121.8, 121.3, 96.5, 73.6, 62.4, 20.7, 21.0;
HRMS (FAB) Calcd for C21H21ClN5O7S: 521.0772 (MH+), Found 521.0768.
2ꢀ-deoxy-3ꢀ,5ꢀ-O-triacetyl-2-chloroadenosine 6
5 (2.00 g, 3.83 mmol), Bu3SnH (2.23 mL, 8.30 mmol), and AIBN (0.04 g,
0.22 mmol) in toluene (20 mL) under argon was heated for 3 hours. After
evaporation of the solvent, the residue was filtered through a short column
of silica gel (AcOEt). The resulting residue after evaporation of AcOEt was
dissolved in ethanol, cooled to 5◦C, and stirred for 2 hours, to afford 6 as
a syrup (0.88 g, 2.38 mmol, 62% based on previous 5; there was no further
purification).
1 H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.88 (brs, 2H), 5.98 (d,
J = 6 Hz, 1H), 5.11 (d, J = 3.9 Hz, 1H), 4.95 (t, J = 4 Hz, 1H), 4.19-4.12 (m,
1H), 3.76 (dd, J = 3.5 Hz, 1H), 3.56-3.51 (m, 1H), 3.45-3.43 (m, 1H), 2.07 (d,
J = 3.2 Hz, 2H), 1.99 (s, 3H), 1.95 (s, 3H); 13C NMR (100 MHz, d6-DMSO)

358
S. Xu et al.
δ 170.6, 170.1, 157.3, 157.7, 150.9, 140.5, 118.6, 87.6, 79.9, 72.7, 71.4, 63.7,
62.4, 25.9; HRMS (FAB) Calcd for C14H17ClN5O6: 385.0789 (MH+), Found
385.0781.
2-chloro-2ꢀ-deoxyadenosine, Cladribine 1
6 (0.88 g, 2.38 mmol) was added to 10 mL saturated NH3/MeOH at
0◦C; the reaction vessel was sealed and stirred at room temperature for
12 hours. Volatiles were evaporated. The residue was dissolved in EtOH and
recrystallization from EtOH when cooled to give 1 as a white solid (0.62 g,
2.17 mmol, 91% based on previous crude syrup 6; there was no further
purification).
1H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.90 (brs, 2H), 6.11 (t,
J = 6.4 Hz, 1H), 5.24 (d, J = 4 Hz, 1H), 5.14 (t, J = 4.8 Hz, 1H), 4.24-4.22 (m,
1H), 3.80 (dd, J = 3.2 Hz, 1H), 3.62-3.60 (m, 1H), 3.58-3.56 (m, 1H), 2.13 (d,
J = 3.2 Hz, 2H); 13C NMR (100 MHz, d6-DMSO) δ 157.5, 153.6, 150.8, 140.5,
118.8, 88.6, 84.2, 71.4, 62.3, 38.0; HRMS (FAB) Calcd for C10H13ClN5O3:
286.0629 (MH+), Found 286.0604.
The combined filtrate of 2 (methanol/ethanol) was concentrated in
vacuum to give a 2.52 g syrup. The syrup was dissolved in 15 mL acetonitrile,
and DMAP (0.06 g, 0.49 mmol), TEA (3.70 mL, 25.59 mmol) and acetic
anhydride (2.20 mL, 23.27 mmol) were added. The mixture was stirred
magnetically and heated to 50◦C. Within 3–5 minutes the mixture became
clear and stirring was continued for 30 minutes. TLC (8: 2 chloroform :
methanol) showed the spot of 2. Added 2 mL methanol to quench the
reaction and evaporated solvent, the residue was suspended in 5 mL ethanol
to give 2 as a white powder.
REFERENCES
1. Christensen, L.F.; Broom, A.D.; Robins, M.J.; Bloch, A. Synthesis and biological activity of selected
2,6-disubstituted(2-deoxy-.alpha.- and -.beta.-D-erythro-pentofuranosyl)purines. J. Med. Chem. 1972,
15(7), 735–739.
2. Carson, D.A.; Wasson, D.B.; Kaye, J.; Ullman, B.; Martin, D.W., Jr.; Robins, R.K.; Montgomery,
J.A. Deoxycytidine kinase-mediated toxicity of deoxyadenosine analogs toward malignant human
lymphoblasts in vitro and toward murine L1210 leukemia in vivo. Proc. Natl. Acad. Sci. 1980, 77(11),
6865–6869.
3. Santana, V.M.; Mirro, J., Jr.; Kearns, C.; Schell, M.J.; Crom, W.; Blakley, R.L. 2-Chlorodeoxyadenosine
produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J. Clin.
Oncol. 1992, 10(3), 364–370.
4. Piro, L.D.; Carrera, C.J.; Beutler, E.; Carson, D.A. 2-Chlorodeoxyadenosine: an effective new agent
for the treatment of chronic lymphocytic leukemia. Blood 1988, 72, 1069–1073.
5. Kong, L.R.; Samuelson, E.; Rosen, S.T.; Roenigk, H.H., Jr.; Tallman, M.S.; Rademaker, A.W.; Kuzel,
T.M. 2-Chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders. Leuk. Lymph. 1997,
26, 89–97.
6. Robak, T.; Gora-Tybor, J.; Krykowski, E.; Walewski, J.A.; et al. Activity of 2-chlorodeoxyadenosine
(cladribine) in 2-hour intravenous infusion in 94 previously treated patients with low grade non-
hodgkin’s lymphoma. Leuk. Lymphoma 1997, 26, 99–105.

2-Chloro-2 ꢁ-deoxyadenosine (Cladribine), CDA)
359
7. Venner, H. Synthesis of the corresponding 2ꢁ-deoxy-nucleosides of adenine, guanine and hypoxan-
thine. Chem. Ber. 1960, 93(1), 140–149.
8. Ikehara, M.; Tada, H. Studies of nucleosides and nucleotides. XXIV.1 Purine cyclonucleosides. I.
8,2ꢁ-cyclonucleoside derived from 2-chloro-8-mercapto-9-β-D-xylofuranosyladenine. J. Am. Chem. Soc.
1965, 87(3), 606–610.
9. Zhong, M.; Nowak, I.; Robins, M.J. Regiospecific and highly stereoselective coupling of 6-(substituted-
imidazol-1-yl)purines with 2-deoxy-3,5-di-O-(p-toluoyl)-r-D-erythro-pentofuranosyl chloride. Sodium-
salt glycosylation in binary solvent mixtures: improved synthesis of cladribine. J. Org. Chem. 2006, 71,
7773–7779.
10. Gupta, P.K.; Munk, S.A. Process for the preparation of 9-beta-anomeric nucleoside analogs. U.S. Pat.
Appl. No. 2004039190.
11. Kazimierczuk, Z.; Kaminski, J. Method of obtaining 2-chloro-2ꢁ-deoxyadenosine. Polish Pat. No.
334152 (A1).
12. Gerszberg, S.; Alonso, D. Method for the production of 2-chloro-2ꢁ-deoxyadenosine (Cladrbine) and
its 3,5-di-O-p-toluoyl derivative. PCT Int. Appl. No. 2000064918.
13. Chen, R.H.K. Intermediates useful in a synthesis of 2-chloro-2ꢁ-deoxyadenosine. U.S. Patent No.
5208327.
14. Janeba, Z.; Francom, P.; Robins, M.J. Efficient syntheses of 2-chloro-2ꢁ-deoxyadenosine (Cladribine)
from 2ꢁ-deoxyguanosine. J. Org. Chem. 2003, 68, 989–992.
15. a) Mikhailopulo, I.A.; Zinchenko, A.I.; Kazimierczuk, Z.; Barai, V.N.; Bokut, S.B.; Kalinichenko, E.N.
Synthesis of 2-chloro-2ꢁ-deoxyadenosine by microbiological transglycosylation. Nucleosides Nucleotides
1993, 12, 417–422. b) Barai, V.N.; Zinchenko, A.I.; Eroshevskaya, L.A.; Kalinichenko, E.N.; Kulak, T.I.;
Mikhailopulo, I.A. A universal biocatalyst for the preparation of base- and sugar-modified nucleosides
via an enzymatic transglycosylation. Helv. Chim. Acta 2002, 85(7), 1901–1908.
16. Robins, M.J.; Wilson, J.; Sawyer, L.; James, M.N.G. Nucleic acid related compounds. 41. Restricted
furanose conformations of 3ꢁ,5ꢁ-O-(1,1,3,3-tetraisopropyldisilox-1,3-diyl)nucleosides provide a con-
venient evaluation of anomeric configuration. Can. J. Chem. 1983, 61, 1911–1920.
17. Ishido, Y.; Sakairi, N.; Okazaki, K.; Nakazaki, N. Partial protection of carbohydrate derivatives. Part
4. Regioselective 2ꢁ-O-deacylation of fully acylated purine and pyrimidine ribonucleosides with hy-
droxylaminium acetate. J. Chem. Soc., Perkin Trans. 1, 1980, 563–573.
18. a) Gaubert, G.; Mathe, C.; Imbach, J.L.; Eriksson, S.; Vincenzetti, S.; Salvatori, Daniela Vita, A.;
Maury, G. Unnatural enantiomers of 5-azacytidine analogues: syntheses and enzymatic properties.
Eur. J. Med. Chem. 2000, 35, 1011–1019. b) Bauman, J.G.; Wirsching, R.C. Process for the preparation
of fludarabine or fludarabine phosphate from guanosine. U.S. Pat. No. 1997, 5602246.