Selective removal of the 2′- and 3′-0-acyl groups from 2′,3′,5′-tri-O-acylribonucleoside derivatives with lithium trifluoroethoxide

Article abstract of DOI:10.1021/jo0600104

Selective cleavage of O2′ and O3′ ester groups from ribonucleoside derivatives has been accomplished with Dowex 1 × 2 (CF ₃CH₂O^-) in 2,2,2-trifluoroethanol (TFE) or lithium trifluoroethoxide/TFE. Deacylations with Li^{+ -}OCH₂CF₃/TFE proceed at ambient temperature (or with mild heating) to give the 5′-O-acyl derivatives in superior yields and higher purity than prior approaches for selective O2′ and O3′ ester deprotection.

Full text of DOI:10.1021/jo0600104

Selective Removal of the 2′- and 3′-O-Acyl Groups from
2′,3′,5′-Tri-O-acylribonucleoside Derivatives with Lithium
Trifluoroethoxide1
Ireneusz Nowak, Carl T. Jones, and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed January 3, 2006
Selective cleavage of O2′ and O3′ ester groups from ribonucleoside derivatives has been accomplished
with Dowex 1 × 2 (CF3CH2O-) in 2,2,2-trifluoroethanol (TFE) or lithium trifluoroethoxide/TFE.
Deacylations with Li+ -OCH2CF3/TFE proceed at ambient temperature (or with mild heating) to give
the 5′-O-acyl derivatives in superior yields and higher purity than prior approaches for selective O2′ and
O3′ ester deprotection.
Introduction
Two-step procedures that involve selective deacylation of di-
and triacetates have been reported,7-9 but the lack of general
applicability, problems with reproducibility, and less than
desirable overall yields leave ample room for improvement. For
example, Ishido and co-workers reported three methods for
selective deacylation at O2′ and O3′ of ribonucleosides.9 They
first employed buffered hydroxylamine acetate (anhydrous
hydroxylamine is neither stable for storage nor commercially
available) with extended reaction times (1 day), and character-
ization of the four final products was not described.9a Their
second method used a strong base (2.5 equiv of solid NaOMe
in THF),9b and our attempted repetition of that procedure gave
a mixture of deacylation products with low selectivity. Hydra-
zine hydrate was used in their third method,9c but extended
reaction times were employed and only two examples (ben-
zoylated adenosine and uridine) were reported. An additional
problem with the hydroxylamine and hydrazine procedures
results from the potential addition of these nitrogen nucleophiles
Selective protection of the primary hydroxyl group in
nucleosides is often required, and development of convenient
new procedures for O5′-protected derivatives can benefit
synthesis of biomedically important compounds. Good selectiv-
ity for O5′ monoprotection2 can usually be achieved with acid-
labile trityl and substituted trityl groups, but their reactivity with
amino groups on the nucleobases is often encountered. The tert-
butyldimethylsilyl and tert-butyldiphenylsilyl groups are more
selective, but the reagents are costly. Base-labile protecting
groups allow deprotection of deoxyoligonucleotides without
deglycosylation and other troublesome side reactions.3
Acylation of the primary hydroxyl group in sugars has been
achieved with thioesters and BOP-derived mixed anhydrides.4
Selective acylations of nucleosides have been reported,5 but
problems involved with chemical procedures stimulated devel-
opment of alternative enzyme-catalyzed processes.6
(1) Nucleic Acid Related Compounds. 134. Patent application filed. Paper
133 is Janeba, Z.; Maklad, N.; Robins, M. J. Can. J. Chem., in press.
(2) Blank, H.-U.; Frahne, D.; Myles, A.; Pfleiderer, W. Liebigs Ann.
Chem. 1970, 742, 34-42.
(6) (a) Wong, C.-H.; Chen, S.-T.; Hennen, W. J.; Bibbs, J. A.; Wang,
Y.-F.; Liu, J. L.-C.; Pantoliano, M. W.; Whitlow, M.; Bryan, P. N. J. Am.
Chem. Soc. 1990, 112, 945-953. (b) Moris, F.; Gotor, V. J. Org. Chem.
1993, 58, 653-660. (c) Ciuffreda, P.; Loseto, A.; Alessandrini, L.; Terraneo,
G.; Santaniello, E. Eur. J. Org. Chem. 2003, 4748-4751.
(7) Michelson, A. M.; Szabo, L.; Todd, A. R. J. Chem. Soc. 1956, 1546-
1549.
(3) (a) Moon, M. W.; Nishimura, S.; Khorana, H. G. Biochemistry 1966,
5, 937-945. (b) Griffin, B. E.; Jarman, M.; Reese, C. B. Tetrahedron 1968,
24, 639-662.
(4) (a) Xia, J.; Hui, Y. Synth. Commun. 1995, 25, 2235-2251. (b)
Liguori, A.; Procopio, A.; Romeo, G.; Sindona, G.; Uccella, N. J. Chem.
Soc., Perkin Trans. 1 1993, 1783-1786.
(8) Albrecht, H. P.; Repke, D. B.; Moffatt, J. G. J. Org. Chem. 1973,
38, 1836-1840.
(5) (a) Shimokawa, S.; Kimura, J.; Mitsunobu, O. Bull. Soc. Chem. Jpn.
1976, 49, 3357-3358. (b) Ligouri, A.; Perri, E.; Sindona, G.; Ucella, N.
Tetrahedron 1988, 44, 229-234. (c) He, G.-X.; Bischofberger, N. Nucleo-
sides Nucleotides 1997, 16, 257-263.
(9) (a) Ishido, Y.; Nakazaki, N.; Sakairi, N. J. Chem. Soc., Perkin Trans.
1 1979, 2088-2098. (b) Ishido, Y.; Sakairi, N.; Okazaki, K.; Nakazaki, N.
J. Chem. Soc., Perkin Trans. 1 1980, 563-573. (c) Nishino, S.; Rahman,
A. M. D.; Takamura, H.; Ishido, Y. Tetrahedron 1985, 41, 5503-5506.
10.1021/jo0600104 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/17/2006
J. Org. Chem. 2006, 71, 3077-3081
3077

Nowak et al.
TABLE 1. Deacylations (Dowex/TFE)a
SCHEME 1. Selective Deacylation
hols.13 Adenosine derivatives with nonpolar groups on the
adenine base facilitated analysis and separation of the poly-
acylated and selectively deprotected pairs (Table 1). Yields were
reasonable with base-stable N6-protecting groups (entries 1-3),
but partial removal of an acyl group from the 6-N,N-bis(4-
methylbenzoyl) imide in 1d lowered the yield of 2d (entry 4).
The acidities and relative reactivities of the 2′-, 3′-, and 5′-
hydroxyl groups in ribonucleosides are affected by changes that
withdraw electron density from the oxyanions. Subtle differences
in these pKa values and reactivities can have major implications
for the recognition, processing, and catalytic properties of
RNAs.14 Acidity data measured under uniform noninvasive
conditions15 indicate that the 2′-hydroxyl group is most acidic
(pKa ) 12.31) for the adenosine moiety in ApG and slightly
less acidic in GpG, CpG, and UpG (pKa ) 12.73-12.77). The
pKa values for the 2′- and 3′-hydroxyl groups in ribonucleosides
were shown to be very similar in different solvents,16 although
they (or the anions derived therefrom) display different reac-
tivities in a number of reactions.17 Primary (5′-OH) alcohol
groups are least acidic (pKa = 14.818), which results in the lowest
reactivity of O5′ esters toward base-promoted solvolysis. This
usually is not apparent unless a base weak enough to promote
subtle discrimination is used. Additional stabilization of a 2′/
3′-oxyanion results from the proximity of the vicinal diol
oxygens and the electron-withdrawing nature of the nucleobase
at C1′. The acidities of TFE (pKa ) 12.37)18 and heptafluoro-
propanol (pKa = 11)19 are close to those of the 2′- and
3′-hydroxyl groups of nucleosidessand quite distinct from the
pKa values (∼15) of the 5′-hydroxyl group. Thus, selective attack
of CF3CH2O- at the ester carbonyl group attached at O2′ and
O3′, relative to attack on 5′-O-acyl groups, would be expected
with this weaker nucleophile.
a Reactions performed by general procedure A (Experimental Section).
b Isolated yields in parentheses.
at C4 and C6 of cytosine nucleosides.9a,10 We now report
selective base-promoted O2′ and O3′ deacylation with solutions
of polyacylated nucleosides in 2,2,2-trifluoroethanol. A number
of nucleobase-protecting groups are stable under these condi-
tions.
Our studies with Dowex 1 × 2 (OH-)/TFE (method A) were
extended to include adenosine 1c, 3a-c, cytidine 3d-g, and
uridine 3h-k derivatives with more diverse ester groups
(Scheme 1). The more sterically hindered propionyl (70 °C)
and isobutyryl (90-110 °C) [and p-toluyl (4-methylbenzoyl)
(90-110 °C)] esters required elevated temperatures to achieve
rates of deprotection of O2′ and O3′ equivalent to those for
acetyl esters at ambient temperature (complete in ∼2 h, TLC).
However, the deacylations promoted by Dowex 1 × 2 (OH-)
Results and Discussion
We had employed SNAr replacement of (1,2,4-triazol-4-yl)11
and (imidazol-1-yl)12 groups by alkoxides on purine nucleosides
using Dowex 1 × 2 (OH-) resin washed with and suspended
in primary alcohols. Such treatment of 1a (Table 1) with Dowex
1 × 2 (OH-) in methanol gave efficient conversion to
6-methoxy-9-(â-D-ribofuranosyl)purine (with concomitant re-
moval of the three acetyl groups). However, selective removal
of the acetyl groups from O2′ and O3′ without SNAr replacement
of the imidazole group occurred upon treatment of 1a with
Dowex 1 × 2 (OH-) in 2,2,2-trifluoroethanol (TFE). We then
began a systematic investigation of selective deprotection of
polyacylated nucleosides in TFE to capitalize on the lower pKa
values and distinctive solvation properties of fluorinated alco-
(13) Be´gue´, J.-P.; Bonet-Delpon, D.; Crousse, B. Synlett 2004, 1, 18-
29.
(14) (a) Fersht, A. R. Enzyme Structure and Mechanism; W. H.
Freeman: San Francisco, CA, 1985; pp 426-431. (b) Cech, T. R. Annu.
ReV. Biochem. 1990, 59, 543-568 and references therein. (c) Rousse, B.;
Puri, N.; Viswanadham, G.; Agback, P.; Glemarec, C.; Sandstro¨m, A.; Sund,
C.; Chattopadhyaya, J. Tetrahedron 1994, 50, 1777-1810.
(15) Acharya, S.; Fo¨ldesi, A.; Chattopadhyaya, J. J. Org. Chem. 2003,
68, 1906-1910.
(10) Brown, D. M.; Schell, P. J. Chem. Soc. 1965, 208-215.
(11) (a) Samano, V.; Miles, R. W.; Robins, M. J. J. Am. Chem. Soc.
1994, 116, 9331-9332. (b) Miles, R. W.; Samano, V.; Robins, M. J. J.
Am. Chem. Soc. 1995, 117, 5951-5957.
(12) Zhong, M.; Nowak, I.; Robins, M. J. Org. Lett. 2005, 7, 4601-
4603.
(16) A° stro¨m, H.; Lime´n, E.; Stro¨mberg, R. J. Am. Chem. Soc. 2004, 126,
14710-14711.
(17) For a recent example, see: Ferguson, C. G.; Gorin, B. I.; Thatcher,
G. R. J. J. Org. Chem. 2000, 65, 1218-1221.
(18) Ballinger, P.; Long, F. A. J. Am. Chem. Soc. 1960, 82, 795-798.
(19) Ballinger, P.; Long, F. A. J. Am. Chem. Soc. 1959, 81, 1050-1053.
3078 J. Org. Chem., Vol. 71, No. 8, 2006

2′,3′-O-Deacylation of Ribonucleoside DeriVatiVes
TABLE 2. Selective Deacylationsa
TABLE 3. Deacylations of 5 (Method B)
entryb
Bc
method
R
Td
te
yieldf
entrya
Bb
R
Tc
td
yielde
1 (1c)
2 (1c)
TrAde
TrAde
TrAde
TrAde
TrAde
TrAde
TrAde
TrAde
TrCyt
TrCyt
TrCyt
TrCyt
BnUra
BnUra
BnUra
BnUra
BnUra
BnUra
BnUra
BnUra
A
B
A
B
A
B
A
B
B
B
B
B
A
B
A
B
A
B
A
B
Me
Me
Et
amb
amb
70
amb
110
60
110
60
amb
amb
60
2.0
0.5
2.0
2.0
2.0
0.5
2.0
0.5
0.5
2.5
0.5
0.5
2.0
0.5
2.0
2.0
2.0
0.5
4.0
0.5
66
88
75
86
51
65
54
76
93
94
87
80
69
91
61
79
52
71
65
90
1 (5a)
2 (5b)
3 (5c)
4 (5d)
5 (5e)
6 (5f)
Ade
Me
Et
amb
amb
60
0.5
2.0
1.0
1.5
0.5
2.5
1.0
1.0
0.5
2.0
1.0
1.5
1.0
1.5
2.0
0.5
70
71
64
81
88
84
83
66
80c
83c
62c
73c
75c
84
g
Ade
Ade
Ade
Cyt
Cyt
Cyt
Cyt
Ura
Ura
Ura
3 (3a)
4 (3a)
5 (3b)
6 (3b)
7 (3c)
iPr
Et
Tol
Me
Et
60
iPr
iPr
Tol
Tol
Me
Et
amb
amb
60
7 (5g)
iPr
8 (3c)
8 (5h)
Tol
Me
Et
60
9 (3d)
10 (3e)
11 (3f)
12 (3g)
13 (3h)
14 (3h)
15 (3i)
16 (3i)
17 (3j)
18 (3j)
19 (3k)
20 (3k)
9 (5i)f
amb
amb
60
60
60
amb
amb
amb
10 (5j)f
11 (5k)f
12 (5l)f
13 (5m)f
14 (5n)f
15 (5o)f
16 (5p)
iPr
Tol
Me
Me
Et
iPr
60
Ura
Tol
Tol
Me
Me
Ph
amb
amb
80
amb
90
60
90
60
Hpx
AcGua
For
Et
FuPym
62h
iPr
iPr
Tol
Tol
a Starting material in parentheses. b Ade: adenin-9-yl, Cyt: cytosin-1-
yl, Ura: uracil-1-yl, Hpx: hypoxanthin-9-yl, AcGua: 2-N-acetylguanin-
9-yl, For: 7-aminopyrazolo[4,3-d]pyrimidin-3(1H)-yl, FuPym: furo[2,3-
d]pyrimidin-2-(3H)-on-3-yl. c Amb: ambient, other temperatures in °C.
d Time in hours. e Isolated % yield. f LiOCH2CF3 (3 equiv). g Complex
mixture. h TFE was used for chromatography in place of MeOH.
a See the Results and Discussion and Experimental Section for methods
A and B. b Starting material in parentheses. c TrAde: 6-N-trityladenin-9-
yl, TrCyt: 4-N-tritylcytosin-1-yl, BnUra: 3-benzyluracil-1-yl. d Amb:
ambient, other temperatures in °C. e Time in hours. f Isolated % yield.
produced results that were less than desirable because partially
(di-O-acylated) and completely deprotected byproducts were
formed. Addition of the hydrogen bond-accepting cosolvent
THF (THF/TFE, 10:1) resulted in more extensive conversion
of 3b to the fully deacylated product, whereas addition of toluene
(toluene/TFE, 5:1) markedly retarded the rate of deacylation.
We then examined replacement of the two-phase system of
Dowex resin (which contains traces of water and OH- anions)
and TFE with homogeneous solutions of metal trifluoroethoxides
in TFE.
FIGURE 1. Structures of For and FuPym.
SCHEME 2. Deacylation of 7
A solution of sodium trifluoroethoxide (generated with excess
TFE and 1 M sodium hexamethyldisilazide/THF) gave rapid
deacylation. However, the above-noted effect of THF-promoted
removal of the O5′ ester gave a lower yield of 4i (52%,
compared with Table 2 entry 16, 79%). Lithium trifluoroethox-
ide/TFE (generated with excess TFE and 1.6 M butyllithium/
hexanes) (method B) caused rapid deacylation, and the selec-
tively deprotected 5′-O-acyl products were isolated in higher
yields (entries 2, 4, 6, 8-12, 14, 16, 18, 20).
Nucleoside derivatives 5 without N-protection (containing
mobile NH and/or OH protons) also were examined (Table 3).
Despite their increased polarity, products 6 and byproducts were
resolved by TLC and purified by column chromatography. An
additional equivalent of LiOCH2CF3 was used with the uridine,
5i-l, hypoxanthine, 5m, and guanine, 5n, derivatives (which
have an acidic imide or amide proton). The deprotections with
5 were slightly less selective than those with the less polar
derivatives 3. Treatment of 2′,3′,5′-tri-O-acetylformycin (5o)
with 3 equiv of LiOCH2CF3/TFE by method B gave formycin
as the major product. The loss of selectivity (the desired product
6o was a minor component) was accompanied by yellow
coloration of the reaction mixture. The proximal pyrazole ring
nitrogen (N2) of the base moiety (For, Figure 1) might
participate in solvolysis of the acetyl group from O5′.
MeOH or NaOMe/MeOH. We were pleased that the decreased
nucleophilicity of LiOCH2CF3/TFE accommodates selective
cleavage of the benzoate esters at O2′ and O3′ (62% isolated
yield, entry 16). Prolonged treatment resulted in removal of the
5′-O-benzoyl group without problematic opening of the furan
ring.
Replacement of the 2′-hydroxyl group by hydrogen caused
dramatic decreases in deacylation rates and loss of selectivity
for cleavage of O3′ versus O5′ esters in 2′-deoxynucleoside
derivatives. For example, 2′-deoxy-3′,5′-di-O-(4-methylbenzo-
yl)uridine remained unchanged after 3 h at 60 °C. Treatment
of 3′,5′-di-O-acetyl-2′-deoxyadenosine (method B, 3.5 h, ambi-
ent temperature) produced a mixture of starting material, 3′-O-
acetyl-2′-deoxyadenosine, 5′-O-acetyl-2′-deoxyadenosine, and
2′-deoxyadenosine (∼3:2:2:1).
Further probing of the effects of sugar structure on our
selective deprotection with LiOCH2CF3/TFE (method B) was
pursued with 9-(2,3,5-tri-O-propanoyl-â-D-arabinofuranosyl)-
6-N-trityladenine (7) (Scheme 2). Inversion of configuration at
C2′ to give the arabino epimer 7 does not significantly alter the
acidity of the vicinal secondary hydroxyl groups, but makes
acyl transfer between the trans O2′ and O3′ termini highly
A demanding application of our method involved removal
of the benzoyl-protecting groups from the sensitive furo[2,3-
d]pyrimidin-2(3H)-one derivative 5p. The fused furan moiety
(FuPym) in 5p is susceptible to nucleophilic attack and
undergoes ring opening upon attempted deprotection with NH3/
J. Org. Chem, Vol. 71, No. 8, 2006 3079

Nowak et al.
H2O and then with distilled H2O until the eluant was neutral. The
resin was next washed with 1 M NaOH/H2O until an aliquot (after
acidification with HNO3/H2O) showed no cloudiness upon addition
of AgNO3/H2O, and then it was washed with distilled H2O until
the eluate was neutral. The Dowex 1 × 2 [OH-] resin, collected
by suction filtration and air-dried, can be stored indefinitely in a
bottle protected from light at refrigerator temperature.
Air-dried Dowex 1 × 2 [OH-] resin was suspended in dried
TFE, stirred for 30 min, filtered with suction, and resuspended in
TFE. This cycle was repeated several times, and the resin was then
dried in vacuo at ambient temperature overnight and stored in a
bottle protected from light in a desiccator.
Method A. Selective Deacylation of Peracylated Nucleosides
with Dowex 1 × 2 [CF3CH2O-] Resin in TFE. Dried Dowex 1
× 2 [CF3CH2O-] resin (0.5 g, ∼0.5 mmol exchange capacity) was
added to a solution of nucleoside 1 or 3 (1 mmol) in TFE (2 mL),
and the suspension was stirred vigorously for the time (and at the
temperature) specified. Reactions at temperatures greater than the
boiling point of TFE (74 °C) were performed in a pressure flask
equipped with a Teflon valve. When selective deprotection was
judged complete (TLC), the suspension was filtered and the resin
was washed thoroughly with EtOAc and then MeOH. The combined
filtrates were concentrated and subjected to silica column chroma-
tography to give the purified products 2 or 4.
Method B. Selective Deacylation of O-Peracylated Nucleo-
sides with LiOCH2CF3/TFE. Butyllithium/hexanes (1.6 M, 0.8
mL, 1.28 mmol) were added dropwise to stirred trifluoroethanol
(2 mL), and moderate evolution of heat occurred. The resulting
solution was added to compound 1 (or 3 or 7) (0.64 mmol) in a
separate flask, and the reaction mixture was stirred at ambient
temperature (or 60 °C) until selective deacylation was judged to
be complete (TLC). Acetic acid (0.5 mL, 8.33 mmol) was added,
and volatiles were evaporated. A suspension of the residue in CH2-
Cl2 was subjected to silica column chromatography to give the
purified compound 4 (or 6 or 8 or 9).
unfavorable. However, acyl transfer between the cis O5′ and
O2′ oxygens is possible. Treatment of 7 under the usual
conditions gave the 5′-ester 8 as the major product accompanied
by the 3′-ester 9 (∼3:2 ratio) in a combined yield of 81%. A
5:1 ratio of 8/9 (39% combined) was obtained with Dowex/
TFE (method A). These results are consistent with more rapid
solvolysis of the 2′-ester followed by migration of the acyl group
from O5′ to O2′. The second cleavage from O2′ is in competition
with solvolysis of the 3′-ester. Migration is dependent on the
acyl group and occurred to a lesser extent with the 2′,3′,5′-tri-
O-(4-methylbenzoyl) analogue (i.e., a larger 5′-/3′-ester ratio
was observed (1H NMR)).
Our methodology with LiOCH2CF3/TFE (readily prepared
with quantitative stoichiometry from TFE and commercial 1.6
M BuLi/hexanes) employs a solvent with unique pKa and
physicochemical properties. The nucleoside derivatives we
examined are readily soluble, and a variety of ester derivatives
1c, 3, and 5 underwent selective deacylation readily (most
reactions were completed in 0.5-2.0 h at ambient temperature
or 60 °C). This procedure is superior to method A (Dowex 1 ×
2 [OH-]/TFE), which requires higher temperatures with hin-
dered alkyl and 4-methylbenzoyl esters and is often less
selective. Others have noted the loss of selectivity for cleavage
of esters of deoxynucleosides. For example, hydrazinolysis of
esters of 2′- and 3′-deoxyadenosine9c and treatment of such
derivatives with ethanolic morpholine (pKa ) ∼8.4)20 gave
mixtures.
Conclusions
We have demonstrated that solutions of O-peracylated
ribonucleosides in lithium trifluoroethoxide/trifluoroethanol
undergo selective deacylation at O2′ and O3′. Increased reaction
times and/or temperatures are required for esters with greater
steric demands in the acyl group. One equivalent of LiOCH2-
CF3 is neutralized by the acidic amide/imide proton on certain
nucleobases, but addition of a further equivalent of LiOCH2-
CF3 results in a negligible effect on the selectivity and yields
of most reactions. The method is mild and rapid (complete
within 3 h in the slowest cases) and provides the 5′-O-acyl
products in 60-90% yields. It is noteworthy that the low
nucleophilicity of CF3CH2O- makes this methodology tolerant
of a 4-amino group and the 5,6-double bond in pyrimidines,
the 6-(imidazol-1-yl) group on purines, and the fused furan
moiety in a furo[2,3-d]pyrimidin-2(3H)-one derivative. A broad
variety of 5′-O-acyl nucleoside derivatives are now readily
available as intermediates for synthesis of deoxynucleosides,21
cyclic nucleosides,17 oligoribonucleotides,22 and nucleoside
prodrugs. They also can be functionalized into numerous other
compounds via 2′,3′-O-(dibutylstannylene) derivatives.23 By the
proper choice of 5′-O-acyl groups, the polarity and crystallinity
of ribonucleoside derivatives can be fine-tuned for purification
and other purposes.
Preparation of 2′,3′,5′-Tri-O-acyl-N-trityl Nucleosides (1c,
3a-g, 7). A solution of the adenine or cytosine 2′,3′,5′-tri-O-acyl
nucleoside and trityl chloride (2 equiv) in dried pyridine was stirred
overnight at 100 °C. Volatiles were evaporated, and the residue
was chromatographed (EtOAc/hexanes) to give purified 1c, 3a-g,
and 7 in 80-90% yields.
2′,3′,5′-Tri-O-acetyl-6-N-trityladenosine24 (1c). 1H NMR δ
2.08, 2.10, 2.12 (3 × s, 3 × 3H), 4.33-4.46 (m, 3H), 5.68 (t, J )
5.1 Hz, 1H), 5.91 (t, J ) 5.4 Hz, 1H), 6.14 (d, J ) 4.9 Hz, 1H),
6.94 (s, 1H), 7.23-7.35 (m, 15H), 7.90 (s, 1H), 8.04 (s, 1H); 13C
NMR δ 20.06, 20.14, 20.4, 62.7, 70.2, 71.0, 72.8, 79.7, 86.0, 121.0,
126.6, 127.5, 128.6, 138.2, 144.5, 148.3, 152.2, 153.8, 169.0, 169.2,
169.9; MS m/z 658 (100%, M + Na+); HMRS Calcd for
C35H33N5O7Na: 658.2277, Found: 658.2375.
2′,3′,5′-Tri-O-acetyl-6-N,N-di(4-methylbenzoyl)adenosine (1d).
p-Toluyl chloride (0.50 mL, 0.58 g, 3.78 mmol) was added to a
solution of 2′,3′,5′-tri-O-acetyladenosine (0.17 g, 0.43 mmol) in
dried pyridine (1 mL), and the solution was stirred for 1 h at 80
°C. Volatiles were evaporated, and the residue was chromatographed
(EtOAc/hexanes 10:1 f EtOAc) to give 1d (0.23 g, 84%): 1H
NMR δ 2.09, 2.10, 2.14 (3 × s, 3 × 3H), 2.35 (s, 6H), 4.36-4.48
(m, 3H), 5.69 (t, J ) 2.7 Hz, 1H), 5.94 (t, J ) 5.2 Hz, 1H), 6.25
(d, J ) 4.9 Hz, 1H), 7.16 (d, J ) 7.8 Hz, 4H), 7.76 (d, J ) 7.8 Hz,
4H), 8.21 (s, 1H), 8.65 (s, 1H); 13C NMR δ 20.0, 20.2, 20.4, 21.3,
62.7, 70.2, 72.7, 80.1, 86.3, 127.4, 129.2, 129.3, 130.8, 143.1, 143.7,
152.0, 152.2, 169.0, 169.2, 169.9, 171.8; MS m/z 652 (100%, M
+ Na+); HMRS Calcd for C32H31N5O9Na: 652.2019; Found:
652.2017.
Experimental Section
Dowex 1 × 2 [CF3CH2O-] Resin. Commercial Dowex 1 × 2
[Cl-] resin was washed with four column volumes of 1 M HCl/
(20) Griffin, B. E.; Reese, C. B. Proc. Natl. Acad. Sci. U.S.A. 1964, 15,
440-444.
(21) Brown, D. M.; Parihar, D. B.; Reese, C. B.; Todd, A. J. Chem.
Soc. 1958, 3035-3038.
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1974, 39, 24-30. (b) Reginato, G.; Ricci, A.; Roelens, S.; Scapecchi, S. J.
Org. Chem. 1990, 55, 5132-5139.
9-(5-O-Acetyl-â-D-ribofuranosyl)-6-(imidazol-1-yl)purine (2a).
Treatment of 9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-6-(imidazol-
(24) Hata, T.; Gokita, N.; Sakairi, N.; Yamaguchi, K.; Sekine, M.; Ishido,
Y. Bull. Chem. Soc. Jpn. 1982, 55, 2949-2955.
3080 J. Org. Chem., Vol. 71, No. 8, 2006

2′,3′-O-Deacylation of Ribonucleoside DeriVatiVes
1-yl)purine25 (1a) by method A at ambient temperature for 2 h gave
2a (75%): 1H NMR (CD3OD) δ 2.08 (s, 3H), 4.29-4.45 (m, 4H),
4.84 (t, J ) 4.9 Hz, 1H), 6.15 (d, J ) 4.4 Hz, 1H), 7.18 (d, J ) 1.0
Hz, 1H), 8.35 (t, J ) 1.5 Hz, 1H), 8.58 (s, 1H), 8.73 (s, 1H), 9.09
(s, 1H); 13C NMR δ 20.9, 65.0, 72.0, 75.2, 83.7, 90.9, 118.9, 124.3,
130.6, 138.8, 146.3, 146.4, 153.3, 154.8, 172.5; MS m/z 383 (100%,
M + Na+); HMRS Calcd for C15H16N6O5Na: 383.1080, Found:
383.1088.
9-(5-O-Acetyl-â-D-ribofuranosyl)-6-(2,5-dimethylpyrrol-1-yl)-
purine (2b). Treatment of 9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-
6-(2,5-dimethylpyrrol-1-yl)purine26 (1b) by method A at ambient
temperature for 1.5 h gave 2b (71%): 1H NMR δ 2.05 (s, 3H),
2.16 (s, 6H), 4.02 (br s, 1H), 4.33-4.43 (m, 4H), 4.60 (t, J ) 4.2
Hz, 1H), 4.99 (br s, 1H), 5.94 (s, 2H), 6.10 (t, J ) 3.9 Hz, 1H),
8.33 (s, 1H), 8.89 (s, 1H); 13C NMR δ 13.4, 20.7, 63.5, 70.7, 74.6,
82.7, 90.0, 109.1, 129.1, 129.8, 143.7, 150.2, 152.1, 152.7, 170.7;
MS m/z 410 (100%, M + Na+); HMRS Calcd for C18H21N5O5Na:
410.1440, Found: 410.1436.
5′-O-Acetyl-6-N-trityladenosine (2c). Method A. Treatment of
1c by method A at ambient temperature for 2 h gave 2c (66%):
1H NMR δ 1.98 (s, 3H), 4.12-4.48 (m, 7H), 5.89 (d, J ) 4.9 Hz,
1H), 6.18 (br s, 1H), 7.14 (s, 1H), 7.20-7.34 (m, 15H), 7.95 (s,
1H); 13C NMR δ 20.6, 63.2, 70.5, 71.3, 74.8, 82.3, 89.8, 120.8,
126.8, 127.7, 128.8, 138.1, 144.5, 147.6, 151.7, 153.9, 170.4; MS
m/z 574 (100%, M + Na+); HMRS Calcd for C31H29N5O5Na:
574.2066, Found: 574.2053.
75.9, 82.9, 92.4, 94.6, 127.6, 128.4, 128.6, 140.0, 143.5, 156.2,
165.5, 173.6; MS m/z 564 (100%, M + Na+); HMRS Calcd for
C31H31N3O6Na: 564.2110, Found: 564.2124.
5′-O-Propionylcytidine (6f). Treatment of 5f by method B at
ambient temperature for 2.5 h gave 6f (84%): 1H NMR (DMSO-
d6) δ 1.04 (t, J ) 7.6 Hz, 3H), 2.37 (q, J ) 7.5 Hz, 2H), 3.89-
4.00 (m, 3H), 4.18 (dd, J ) 5.4, 11.8 Hz, 1H), 4.27 (dd, J ) 2.9,
11.8 Hz, 1H), 5.22 (br s, 1H), 5.43 (br s, 1H), 5.74 (d, J ) 7.8 Hz,
1H), 5.76 (d, J ) 3.9 Hz, 1H), 7.19 (br s, 1H), 7.24 (br s, 1H),
7.59 (d, J ) 7.9 Hz, 1H); 13C NMR (DMSO-d6) δ 9.0, 26.7, 63.7,
69.7, 73.4, 80.4, 90.0, 94.2, 141.3, 155.2, 165.6, 173.5; MS m/z
322 (100%, M + Na+); HMRS Calcd for C12H17N3O6Na: 322.1010,
Found: 322.1014.
5′-O-Isobutyrylcytidine (6g). Treatment of 5g by method B at
60 °C for 1 h gave 6g (83%): 1H NMR (DMSO-d6) δ 1.10 (t, J )
6.8 Hz, 6H), 2.54-2.62 (m, 1H), 3.89-4.00 (m, 3H), 4.19 (dd, J
) 3.9, 12.2 Hz, 1H), 4.26 (dd, J ) 2.9, 12.2 Hz, 1H), 5.21 (d, J )
6.4 Hz, 1H), 5.43 (d, J ) 5.4 Hz, 1H), 5.73 (d, J ) 7.3 Hz, 1H),
5.76 (d, J ) 3.9 Hz, 1H), 7.18 (br s, 1H), 7.22 (br s, 1H), 7.59 (d,
J ) 7.3 Hz, 1H); 13C NMR (DMSO-d6) δ 19.3, 19.4, 34.6, 64.5,
71.2, 76.1, 82.6, 92.0, 95.8, 142.0, 157.4, 167.2, 177.0; MS m/z
314 (100%, M + H+); HMRS Calcd for C13H20N3O6: 314.1347,
Found: 314.1352.
5′-O-(4-Methylbenzoyl)uridine (6l). Treatment of 5l by method
B at 60 °C for 1.5 h gave 6l (73%): 1H NMR (DMSO-d6) δ 2.40
(s, 3H), 4.06-4.18 (m, 3H), 4.44 (dd, J ) 5.4, 11.7 Hz, 1H), 4.54
(dd, J ) 2.9, 11.7 Hz, 1H), 5.39 (br s, 1H), 5.54 (d, J ) 8.3 Hz,
1H), 5.56 (br s, 1H), 5.79 (d, J ) 4.4 Hz, 1H), 7.37 (d, J ) 8.3 Hz,
2H), 7.64 (d, J ) 7.8 Hz, 1H), 7.88 (d, J ) 7.8 Hz, 2H), 11.40 (br
s, 1H); 13C NMR (DMSO-d6) δ 21.2, 64.1, 69.7, 72.8, 81.1, 89.0,
101.9, 126.7, 129.3, 129.5, 140.8, 144.0, 150.6, 163.1, 165.6; MS
m/z 363 (100%, M + H+); HMRS Calcd for C17H19N2O7:
363.1187, Found: 363.1183.
3-(5-O-Benzoyl-â-D-ribofuranosyl)furo[2,3-d]pyrimidin-2(3H)-
one (6p). Treatment of 5p by method B at ambient temperature
for 0.5 h gave 6p (62%): 1H NMR (DMSO-d6) δ 4.09-4.14 (m,
2H), 4.28-4.32 (m, 1H), 4.58 (dd, J ) 5.4, 12.7 Hz, 1H), 4.71
(dd, J ) 2.4, 12.2 Hz, 1H), 5.66 (br s, 1H), 5.87 (s, 1H), 5.96 (br
s, 1H), 6.39 (dd, J ) 1.0, 2.4 Hz, 1H), 7.54 (t, J ) 7.3 Hz, 2H),
7.68-7.71 (m, 1H), 8.01 (d, J ) 8.3 Hz, 2H), 8.50 (s, 1H), 8.57
(s, 1H); 13C NMR (DMSO-d6) δ 63.9, 68.9, 74.7, 79.2, 80.7, 92.6,
105.0, 128.8, 129.3, 133.5, 138.9, 144.9, 153.8, 165.6, 166.0, 171.4;
MS m/z 373 (100%, M + H+); HMRS Calcd for C18H17N2O7:
373.1030, Found: 373.1035.
Method B. Treatment of 1c by method B at ambient temperature
for 0.5 h gave 2c (88%) with identical spectral data.
5′-O-Acetyl-6-N,N-di(4-methylbenzoyl)adenosine (2d). Treat-
ment of 1d by method A at ambient temperature for 1 h gave 2d
(39%): 1H NMR δ 2.00 (s, 3H), 2.34 (s, 6H), 3.67 (d, J ) 3.9 Hz,
1H), 4.24-4.36 (m, 4H), 4.57 (m, 1H), 4.95 (d, J ) 3.9 Hz, 1H),
6.00 (d, J ) 4.9 Hz, 1H), 7.14 (d, J ) 7.8 Hz, 4H), 7.73 (d, J )
7.8 Hz, 4H), 8.18 (s, 1H), 8.58 (s, 1H); 13C NMR δ 20.7, 21.6,
63.6, 70.7, 74.4, 82.4, 89.6, 127.5, 129.47, 129.54, 130.9, 143.6,
144.2, 151.9, 152.0, 152.3, 170.7, 172.3; MS m/z 568 (100%, M
+ Na+); HMRS Calcd for C28H27N5O7Na: 568.1808, Found:
568.1804.
2′,3′,5′-Tri-O-propionyl-4-N-tritylcytidine (3e). 1H NMR δ 1.06
(t, J ) 7.3 Hz, 3H), 1.13 (t, J ) 7.3 Hz, 6H), 2.17-2.48 (m, 6H),
4.25-4.38 (m, 3H), 5.04 (d, J ) 7.8 Hz, 1H), 5.26 (t, J ) 5.6 Hz,
1H), 5.34 (t, J ) 4.6 Hz, 1H), 6.11 (d, J ) 3.9 Hz, 1H), 6.93 (br
s, 1H), 7.20-7.36 (m, 16H); 13C NMR δ 8.49, 8.56, 26.79, 26.89,
62.1, 69.0, 70.6, 73.3, 78.9, 88.3, 94.5, 127.3, 128.1, 128.3, 139.7,
143.4, 154.3, 165.1, 172.5, 172.6, 173.1; MS m/z 676 (100%, M
+ Na+); HMRS Calcd for C37H39N3O8Na: 676.2635, Found:
676.2637.
5′-O-Propionyl-4-N-tritylcytidine (4e). Treatment of 3e by
method B at ambient temperature for 2.5 h gave 4e (94%): 1H
NMR δ 1.00 (t, J ) 7.3 Hz, 3H), 2.04-2.19 (m, 2H), 3.61 (br s,
1H), 4.10-4.44 (m, 5H), 5.09 (d, J ) 7.8 Hz, 1H), 5.73 (d, J )
2.9 Hz, 1H), 6.11 (br s, 1H), 7.02 (br s, 1H), 7.22-7.35 (m, 15H),
7.37 (d, J ) 7.8 Hz, 1H); 13C NMR δ 8.9, 27.2, 63.3, 70.8, 71.0,
Acknowledgment. We gratefully acknowledge pharmaceuti-
cal company unrestricted gift funds (M.J.R.), and Brigham
Young University for support of this research.
Supporting Information Available: 1H NMR, 13C NMR, and
mass spectral data for less accessible polyacylated starting materials
and selective deacylation products; representative 1H NMR spectra
(for 4a, 4h, 6h, 6k, 6m, 9); 13C NMR spectra (for 1c, 1d, 2a-d,
3a-g, 3i-k, 4a-k, 5m, 5n, 5p, 6a-n, 6p, 7-9). This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497-3499.
(26) Nowak, I.; Robins, M. J. Org. Lett. 2003, 5, 3345-3348.
JO0600104
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