Regiospecific and highly stereoselective coupling of 6-(substituted- imidazol-1-yl)purines with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro- pentofuranosyl chloride. Sodium-salt glycosylation in binary solvent mixtures: Improved synthesis of cladribine

Article abstract of DOI:10.1021/jo061282+

(Chemical Equation Presented) Glycosylation of 6-(substituted-imidazol-1- yl)purine sodium salts with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro- pentofuranosyl chloride proceeds with regiospecific formation of the N9 isomers. Base substrates with lipophilic substituents on the C6-linked imidazole moiety are more soluble in organic solvents, and the solubility is further increased with binary solvent mixtures. Selective solvation also diminishes the extent of anomerization of the chlorosugar. Stirred reaction mixtures of the modified-purine sodium salts generated in a polar solvent and cooled solutions of the protected 2-deoxysugar chloride in a nonpolar solvent give 2′-deoxynucleoside derivatives with N9 regiochemistry and enhanced β/α configuration ratios. Application of the binary-solvent methodology with 2-chloro-6-(substituted-imidazol-1-yl)purine salts in cold acetonitrile and the chlorosugar in cold dichloromethane gives essentially quantitative yields of the N9 isomers of β-anomeric 2′- deoxynucleoside intermediates. Direct ammonolysis (NH₃MeOH) of such intermediates or benzylation of the imidazole ring followed by milder ammonolysis of the imidazolium salt gives high yields of the clinical anticancer drug cladribine (2-chloro-2′-deoxyadenosine).

Full text of DOI:10.1021/jo061282+

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 Cladribine1
Minghong Zhong, Ireneusz Nowak, and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed June 21, 2006
Glycosylation of 6-(substituted-imidazol-1-yl)purine sodium salts with 2-deoxy-3,5-di-O-(p-toluoyl)-R-
D-erythro-pentofuranosyl chloride proceeds with regiospecific formation of the N9 isomers. Base substrates
with lipophilic substituents on the C6-linked imidazole moiety are more soluble in organic solvents, and
the solubility is further increased with binary solvent mixtures. Selective solvation also diminishes the
extent of anomerization of the chlorosugar. Stirred reaction mixtures of the modified-purine sodium salts
generated in a polar solvent and cooled solutions of the protected 2-deoxysugar chloride in a nonpolar
solvent give 2′-deoxynucleoside derivatives with N9 regiochemistry and enhanced â/R configuration
ratios. Application of the binary-solvent methodology with 2-chloro-6-(substituted-imidazol-1-yl)purine
salts in cold acetonitrile and the chlorosugar in cold dichloromethane gives essentially quantitative yields
of the N9 isomers of â-anomeric 2′-deoxynucleoside intermediates. Direct ammonolysis (NH3/MeOH)
of such intermediates or benzylation of the imidazole ring followed by milder ammonolysis of the
imidazolium salt gives high yields of the clinical anticancer drug cladribine (2-chloro-2′-deoxyadenosine).
Introduction
leukemia,6 chronic myelogenous leukemia, cutaneous T-cell
lymphoma,7 and non-Hodgkin’s lymphoma.8 Clinical investiga-
tions with CdA for treatment of multiple sclerosis, systemic
lupus erythematosis-associated glomerulonephritis, and other
rheumatoid and immune disorders are in progress.9
One approach for the synthesis of CdA involves transforma-
tion of natural nucleosides. Chen10 prepared CdA in eight steps
from guanosine (2.8% overall yield). We11 have reported concise
The deaminase-resistant drug cladribine2 (2-chloro-2′-deoxy-
adenosine, CdA), a close analogue of 2′-deoxyadenosine, is used
for treatment of patients with hairy cell leukemia. Complete
clinical responses at the 85% level have been reported,3 and
CdA also has been employed for treatment of other neoplasms4
including acute myelogenous leukemia,5 chronic lymphatic
(1) (a) Nucleic Acid Related Compounds. 137. For Paper 136 see: Lin,
X.; Robins, M. J. Collect. Czech. Chem. Commun., in press. (b) Patent
application filed.
(2) (a) Robins, M. J.; Robins, R. K. J. Am. Chem. Soc. 1965, 87, 4934-
4940. (b) Christensen, L. F.; Broom, A. D.; Robins, M. J.; Bloch, A. J.
Med. Chem. 1972, 15, 735-739.
(3) (a) Piro, L. D.; Carrera, C. J.; Carson, D. A.; Beutler, E. N. Engl. J.
Med. 1990, 322, 1117-1121. (b) Jehn, U.; Bartl, R.; Dietzfelbinger, H.;
Vehling-Kaiser, U.; Wolf-Hornung, B.; Hill, W.; Heinemann, V. Ann.
Hematol. 1999, 78, 139-144.
(4) Bryson, H. M.; Sorkin, E. M. Drugs 1993, 46, 872-894.
10.1021/jo061282+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7773-7779
7773

Zhong et al.
syntheses of CdA from 2′-deoxyguanosine (64-75% overall)
by conversion of the 6-oxo group to Cl or arylsulfonyloxy,
diazotization/chloro-dediazoniation at C2, and ammonolysis at
C6 with concomitant deprotection of the sugar moiety. Enzy-
matic glycosyl transfer methods for the preparation of CdA have
been developed.12
Several synthetic sequences have employed purine-sugar
coupling procedures. A Fischer-Helferich synthesis of 2′-
deoxynucleosides reported in 196013 included 2-chloro-2′-
deoxyadenosine as an intermediate. Ikehara and Tada also
employed CdA as an intermediate for the preparation of 2′-
deoxyadenosine in a sequence that involved coupling of a
mercury salt of 2,8-dichloroadenine with a xylofuranosyl
chloride derivative and desulfurization of a late-stage 8,2′-
anhydro-9-(â-D-arabinofuranosyl)-2-chloro-8-thioadenine cy-
clonucleoside.14
Our first synthesis of cladribine for biological activity
evaluations involved fusion coupling of 2,6-dichloropurine with
1,3,5-tri-O-acetyl-2-deoxy-R-D-erythro-pentofuranose.2a Am-
monolysis of the anomeric mixture resulted in regiospecific
replacement of the chloride at C6 and concomitant cleavage of
the sugar esters to give CdA and its R-isomer. Reacylation of
that mixture with p-toluoyl chloride, chromatographic separation
of the anomers, and deprotection gave CdA (16% overall).2b
Fusion of 2,6-dichloropurine and methyl 2-deoxy-3,5-di-O-(p-
toluoyl)-D-erythro-pentofuranoside gave a mixture of anomers
that was processed to give CdA (8% overall).2b
The purine sodium-salt glycosylation method for industrial
production of CdA was devised by Robins et al.15 It gives good
â/R anomeric stereoselectivity but variable selectivity for the
N9 versus N7 purine regioisomers. The resulting mixtures of
four regio- and diastereoisomers with similar chromatographic
mobilities can be difficult to separate, which can diminish the
yields of pure CdA. In the original procedure,15a the sodium
salt of 2,6-dichloropurine and 2-deoxy-3,5-di-O-(p-toluoyl)-R-
D-erythro-pentofuranosyl chloride were coupled in acetonitrile
to give â anomers of the N9 (59%) and N7 (13%) regioisomers
(yields of the R anomers were not reported). Hildebrand and
Wright16 reported yields of 9-â- (50%), 9-R- (1.5%), and 7-â-
(15%). The ambident character of purine sodium salts (N9 and
N7 of the imidazole ring and sometimes N3 of the pyrimidine)
results in formation of regioisomers in the absence of demanding
steric and/or electronic effects. Chromatographic separation
followed by heating the protected 9-â isomer in methanolic
ammonia at 100 °C gave CdA in 42% overall yield.
Gupta and Munk17 prepared CdA by coupling the potassium
salt of 2-chloro-6-N-(heptanoyl)adenine and the 2-deoxy chlo-
rosugar derivative in THF, which reduced the amount of N7
regioisomer and enhanced â-anomer formation. Kazimierczuk
and Kaminski18 examined couplings of 2-chloro-6-substituted
(e.g., alkoxy, halo, alkylthio) purine derivatives with 2-deoxy-
3,5-di-O-aroyl-R-D-erythro-pentofuranosyl chlorides in the pres-
ence of alkali metal hydrides or hydroxides and phase-transfer
catalysts, but formation of N7 regioisomers persisted. Gerszberg
and Alonso19 used the sodium-salt method with acetone as
solvent, and high stereoselectivity was achieved by careful
control of reaction times. The overall yield of CdA was low
(30% based on 2-chloroadenine), which can be attributed to the
meager solubility of purine sodium salts in acetone. It might
be possible that the noted regioselectivity enhancement was
augmented by hydrogen bonding of acetone with the purine
6-amino group to create steric congestion in the space proximal
to N7. A clear need exists for cost-effective and selective
methods for the preparation of CdA.
We reasoned that improvements in the regioselectivity for
N9 isomer formation as well as enhancements of â anomeric
stereoselectivity might be achieved by alteration of the lipophilic
properties of the purine bases and selective solvation of reactants
in mixed-solvent reaction media. We recently reported methods
for the preparation of 6-(substituted-imidazol-1-yl)purines from
readily available purines and purine nucleosides;20 such purine
acceptors undergo regiospecific N9 glycosylation with furanosyl
and pyranosyl sugar donors.21 We now report improved coupling
methodology that gives N9 regiospecific glycosylation of
6-(substituted-imidazol-1-yl)purines with 2-deoxy-3,5-di-O-(p-
toluoyl)-R-D-erythro-pentofuranosyl chloride in binary solvent
mixtures. We show that solvent combinations exert a powerful
influence on the stereoselectivity of glycosylation with an
activated sugar derivative that does not have a participating
group adjacent to the anomeric center and describe examples
of efficient coupling syntheses of cladribine.
(5) Santana, V. M.; Mirro, J., Jr.; Kearns, C.; Schell, M. J.; Crom, W.;
Blakley, R. L. J. Clin. Oncol. 1992, 10, 364-370.
(6) Piro, L. D.; Carrera, C. J.; Beutler, E.; Carson, D. A. Blood 1988,
72, 1069-1073.
(7) Kong, L. R.; Samuelson, E.; Rosen, S. T.; Roenigk, H. H., Jr.;
Tallman, M. S.; Rademaker, A. W.; Kuzel, T. M. Leuk. Lymphoma 1997,
26, 89-97.
Results and Discussion
(8) Robak, T.; Gora-Tybor, J.; Krykowski, E.; Walewski, J. A.; Borawska,
A.; Pluzanska, A.; Potemski, P.; Hellmann, A.; Zaucha, J. M.; Konopka,
L.; Ceglarek, B.; Durzynski, T.; Sikorska, A.; Michalak, K.; Urasinski, J.;
Opalinska, J.; Dmoszynska, A.; Adamczyk-Cioch, M. B.; Kuratowska, Z.;
Dwilewicz-Trojaczek, J.; Boguradzki, P.; Deren, M.; Maj, S.; Grieb, P. Leuk.
Lymphoma 1997, 26, 99-105.
Lewis acid catalyzed glycosylations with peracylated sugars
are believed to occur via SN1-related mechanisms with ac-
companying anchimeric assistance by a neighboring acyl group
at C2. Stepwise or concerted formation of a bicyclo[n.3.0]
cationic bridge involving the C1-C2 bond of the sugar ring
directs the approach of incoming nucleophiles from the side
opposite to the fused acyloxonium ring, which usually results
(9) Beutler, E.; Sipe, J. C.; Romine, J. S.; Koziol, J. A.; McMillan, R.;
Zyroff, J. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 1716-1720.
(10) Chen, R. H. K. U.S. Patent 5,208,327, 1993; Chem. Abst. 1993,
119, 160729.
(11) Janeba, Z.; Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68,
989-992.
(12) (a) Mikhailopulo, I. A.; Zinchenko, A. I.; Kazimierczuk, Z.; Barai,
V. N.; Bokut, S. B.; Kalinichenko, E. N. 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. HelV. Chim. Acta
2002, 85, 1901-1908.
(16) Hildebrand, C.; Wright, G. E. J. Org. Chem. 1992, 57, 1808-1813.
(17) Gupta, P. K.; Munk, S. A. U.S. Pat. Appl. 2004/039190, 2004; Chem.
Abst. 2004, 140, 199639.
(18) Kazimierczuk, Z.; Kaminski, J. Polish Patent 177,960, 2000; Chem.
Abst. 2001, 134, 208061.
(19) Gerszberg, S.; Alonso, D. PCT Int. Appl. 2000064918, 2000; Chem.
Abst. 2000, 133, 310116.
(20) Zhong, M.; Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem.
2006, 71, 4216-4221.
(21) Zhong, M.; Nowak, I.; Robins, M. J. Org. Lett. 2005, 7, 4601-
4603.
(13) Venner, H. Chem. Ber. 1960, 93, 140-149.
(14) (a) Ikehara, M.; Tada, H. J. Am. Chem. Soc. 1963, 85, 2344-2345.
(b) Ikehara, M.; Tada, H. J. Am. Chem. Soc. 1965, 87, 606-610.
(15) (a) Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.; Robins, R.
K. J. Am. Chem. Soc. 1984, 106, 6379-6382. (b) Robins, R. K.; Revankar,
G. R. Eur. Pat. Appl. 173,059, 1986; Chem. Abst. 1986, 105, 60911u.
7774 J. Org. Chem., Vol. 71, No. 20, 2006

Sodium-Salt Glycosylation in Binary SolVent Mixtures
SCHEME 1. Sodium Salt Glycosylations of
6-(Heteroaryl)purines with 2
in highly stereoselective diastereomer formation. However, the
absence of a stereodirecting group at C2 allows formation of
R/â anomeric mixtures, which are obtained in syntheses of 2′-
deoxynucleosides unless stereocontrol is achieved by other
means. A partial solution to the problem was realized by the
discovery22 that 2-deoxy-3,5-di-O-(p-toluoyl)-R-D-erythro-
pentofuranosyl chloride crystallized selectively from anomeric
mixtures of the glycosyl halide. Displacements of the SN2-type
resulting from treatment of the R-chloro sugar with the sodium
salt of certain purines or silyl ethers of some pyrimidines give
the â-anomer of 2′-deoxynucleosides with high stereoselectivity.
However, the selectivity varies markedly with the nature of the
heterocyclic base, the countercation, and reaction conditions
(e.g., solvent, temperature, time), and solvent polarity is a major
factor. Hubbard et al.23 evaluated changes in the anomeric
composition of the noted 2-deoxysugar chloride in different
solvents at various times and temperatures. They observed that
nonpolar solvents decreased rates of anomerization and decom-
position of the chlorosugar, whereas solutions in polar solvents
(such as DMF) underwent rapid anomerization, even at reduced
temperatures. Also, the rates of glycosylation with the â-anomer
of the chlorosugar are higher. Unfortunately, purine sodium salts
are virtually insoluble in nonpolar solvents. Miniscule purine-
salt concentrations severely limit the rates of SN2 glycosylation
in two-phase solution/salt mixtures; anomerization of the
chlorosugar becomes increasingly problematic with time. Purine
salts have slightly increased solubility in the more polar acetone,
but yields were low to moderate;19,24 stereoselective glycosy-
lations of 7-deazapurines with 5-deoxy-2,3-O-isopropylidene-
R-D-ribofuranosyl chloride in toluene were effected with phase
transfer catalysis.25
We first mixed a purine sodium salt in DMF or acetonitrile
(ACN) with a solution of 2-deoxy-3,5-di-O-(p-toluoyl)-R-D-
erythro-pentofuranosyl chloride in DMF or ACN. Nearly equal
amounts of R- and â-anomers were formed, in harmony with
prior studies. Changes in temperature, reactant structure, and
reaction media were examined to evaluate effects on yields and
anomeric compositions. Lower temperatures decreased the
chlorosugar anomerization rate and gave slightly higher â/R
coupling ratios. Purine-salt solubility in nonpolar solvents was
increased by introduction of lipophilic substituents.20 Binary
solvent combinations were used to fine-tune the average
dielectric constant of reaction media and promote preferential
solvation of the reactants26 (a nonpolar chlorosugar and a polar
purine salt).
TABLE 1. Glycosylation Stereoselectivitya
entryb
solventsc
X
R
(3:4)d
1 (1a)
2 (1a)
3 (1a)
4 (1b)
5 (1b)
6 (1b)
7 (1b)
8 (1c)
9 (1c)
10 (1c)
11 (1c)
DMF/DMF
ACN/ACN
DMF/ACN
DMF/DMF
ACN/ACN
DMF/ACN
ACN/toluene
DMF/DMF
ACN/ACN
ACN/toluene
ACN/DCM
N
N
N
H
H
H
H
H
H
H
Pr
Pr
Pr
Pr
∼1:1
<1:1
∼2.5:1
<1:1
<1:1
∼1:1
>5:1
<1:1
∼4:1
>30:1
e
CH
CH
CH
CH
CH
CH
CH
CH
a See Experimental Section for details. b Starting material in parentheses.
c Solvents (A/B); ACN ) acetonitrile, DCM ) dichloromethane. d By H
1
NMR. e Only â-anomer was detected (solutions of both 1c and 2 were at
0 °C).
increases in â/R anomer (3a/4a) ratios]. Isolated yields of (3a
+ 4a) were about 50%, with exclusive formation of N9
regioisomers but little â-anomer stereoselectivity (Table 1,
entries 1-3). Coupling of the sodium salt of 6-(imidazol-1-yl)-
purine (1b) and 2 in polar solvents gave similar results (entries
4-6), but >5:1 â/R stereoselectivity was observed with the
sodium salt of 1b in ACN and 2 in toluene (entry 7).
Glycosylation of the sodium salt of the more lipophilic 6-(2-
propylimidazol-1-yl)purine20 (1c) in DMF with 2 in DMF gave
3c and 4c with the R-anomer formed in excess (entry 8). A
parallel reaction with ACN as solvent for both components gave
3c/4c (∼4:1) (entry 9), whereas the salt of 1c in ACN and 2 in
toluene gave 3c and 4c with >30:1 â/R stereoselectivity (entry
10). Mixing the sodium salt of 1c in ACN and 2 in DCM (both
at 0 °C) gave the N9-linked â anomer 3c as the only product
detected (1H NMR before chromatography). Thus, the composi-
tion of the binary mixture with a nonpolar solvent for the
chlorosugar was the most important factor, followed by solubil-
ity enhancement with more lipophilic20 purine salts. Only minor
variations in yields and anomeric ratios of the glycosylation
products were observed with the sodium salts of 6-(2-propyl-,
butyl-, or pentylimidazol-1-yl)purines under our standard condi-
tions. However, remarkably inferior results were obtained with
the 6-(2-hexyl- and dodecylimidazol-1-yl)purines. It might be
possible that analogues with longer alkyl side-chains undergo
self-association that impedes coupling processes. However,
regiospecific N9 glycosylation occurred with the longer-chain
analogues as well as with the more favorable purine substrates.
A polar solute interacts differently with each component of
a solvent mixture, and solvent compositions in the immediate
vicinity of a solute differ from the bulk solvent composition.
Wilson27 proposed a local composition (LC) model to describe
microscopic solution structures, and the LC model has been used
The highly polar 6-(1,2,4-triazol-4-yl)purine (1a) (Scheme
1) was virtually insoluble in solvents other than DMF (and ACN
to a smaller extent). Suspensions of the sodium salt of 1a
(generated with NaH in DMF or ACN) were mixed with
solutions of the chlorosugar 2, and the reaction mixtures were
stirred at ambient temperature [lower temperatures gave minor
(22) (a) Hoffer, M. Chem. Ber. 1960, 93, 2777-2781. (b) Rolland, V.;
Kotera, M.; Lhomme, J. Synth. Commun. 1997, 27, 3505-3511.
(23) Hubbard, A. J.; Jones, A. S.; Walker, R. T. Nucleic Acids Res. 1984,
12, 6827-6837.
(24) Kawakami, H.; Matsushita, H.; Naoi, Y.; Itoh, K.; Yoshikoshi, H.
Chem. Lett. 1989, 235-238.
(25) Ugarkar, B. G.; Castellino, A. J.; DaRe, J. M.; Kopcho, J. J.;
Wiesner, J. B.; Schanzer, J. M.; Erion, M. D. J. Med. Chem. 2000, 43,
2894-2905.
(26) (a) Khajehpour, M.; Kauffman, J. F. J. Phys. Chem. A 2000, 104,
7151-7159. (b) Khajehpour, M.; Welch, C. M.; Kleiner, K. A.; Kauffman,
J. F. J. Phys. Chem. A 2001, 105, 5372-5379. (c) Marcus, Y. SolVent
Mixtures; Marcel Dekker: New York, 2002. (d) Wu, Y. G.; Tabata, M.;
Takamuku, T. J. Solution Chem. 2002, 31, 381-395.
(27) Wilson, G. M. J. Am. Chem. Soc. 1964, 86, 127-130.
J. Org. Chem, Vol. 71, No. 20, 2006 7775

Zhong et al.
SCHEME 3. Transformation of Intermediates 6 into 10
SCHEME 2. Glycosylation of Purine Sodium Salts with 2
TABLE 2. Glycosylation Stereoselectivity and Yielda
entryb
X
R
R′
(6:7)c
(6 + 7)d
1 (5a)
2 (1c)
3 (5b)
4 (5c)
5 (5d)
6 (5e)
7 (5f)
8 (5g)
9 (5h)
Cl
H
H
H
H
H
H
H
H
H
H
Ph
65:35
e,f
e
98:2
96:4
98:2
98:2
98:2
e
71
Pr
Pr
iPr
57f
Cl
Cl
Cl
Cl
Cl
Cl
Cl
95
∼100
Bu
86
Pent
2-PhPr
PhCH2
H
∼100
∼99
85
∼100
a See Experimental Section for details. b Starting materials in parentheses.
c By 1H NMR. d Isolated % yield (relative to 1 or 5). e Only â-anomer
detected. f Product was 3c.
Highly stereoselective coupling was observed with the purine
acceptors with lipophilic substituents on the appended imidazole
ring (entries 2-9). The poor â/R coupling stereoselectivity
(∼1.9:1, entry 1) observed with 2-chloro-6-(imidazol-1-yl)purine
(5a) might result from the decreased solubility of the sodium
salt of 5a and/or a less favorable LC environment. Glycosylation
of 1c (entry 2) (no 2-chloro substituent on the purine ring) was
highly stereoselective and the reaction was complete (TLC),
although a moderate isolated yield of 3c was obtained. Exclusive
formation of N9 regioisomers was observed with all of the
coupling products (1H NMR) in agreement with our prior
results.21 It is noteworthy that the â-anomeric N9-regioisomer
6h was the only coupling product detected in the glycosylation
of 5h with 2. The X-ray crystal structure of a nucleoside
derivative of 5h showed a dihedral projection angle of ∼57°
between the planes of the C6-linked-purine and imidazole
rings,20 and alkylation of 5h with iodoethane gave a minor
amount of the N7 regioisomer in addition to the major 9-ethyl
product.33
We next turned our attention to transformations of the
intermediates 6 into cladribine. We have previously noted that
treatment of 6-(imidazol-1-yl)purine nucleosides with NH3/
MeOH at ambient temperature resulted in retention of the
imidazoyl group.21 Heating such solutions at 100 °C (pressure
vessel) effected slow displacement of imidazole with ac-
companying formation of 6-methoxypurine derivatives. The
more electrophilic 2-chloropurine analogue 6b underwent SN-
Ar displacements with NH3/MeOH at 40 °C (15 h) to give the
2-chloro-6-methoxypurine nucleoside 8 plus cladribine (10) (∼2:
1, respectively) (Scheme 3). Heating 6b with NH3/MeOH at
80 °C gave 10 plus 2-propylimidazole (1:1), which were not
readily separated by chromatography. Higher reaction temper-
atures (g100 °C) caused loss of 2-chloroadenine from 10. Thus,
the 2-propylimidazole group at C6 is replaced more readily by
a methoxyl group,21 which undergoes ammonolysis. Such a
extensively to correlate vapor-liquid equilibrium data for binary
and multicomponent mixtures. Deng et al.28 reported correlations
1
of H NMR chemical shifts of binary mixtures with composi-
tions based on the LC model. Preferential solvation of reaction
species can result in altered free energies of activation,29 which
can change the ratios of two competitive pathways. Preferential
solvation can increase the solubility of a polar solute, and such
“cosolvent effects” have been demonstrated most dramatically
in supercritical binary mixtures.30
We reasoned that the use of appropriate solvent mixtures
might result in enhanced LC solvation of polar regions of our
purine sodium salts by a polar solvent and preferential solvation
of lipophilic regions of the purine substituent, as well as the
chlorosugar, by less polar LC environments in binary solvent
mixtures. Although the dielectric constant of toluene is lower
than that of DCM,31 the dipolarity/polarizability and hydrogen-
bond-donor acidity of DCM are significantly greater than those
of toluene.32 DCM is a better solvent than toluene for purine
salts as well as for the chlorosugar 2, and it is easily evaporated.
Therefore, DCM was chosen as the low polarity solvent for 2,
and ACN was used for sodium salt glycosylations with the
2-chloro-6-(substituted-imidazol-1-yl)purines (5) (Scheme 2,
Table 2) that might provide convenient access to cladribine.
After completion of our solvent-effect studies,33 Bauta et al.
reported empirical combinations of additives, bases, and solvents
for an improved synthesis of clofarabine [6-amino-2-chloro-9-
(2-deoxy-2-fluoro-â-D-arabinofuranosyl)purine].34
(28) Deng, D.; Li, H.; Yao, J.; Han, S. Chem. Phys. Lett. 2003, 376,
125-129.
(29) Jaworski, J. S. J. Phys. Org. Chem. 2002, 15, 319-323.
(30) (a) Zhong, M.; Han, B.; Yan, H. J. Supercrit. Fluids 1997, 10, 113-
118. (b) Zhong, M.; Han, B.; Yan, H.; Peng, D.-Y. Fluid Phase Equilib.
1997, 134, 175-183.
(31) CRC Handbook of Chemistry and Physics, 86th ed.; Lide, D. R.,
Ed.; Taylor & Francis: Boca Raton, 2005-2006; pp 8-127.
(32) (a) Abraham, M. H.; Taft, R. W.; Kamlet, M. J. J. Org. Chem. 1981,
46, 3053-3056. (b) Taft, R. W.; Abboud, J.-L. M.; Kamlet, M. J.; Abraham,
M. H. J. Solution Chem. 1985, 14, 153-186.
(34) Bauta, W. E.; Schulmeier, B. E.; Burke, B.; Puente, J. F.; Cantrell,
W. R., Jr.; Lovett, D.; Goebel, J.; Anderson, B.; Ionescu, D.; Guo, R. Org.
Process Res. DeV. 2004, 8, 889-896.
(33) Zhong, M. Ph.D. Dissertation, Brigham Young University, 2004.
7776 J. Org. Chem., Vol. 71, No. 20, 2006

Sodium-Salt Glycosylation in Binary SolVent Mixtures
1). A mixture of the 6-(heteroaryl)purine 1a-1c (1.0 mmol) and
NaH (60 mg, 60% w/w dispersion, 1.5 mmol) in a dried polar
solvent A was stirred at ambient temperature under a positive
pressure of N2 for 2 h. A solution of 2 (700 mg, 1.8 mmol) in a
dried less-polar solvent B was added with a syringe, and the mixture
was stirred for 22 h. Volatiles were evaporated in vacuo, and the
composition of the residue was evaluated (1H NMR). Some of the
residues were chromatographed and isolated yields were de-
termined.
General Method 2. Glycosylation of 1c, 5a-5h with 2-Deoxy-
3,5-di-O-(p-toluoyl)-r-D-erythro-pentofuranosyl Chloride (2) (Table
2). A mixture of 1c or the 2-chloro-6-(substituted-imidazol-1-yl)-
purine 5a-5h (1.0 mmol) and NaH (60 mg, 60% w/w dispersion,
1.5 mmol) in dried CH3CN (10 mL) was stirred under N2 at ambient
temperature for 8 h, and the solution was cooled to 0 °C. A solution
of 2 (700 mg, 1.8 mmol) in cold, dried CH2Cl2 (0 °C, 10 mL) was
then added with a syringe. The reaction mixture was stirred for 22
h with gradual warming to ambient temperature. Volatiles were
evaporated in vacuo, and the residue was chromatographed (25 g
of silica gel; MeOH/CH2Cl2, 1:30).
2-chloro-6-methoxypurine f 6-amino-2-chloropurine transfor-
mation had been reported with a riboside derivative.35 Neither
selective crystallization of 10 nor extraction of 2-propylimida-
zole into an organic phase was successful. However, quantitative
ammonolysis of 6e (TLC), evaporation of volatiles, and extrac-
tion of the more lipophilic 2-pentylimidazole into DCM gave
10 (70%) as a colorless powder. Additional 10 (15%) was
recovered from the DCM extract by chromatography/ex-
traction.
Although quantitative ammonolysis of the 2-chloro-6-
(substituted-imidazol-1-yl)purine intermediates (TLC) completed
our successful synthesis of cladribine, this step remained
problematic with analogues lacking the 2-chloro substituent.
Imidazolium (pKa ∼7) is known to be far superior to imidazole
(pKa ∼14.5) as a leaving group;36 we reasoned that activation
of a 6-(imidazol-1-yl) group by alkylation would both increase
the SNAr ammonolysis rate and produce an organic-soluble
byproduct. Methylation of the imidazole moiety did not proceed
to completion, but treatment of 9-(2,3,5-tri-O-acetyl-â-D-ribo-
furanosyl)-2-chloro-6-(2-propylimidazol-1-yl)purine20 with ben-
zyl iodide (generated in situ with PhCH2Cl and NaI in ACN)
gave the 3-benzyl-2-propylimidazolium iodide. Ammonolysis
of that salt (NH3/MeOH, 60 °C, 4 h) gave 2-chloroadenosine
(50% after chromatography and recrystallization).
The activation strategy also was successful for syntheses of
10. In situ benzylation of 6 f 9 was complete, except with 6c
and 6h (darkening and some decomposition occurred with 6a).
Ammonolysis of 9 liberated 1-benzyl-2-propylimidazole and
cleaved the toluoyl esters to give 10 (optimization of 5b f 6b
f 9 f 10 gave purified cladribine in >90% yield). Chroma-
tography was used routinely for purification of 10, but polarity
differences for extraction workup are much greater with the
2-alkyl-1-benzylimidazoles than with the 2-alkylimidazole
byproducts.
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-r/â-D-erythro-pento-
furanosyl]-6-(imidazol-1-yl)purine (6a/7a). 1H NMR (300 MHz)
δ 6.66 (dd, J ) 5.8, 1.8 Hz, 1H, H1′ of the R anomer), 6.58 (“t”,
J ) 6.8 Hz, 1H, H1′ of the â anomer).
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-â-D-erythro-pento-
furanosyl]-6-(2-propylimidazol-1-yl)purine (6b). Yield 83%;
analytical sample (recrystallized from EtOAc): mp 192-193 °C;
UV max 220, 239, 287 nm (ꢀ 40 700, 38 300, 16 700), min 231,
1
265 nm (ꢀ 35 900, 10 300); H NMR (500 MHz) δ 8.52 (s, 1H),
8.27 (s, 1H), 8.00 (d, J ) 7.8 Hz, 2H), 7.86 (d, J ) 7.8 Hz, 2H),
7.32 (d, J ) 7.8 Hz, 2H), 7.28 (d, J ) 7.8 Hz, 2H), 7.20 (s, 1H),
6.61 (t, J ) 7.1 Hz, 1H), 5.82-5.83 (m, 1H), 4.68-4.84 (m, 3H),
3.29 (t, J ) 7.8 Hz, 2H), 2.98-3.01 (m, 2H), 2.47 (s, 3H), 2.38 (s,
3H), 1.86 (sext, J ) 7.5 Hz, 2H), 1.07 (t, J ) 7.3 Hz, 3H); 13C
NMR (125 MHz) δ 166.3, 166.2, 154.4, 153.4, 151.5, 148.2, 145.0,
144.7, 142.4, 130.1, 129.8, 129.61, 129.56, 129.2, 126.6, 126.4,
123.0, 120.6, 85.5, 83.8, 75.2, 64.1, 38.9, 33.1, 22.0, 21.9, 21.6,
14.3; HRMS m/z 637.1940 (MNa+ [C32H31ClN6O5Na ) 637.1942]).
Anal. Calcd for C32H31ClN6O5: C, 62.49; H, 5.08; N, 13.66.
Found: C, 62.44; H, 5.18; N, 13.72.
Summary and Conclusions
A larger scale reaction with the sodium salt of 5b (1.54 g, 5.87
mmol) in dried CH3CN (100 mL) and 2 (3.74 g, 9.62 mmol) in
dried CH2Cl2 (general method 2) for 5 h (complete by TLC) gave
6b (3.42 g, 95%).
We have described new 6-(substituted-imidazol-1-yl)purines
that undergo regiospecific glycosylation at N9. An approach to
highly stereoselective glycosylation of 6-(substituted-imidazol-
1-yl)purine sodium salts with 2-deoxy-3,5-di-O-(p-toluoyl)-R-
D-erythro-pentofuranosyl chloride in binary solvent mixtures
(purine salt/acetonitrile and chlorosugar/dichloromethane) gives
â-anomeric N9 regioisomers in good to high yields. Am-
monolysis (NH3/MeOH) produces the nucleosides directly.
Benzylation of the imidazole moiety at C6 followed by
ammonolysis of the resulting imidazolium salt permits SNAr
displacement of the 2-alkyl-1-benzylimidazole leaving groups
under milder conditions. Application of these procedures to the
synthesis of cladribine (2-chloro-2′-deoxyadenosine) provides
the purified clinical anticancer drug in >90% overall yields.
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-â-D-erythro-pento-
furanosyl]-6-(2-isopropylimidazol-1-yl)purine (6c). UV max 223,
241, 285 nm (ꢀ 32 100, 35 400, 14 800), min 230, 265 nm (ꢀ 30
300, 9200); 1H NMR (500 MHz) δ 8.42 (d, J ) 1.0 Hz, 1H), 8.26
(s, 1H), 7.99 (d, J ) 7.8 Hz, 2H), 7.85 (d, J ) 8.3 Hz, 2H), 7.30
(d, J ) 7.8 Hz, 2H), 7.20 (d, J ) 8.8 Hz, 2H), 7.11 (d, J ) 1.0 Hz,
1H), 6.60 (t, J ) 6.8 Hz, 1H), 5.81 (br s, 1H), 4.78-4.83 (m, 1H),
4.67-4.71 (m, 2H), 4.08 (sept, J ) 6.8 Hz, 1H), 2.97-3.01 (m,
2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.43 (d, J ) 6.8 Hz, 3H), 1.41 (d,
J ) 6.8 Hz, 3H); 13C NMR (125 MHz) δ 166.1, 166.0, 156.2, 154.2,
153.2, 148.2, 144.7, 144.4, 142.3, 129.9, 129.6, 129.4, 129.3, 128.8,
126.4, 126.3, 123.0, 120.4, 85.2, 83.6, 74.9, 63.9, 38.6, 28.8, 21.8,
21.6; HRMS m/z 637.1931 (MNa+ [C32H31ClN6O5Na ) 637.1942]).
6-(2-Butylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-tolu-
oyl)-â-D-erythro-pentofuranosyl]purine (6d). UV max 223, 241,
287 nm (ꢀ 29 900, 33 400, 13 200), min 230, 265 nm (ꢀ 28 100,
Experimental Section37
1
7500); H NMR (500 MHz) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.98 (d,
The starting 6-(substituted-imidazol-1-yl)purines were prepared
and characterized as described.20
General Method 1. Glycosylation of 1a-1c with 2-Deoxy-
3,5-di-O-(p-toluoyl)-r-D-erythro-pentofuranosyl Chloride (2) (Table
J ) 8.0 Hz, 2H), 7.84 (d, J ) 8.0 Hz, 2H), 7.30 (d, J ) 8.0 Hz,
2H), 7.19 (d, J ) 8.0 Hz, 2H), 7.09 (s, 1H), 6.60 (t, J ) 6.9 Hz,
1H), 5.80 (br s, 1H), 4.78-4.81 (m, 1H), 4.66-4.70 (m, 2H), 3.31
(t, J ) 7.8 Hz, 2H), 2.97-3.00 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H),
1.80 (quint, J ) 7.4 Hz, 2H), 1.50 (sext, J ) 7.4 Hz, 2H), 0.97 (t,
J ) 7.5 Hz, 3H); 13C NMR (125 MHz) δ 166.1, 165.0, 154.1, 153.2,
151.4, 147.9, 144.7, 144.4, 142.2, 129.9, 129.5, 129.4, 129.3, 128.9,
126.4, 126.2, 122.7, 120.3, 85.2, 83.6, 74.9, 63.9, 38.6, 30.7, 30.1,
(35) Schaeffer, H. J.; Thomas, H. J. J. Am. Chem. Soc. 1958, 80, 3738-
3742.
(36) Zhong, M.; Strobel, S. A. Org. Lett. 2006, 8, 55-58.
(37) General experimental items are in Supporting Information.
J. Org. Chem, Vol. 71, No. 20, 2006 7777

Zhong et al.
22.6, 21.8, 21.7, 13.9; HRMS m/z 629.2270 (MH+ [C33H34ClN6O5
) 629.2279]).
was continued at 60 °C for 1.5 h. Volatiles were evaporated, and
the residue was chromatographed (MeOH/CH2Cl2, 1:90 f 1:30)
to give 1-[9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-2-chloropurin-
6-yl]-3-benzyl-2-propylimidazolium iodide: 1H NMR (500 MHz)
δ 8.97 (d, J ) 2.0 Hz, 1H), 8.59 (s, 1H), 7.86 (d, J ) 2.5 Hz, 1H),
7.43-7.51 (m, 5H), 6.37 (d, J ) 5.5 Hz, 1H), 5.84 (t, J ) 5.8 Hz,
1H), 5.80 (s, 2H), 5.58-5.60 (m, 1H), 4.45-4.54 (m, 3H), 3.70 (t,
J ) 7.5 Hz, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 1.77
(sext, J ) 7.8 Hz, 2H), 1.14 (t, J ) 7.5 Hz, 3H); HRMS m/z
611.2026 (M+ [C29H32ClN6O7] ) 611.2021). This salt was stirred
in NH3/MeOH (∼26%, 50 mL) at 60 °C for 11 h (reaction complete,
TLC). Volatiles were evaporated, and the residue was chromato-
graphed (MeOH/CH2Cl2, 1:20 f 1:15) to give a solid (quantitative).
Recrystallization (EtOH) gave the title compound (92 mg). Volatiles
were evaporated from the mother liquor, and the residue was
recrystallized (H2O) to give additional product (255 mg, 50%
total): UV max 212, 265 nm (ꢀ 21 200, 13 300), min 230 nm (ꢀ
2300); 1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.86 (br s,
2H), 5.81 (d, J ) 6.1 Hz, 1H), 5.48 (d, J ) 6.1 Hz, 1H), 5.21 (d,
J ) 4.9 Hz, 1H), 5.07 (dd, J ) 6.4, 5.2 Hz, 1H), 4.51 (dd, J )
11.0, 6.1 Hz, 1H), 4.10-4.13 (m, 1H), 3.92-3.94 (m, 1H), 3.64-
3.68 (m, 1H), 3.53-3.57 (m, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 156.7, 152.9, 150.2, 139.9, 118.1, 87.2, 85.6, 73.5, 70.3, 61.3;
HRMS m/z 301.0576 (M+ [C10H12ClN5O4] ) 301.0578).
6-(2-Butylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-tolu-
oyl)-r-D-erythro-pentofuranosyl]purine (7d). 1H NMR (500 MHz)
δ 8.59 (s, 1H), 8.41 (s, 1H), 7.97 (d, J ) 8.3 Hz, 2H), 7.57 (d, J
) 8.3 Hz, 2H), 7.30 (d, J ) 8.0 Hz, 2H), 7.13-7.14 (m, 3H), 6.67
(dd, J ) 6.4, 1.8 Hz, 1H), 5.72-5.73 (m, 1H), 4.96-4.97 (m, 1H),
4.62-4.70 (m, 2H), 3.31 (t, J ) 7.8 Hz, 2H), 3.06-3.15 (m, 2H),
2.46 (s, 3H), 2.14 (s, 3H), 1.80 (quint, J ) 7.4 Hz, 2H), 1.50 (sext,
J ) 7.4 Hz, 2H), 0.97 (t, J ) 7.3 Hz, 3H).
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-â-D-erythro-pento-
furanosyl]-6-(2-pentylimidazol-1-yl)purine (6e). UV max 223,
241, 287 nm (ꢀ 32 100, 34 700, 15 000), min 231, 265 nm (ꢀ 30
000, 9300); 1H NMR (500 MHz) δ 8.50 (s, 1H), 8.26 (s, 1H), 7.98
(d, J ) 8.2 Hz, 2H), 7.84 (d, J ) 7.9 Hz, 2H), 7.30 (d, J ) 7.9 Hz,
2H), 7.19 (d, J ) 7.9 Hz, 2H), 7.09 (s, 1H), 6.60 (t, J ) 7.0 Hz,
1H), 5.80 (br s, 1H), 4.80-4.81 (m, 1H), 4.67-4.69 (m, 2H), 3.28-
3.29 (m, 2H), 2.98-3.03 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.82
(quint, J ) 7.6 Hz, 2H), 1.36-1.48 (m, 4H), 0.93 (t, J ) 7.6 Hz,
3H); 13C NMR (125 MHz) δ 166.04, 165.99, 154.1, 153.2, 151.5,
148.0, 144.7, 144.4, 142.2, 129.9, 129.5, 129.4, 129.3, 128.9, 126.4,
126.2, 122.7, 120.3, 85.2, 83.6, 75.0, 63.9, 38.6, 31.8, 31.0, 27.7,
22.5, 21.8, 21.7, 14.1; HRMS m/z 643.2426 (MH+ [C34H36ClN6O5
) 643.2436]).
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-â-D-erythro-pento-
furanosyl]-6-{2-[2(R/S)-phenylpropyl]imidazol-1-yl}purine (6f).
UV max 241, 285 nm (ꢀ 33 300, 11 000), min 222, 266 nm (ꢀ 27
Conversion of 6b to Cladribine11 (10) by General Method 3.
Intermediate 6b (615 mg, 1.0 mmol) was added to BnI/CH3CN
(0.3 M, 40 mL, 12 mmol), and the mixture was stirred at 60 °C for
1.5 h. Volatiles were evaporated to give the residual benzylimida-
zolium iodide 9 (830 mg): 1H NMR (500 MHz) δ 8.94 (s, 1H),
8.49 (s, 1H), 8.00 (d, J ) 8.5 Hz, 2H), 7.88 (d, J ) 8.0 Hz, 2H),
7.81 (s, 1H), 7.46-7.50 (m, 5H), 7.32 (d, J ) 8.0 Hz, 2H), 7.25
(d, J ) 8.0 Hz, 2H), 6.67 (t, J ) 7.3 Hz, 1H), 5.75-5.85 (m, 3H),
4.71-4.82 (m, 3H), 3.67-3.74 (m, 2H), 2.99-3.02 (m, 2H), 2.47
(s, 3H), 2.42 (s, 3H), 1.75-1.81 (m, 2H), 1.17 (t, J ) 7.5 Hz, 3H);
HRMS m/z 705.2606 (M+ [C39H38ClN6O5 ) 705.2592]). This
material was transferred into a pressure flask with a small volume
of MeOH, cooled at -4 °C, and cold NH3/MeOH (∼26%, 50 mL)
was added. The sealed mixture was stirred and heated at 60 °C for
11 h. Volatiles were evaporated, and the residue was dissolved in
H2O and applied to a column of Dowex 1 × 2 (OH-) resin packed
in H2O. The product was eluted (H2O f MeOH/H2O, 2:3) rapidly
(MeO- and HO- can displace the 2-chloro group upon extended
exposure) to give 10 (quantitative). A small sample of this
homogeneous (TLC and 1H NMR) product was recrystallized
(EtOAc) to give analytically pure 10: mp >300 °C; UV max 212,
1
200, 6900); H NMR (500 MHz) δ 8.30 (8.28) (s, 1H), 8.22 (s,
1H), 7.98-8.00 (m, 2H), 7.85-7.89 (m, 2H), 7.18-7.31 (m, 4H),
7.06-7.12 (m, 5H), 6.90 (br s, 1H), 6.58-6.59 (m, 1H), 5.80 (s,
1H), 4.80-4.82 (m, 1H), 4.68-4.70 (m, 2H), 3.75-3.82 (m, 1H),
3.55-3.60 (m, 1H), 3.30-3.36 (m, 1H), 2.94-2.99 (m, 2H), 2.45
(s, 3H), 2.36 (s, 3H), 1.32 (d, J ) 7.0 Hz, 3H); 13C NMR (125
MHz) δ 166.1, 166.0, 154.1, 153.0, 149.4, 149.3, 147.9, 145.9,
145.8, 144.7, 144.4, 142.3, 129.9, 129.6, 129.4, 128.9, 128.0,
127.01, 126.98, 126.5, 126.3, 125.7, 122.9, 120.6, 85.1, 83.6 (83.5),
74.9, 63.9, 39.6 (39.5), 38.6, 38.5, 21.8, 21.7, 20.8; HRMS m/z
691.2439 (MH+ [C38H36ClN6O5 ) 691.2436]).
6-(2-Benzylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-
toluoyl)-â-D-erythro-pentofuranosyl]purine (6g). UV max 240,
289 nm (ꢀ 35 900, 14 600), min 231, 266 nm (ꢀ 33 500, 9300); 1H
NMR (500 MHz) δ 8.60 (s, 1H), 8.22 (s, 1H), 7.97 (d, J ) 8.3 Hz,
2H), 7.83 (d, J ) 9.0 Hz, 2H), 7.11-7.33 (m, 10H), 6.55 (t, J )
6.8 Hz, 1H), 5.77-5.78 (m, 1H), 4.77-4.80 (m, 3H), 4.64-4.68
(m, 2H), 2.92-2.94 (m, 2H), 2.45 (s, 3H), 2.36 (s, 3H); 13C NMR
(125 MHz) δ 166.03, 165.96, 154.0, 153.0, 149.1, 147.5, 144.7,
144.4, 142.2, 137.4, 129.9, 129.5, 129.34, 129.31, 129.2, 129.1,
128.2, 126.4, 126.3, 126.2, 122.5, 120.9, 85.1, 83.5, 74.9, 63.9,
38.6, 36.8, 21.8, 21.7; HRMS m/z 663.2108 (MH+ [C36H32ClN6O5]
) 663.2123).
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-â-D-erythro-pento-
furanosyl]-6-(4,5-diphenylimidazol-1-yl)purine (6h). UV max
240, 275 nm (ꢀ 53 400, 19 300), min 223, 270 nm (ꢀ 42 000, 19
100); 1H NMR (500 MHz) δ 8.97 (s, 1H), 8.25 (s, 1H), 7.97 (d, J
) 7.9 Hz, 2H), 7.86 (d, J ) 7.9 Hz, 2H), 7.55 (d, J ) 8.2 Hz, 2H),
7.19-7.40 (m, 12H), 6.56 (t, J ) 7.0 Hz, 1H), 5.77-5.78 (m, 1H),
4.76-4.79 (m, 1H), 4.65-4.69 (m, 2H), 2.92-2.96 (m, 2H), 2.45
(s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz) δ 166.1, 165.9, 154.0,
153.2, 147.1, 144.7, 144.5, 142.8, 140.4, 139.2, 133.5, 131.0, 129.9,
129.6, 129.4, 129.3, 128.3, 128.2, 127.5, 127.2, 126.4, 126.2, 124.0,
85.1, 83.5, 74.9, 63.8, 38.6, 21.8, 21.7; HRMS m/z 747.2100 (MNa+
[C41H33ClN6O5Na] ) 747.2099).
1
265 nm (ꢀ 24 000, 14 600), min 229 nm (ꢀ 2000); H NMR (500
MHz, DMSO-d6) δ 8.36 (s, 1H), 7.83 (br, 2H), 6.26 (t, J ) 6.7
Hz, 1H), 5.32 (d, J ) 4.3 Hz, 1H), 4.97 (t, J ) 5.5 Hz, 1H), 4.38
(s, 1H), 3.85 (s, 1H), 3.57-3.61 (m, 1H), 3.48-3.53 (m, 1H), 2.62-
2.67 (m, 1H), 2.25-2.29 (m, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 157.5, 153.6, 150.8, 140.5, 118.8, 88.6, 84.2, 71.4, 62.3, 38.0;
HRMS m/z 285.0615 (M+ [C10H12ClN5O3] ) 285.0629). Anal.
Calcd for C10H12ClN5O3: C, 42.04; H, 4.23; N, 24.51. Found: C,
41.87; H, 4.50; N, 24.39.
General Method 4. Direct Conversion of 6e to Cladribine
(10). A solution of 6e (350 mg, 0.55 mmol) in NH3/MeOH (∼14%)
was stirred at 80 °C for 13 h. Volatiles were evaporated, and the
oily residue was extracted with CH2Cl2 (10 mL) to remove lipophilic
byproducts. The resulting semisolid was dissolved in acetone (with
small additions of MeOH if necessary), volatiles were evaporated,
and the residue was allowed to crystallize (∼1 h). This material
was extracted with CH2Cl2 (10 mL), and the 1H NMR spectrum of
the resulting white powder (113 mg, 70%) was identical to that of
10 prepared by general method 3. Additional 10 (24 mg, 15%;
containing traces of the R anomer) was recovered from the
combined CH2Cl2 extracts by chromatography (EtOAc f MeOH/
EtOAc, 1:10) followed by extraction (CH2Cl2) of byproducts.
2-Chloroadenosine.35 General Method 3. A stock solution of
benzyl iodide in acetonitrile (∼0.3 M) was prepared in situ by
stirring NaI (15 g, 94 mmol) and BnCl (3.50 mL, 3.85 g, 30.4
mmol) in CH3CN (100 mL) at ambient temperature. A sample of
9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-2-chloro-6-(2-propylimida-
zol-1-yl)purine20 (890 mg, 1.71 mmol) was added to a stirred
solution of BnI/CH3CN (0.3 M, 70 mL, 21 mmol), and stirring
7778 J. Org. Chem., Vol. 71, No. 20, 2006

Sodium-Salt Glycosylation in Binary SolVent Mixtures
Supporting Information Available: General experimental items
and NMR spectra of compounds 6c-6h and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge pharmaceuti-
cal company unrestricted gift funds (M.J.R.) and a Roland K.
Robins Graduate Research Fellowship (M.Z.) from Brigham
Young University.
JO061282+
J. Org. Chem, Vol. 71, No. 20, 2006 7779