Removal of acetal, silyl, and 4, 4′-dimethoxytrityl protecting groups from hydroxyl functions of carbohydrates and nucleosides with clay in aqueous methanol

Full text of DOI:10.1021/jo961376r

9026
J . Org. Chem. 1996, 61, 9026-9027
Rem ova l of Aceta l, Silyl, a n d
4,4′-Dim eth oxytr ityl P r otectin g Gr ou p s
fr om Hyd r oxyl F u n ction s of Ca r boh yd r a tes
a n d Nu cleosid es w ith Cla y in Aqu eou s
Meth a n ol
J un-ichi Asakura,*,† Morris J . Robins,‡
Yukihiro Asaka,§ and Tong Hei Kim§
Departments of Biochemistry and Chemistry,
Kinki University School of Medicine, Ohno-higashi,
Osaka-sayama, Osaka 589, J apan, and Department of
Chemistry and Biochemistry, Brigham Young University,
Provo, Utah 84602-5700
Received J uly 22, 1996
Protection and deprotection of hydroxyl groups are
important procedures in carbohydrate and nucleoside/
nucleotide chemistry, and cyclic acetals, silyl ethers, and
trityl ethers are frequently used. Such derivatives are
useful intermediates for the synthesis of biologically
active analogues and chemical syntheses of oligonucle-
otides.1 Acetic or formic acids and aqueous mineral acids
are frequently used for hydrolysis of acetals and trityl
ethers. Tetrabutylammonium fluoride (TBAF) in tetra-
hydrofuran (THF) and other fluoride reagent/solvent
combinations are commonly used for deprotection of silyl
ethers.1c,2,3 However, strong acids and/or TBAF often
cause difficulties in the workup and purification of
products.
Recently, various types of montmorillonite clays have
been shown to function as effective heterogeneous acid
catalysts for organic syntheses.4 Positive features of
these inexpensive clays include stability, ease of han-
dling, lack of corrosiveness and other environmental
hazards, and ease of regeneration. Clays are experimen-
tally convenient with respect to treatment and catalyst
removal since they are insoluble. We have recently
reported a simple method for the preparation of isopro-
pylidene derivatives of carbohydrates with K 10 clay in
acetone5 and deprotection of acylated nucleosides under
neutral or weakly basic conditions.6,7 We now report a
F igu r e 1.
facile method for the deprotection of isopropylidene, silyl,
and trityl carbohydrate and nucleoside derivatives with
K 10 clay in 50% aqueous methanol.
Treatment of nucleoside derivatives 1-10 and isopro-
pylidene sugars 11-13 (Figure 1) with K 10 clay in
MeOH/H2O (1:1) at an adequate temperature (ambient,
50 °C, or 75 °C) resulted in deprotection to give adeno-
sine, uridine, 2′-deoxyuridine, D-glucose, L-rhamnose, or
D-ribose. The pH of the reaction mixtures was 4.1-5.0
(uridine derivatives), 5.1-5.4 (adenosine derivatives), and
3.6-4.0 (carbohydrate derivatives), and the pH was not
remarkably changed during the each deprotection reac-
tion. The pH of the each filtrate from which clay was
removed by filtration, was 5.7-6.7. The deprotected
compounds were purified by crystallization or silica
column chromatography to give TLC homogeneous prod-
ucts with yields listed in Table 1.
Effects of solvent and temperature were examined with
2′,3′-O-isopropylideneuridine (1) (entry numbers 1-5).
Treatment of 1 with K 10 clay (500 mg/mmol of 1) in
MeOH at ambient temperature for 48 h resulted in low
conversions (TLC) to uridine (mainly unchanged 1, entry
1). The use of MeOH/H2O (1:1) at elevated temperatures
accelerated the reaction and increased the isolated yields
of uridine (entries 1-5). Similar deprotection of 2′,3′-O-
isopropylideneadenosine (2) with K 10 clay (500 mg/mmol
of 2) in MeOH/H2O (1:1) at 75 °C for 55 h gave adenosine
(80%, entry 6).
Cleavage of the silyl ether groups from 5′-O-TBDMS-
Urd (3), 5′-O-TBDMS-Ado (4), 3′,5′-O-(1,1,3,3-tetraiso-
propyl-1,3-disiloxanyl)Urd (5), 3′,5′-O-TIPDS-dUrd (6),
and 3′,5′-di-O-TBDMS-dUrd (7) occurred readily upon
treatment of 3-7 with 500 mg of K 10 clay/mmol of
substrate in MeOH/H2O (1:1) at 75 °C (entries 7-11).
However, attempted deprotection of 5′-O-TBDPS-dUrd
(8) under these conditions for 48 h resulted in low
conversions to dUrd (entry 12). The enhanced stability
of 8 against hydrolysis by K 10 clay is in agreement with
the generally more vigorous acidic requirements for
hydrolyses of tert-butyldiphenylsilyl ethers.1c,8
† Department of Biochemistry, Kinki University.
‡ Department of Chemistry, Kinki University.
§ Brigham Young University.
(1) (a) De Belder, A. N. Adv. Carbohydr. Chem. Biochem. 1977, 34,
179. (b) Clode, D. M. Chem. Rev. 1979, 79, 491. (c) Lalonde, M.; Chan,
T. H. Synthesis 1985, 817. (d) Greene, T. W.; Wuts, P. G. M. In
Protective Groups in Organic Synthesis, 2nd ed.; J ohn Wiley & Sons:
New York, 1991; pp 53-86, 119-142 and references therein.
(2) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(3) (a) Shekhani, M. S.; Khan, K. M.; Mahmood, K. Tetrahedron Lett.
1988, 29, 6161. (b) Monger, S. J .; Parry, D. M.; Roberts, S. M. J . Chem.
Soc., Chem. Commun. 1989, 381. (c) Cormier, J . F. Tetrahedron Lett.
1991, 32, 187. (d) Zhang, W.; Robins, M. J . Tetrahedron Lett. 1992,
33, 1177 and references therein.
(4) (a) Hoyer, S.; Laszlo, P. Synthesis 1986, 655. (b) Kawai, M.;
Onaka, M.; Izumi, Y. Bull. Chem. Soc. J pn. 1988, 61, 2157. (c) Labiad,
B.; Villemin, D. Synthesis 1989, 143. (d) Labiad, B.; Villemin, D. Synth.
Commun. 1989, 19, 31. (e) Higuchi, K.; Onaka, M.; Izumi, Y. J . Chem.
Soc., Chem. Commun. 1991, 1035. (f) Tsujimoto, M.; Matsubara, Y.;
Yoshihara, M.; Maeshima, T.; Asakura, J . Chem. Express 1991, 6, 825.
(g) Onaka, M.; Shinoda, T.; Izumi, Y.; Nolen, E. Chem. Lett. 1993, 117.
(h) Fukase, K.; Winarno, H.; Kusumoto, S. Chem. Express 1993, 8, 409.
(i) Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y. Synlett 1993, 141. (j)
Tateiwa, J .; Horiuchi, H.; Uemura, S. J . Org. Chem. 1995, 60, 4039
and references therein.
Cleavage of dimethoxytrityl ethers was investigated
with 5′-O-(4,4′-dimethoxytrityl)Urd (9) and 5′-O-(4,4′-
dimethoxytrityl)Ado (10). Deprotection of 9 and 10
occurred readily with 500 mg of K 10 clay/mmol of
(5) Asakura, J .; Matsubara, Y.; Yoshihara, M. J . Carbohydr. Chem.
1996, 15, 231.
(6) Asakura, J .; Tomura, T. Nucleosides Nucleotides 1988, 7, 245.
(7) Asakura, J . Nucleosides Nucleotides 1993, 12, 701.
(8) Cunico, R. F.; Bedell, L. J . Org. Chem. 1980, 45, 4797.
S0022-3263(96)01376-X CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9027
Ta ble 1. K 10 Cla y-Ca ta lyzed Dep r otection of 1-13a
a J asco DIP-140 polarimeter. Elemental analyses were deter-
mined by the Analytical Center of Dainippon Pharmaceutical
Co., Ltd. The pH was measured with Horiba M-8 AD pH meter.
TLC was performed on Merck kieselgel 60 F-254 sheets, and
compounds were detected by visualization under 254 nm light
or by spraying the plates with H2SO4/MeOH. Merck kieselgel
60 (230-400 mesh) was used for column chromatography.
Protected starting materials were prepared by literature
methods,5,10-15 and “diffusion crystallization” was performed as
described.16
Dep r otection P r oced u r e. Mixtures of 500 mg of the
substrate (1-13), K 10 clay, and solvent (20 mL) were stirred
for indicated periods under the noted reaction conditions (Table
1). Mixtures were filtered (Celite pad) and washed with MeOH.
Combined filtrates were concentrated, and the residues were
coevaporated (× 3) with EtOH/toluene (1:2) under reduced
pressure. Purification of deprotected products gave compounds
with data noted in the following summaries and Table 1.
Byproducts were not isolated or characterized.
Ur id in e. The residue was treated with charcoal (EtOH/∆)
and crystallized [EtOH/hexanes (diffusion)] to give Urd (needles):
mp 166.5-167 °C; UVmax 262 nm (ꢀ 10 000), min 230 nm (ꢀ 2100);
FAB-HRMS m/ z 243.0600 ([M- - H] C9H11N2O6 ) 243.0617).
2′-Deoxyu r id in e. The residue was treated with charcoal
(EtOH/∆) and crystallized [EtOH/hexanes (diffusion)] to give
dUrd (needles): mp 164-164.5 °C; UVmax 262 nm (ꢀ 10 000),
min 230 nm (ꢀ 1900); FAB-HRMS m/ z 227.0695 ([M- - H]
C9H11N2O5 ) 227.0668).
Ad en osin e. The residue was treated with charcoal (MeOH/
∆) and crystallized (MeOH) to give Ado (needles): mp 225-227
°C dec; UVmax 260 nm (ꢀ 14 800), min 228 nm (ꢀ 2100); FAB-
HRMS m/ z 266.0889 ([M- - H] C10H12N5O4 ) 266.0889).
D-Glu cose. The residue was treated with charcoal (EtOH/
∆) and crystallized [MeOH/Et2O (diffusion)] to give D-glucose
(fine plates): mp 147-151 °C; [R]21D +52.7° (c, 1.05; H2O); FAB-
HRMS m/ z 179.0577 ([M- - H] C6H11O6 ) 179.0556).
L-Rh a m n ose. The residue was treated with charcoal (EtOH/
∆) and crystallized [EtOH/Et2O (diffusion)] to give L-rhamnose
(fine plates): mp ∼ 92 °C; [R]21D +8.0° (c, 1.01; H2O); FAB-HRMS
m/ z 163.0619 ([M- - H] C6H11O5 ) 163.0606).
temp, time,
productb
entry compd
solvent
MeOH
°C
h
(yield %)c
1
2
1
1
rt
48
48
48
50
26
55
5
10
36
60
12
48
Ur d
(trace)d,e
MeOH
50
75
50
75
75
75
75
75
75
75
75
75
rt
Ur d
Ur d
Ur d
Ur d
Ad o
Ur d
Ad o
Ur d
(<60)e
(<80)e
(90)
3
1
MeOH
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1
1
2
3
4
5
6
7
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
(94)
(80)
(95)
(93)
(97)
d Ur d (90)
d Ur d (94)
8
9
9
d Ur d (trace)d,e
0.5 Ur d
12
0.5 Ad o
20
72
72
12
5
72
50
(96)
(95)
(94)
(95)
(77)
(83) f
Ur d
10
10
11
11
12
13
13
13
75
rt
Ad o
Glu
Glu
75
75
75
75
50
rt
Rh a m (90)
Rib
Rib
Rib
(73)
(75)
(trace)d,e
a
Deprotection reactions were effected with 500 mg of starting
material, and 500 mg of K 10 clay/mmol of substrate in 20 mL of
b
solvent. Urd ) uridine, Ado ) adenosine, dUrd ) 2′-deoxyuri-
dine, Glu ) D-glucose, Rham ) L-rhamnose, Rib ) d-ribose.
d
c Isolated yields of homogeneous products. Starting material was
mainly unchanged (TLC). e Estimated by TLC. f 1 g of K 10 clay/
mmol of substrate.
substrate in MeOH/H2O (1:1) at 75 °C. Urd and Ado were
obtained in excellent yields (95%) even at ambient
temperature (entries 13-16). As expected, clay-catalyzed
hydrolysis of dimethoxytrityl ethers proceeded more
readily than cleavage of silyl ethers and isopropylidene
groups.
D-Ribose. The residue was purified by dry-packed column
chromatography [60 g, 2.2 × 30 cm; EtOAc/i-PrOH/H2O (4:1:2,
upper phase)] to give homogeneous product. An analytical
sample was prepared by treatment of this product with charcoal
(EtOH/∆) and crystallization [EtOH/Et2O (diffusion)] to give
D-ribose (fine plates): mp 77-80 °C; [R]21D -19.7° (c, 0.96; H2O);
FAB-HRMS m/ z 149.0452 ([M- - H] C5H9O5 ) 149.0450).
1H NMR spectra and physical data on these known com-
pounds were identical with those measured with commercial
samples. Elemental analyses agreed with calculated values.
Treatment of 1,2:5,6-di-O-isopropylidene-R-D-gluco-
furanose (11) or the monoprotected 2,3-O-isopropylidene-
â-L-rhamnofuranose (12) and 2,3-O-isopropylidene-D-
ribofuranose (13) derivatives with 500 mg of K 10 clay/
mmol of substrate in MeOH/H2O (1:1) at 75 °C afforded
the deprotected sugars in good yields (73-90%, entries
17, 19, 20). A larger ratio of K 10 clay (1 g/mmol)
increased the yield slightly with 11 (83%, entry 18), and
treatment of 13 for 5 h at 75 °C gave cleaner deprotection
to D-ribose.9
In summary, treatment of isopropylidene-, silyl-, and
4,4′-dimethoxytrityl-protected nucleosides with K 10 clay
in 50% aqueous methanol effected efficient hydrolysis to
give the parent nucleosides. Analogous treatment of
isopropylidene-monosaccharides gave the deprotected
sugars in good to excellent yields under mild reaction
conditions with straightforward workup. Investigation
of other acid-catalyzed organic reactions with K 10 clay
as a mild and convenient alternative catalyst are in
progress.
Ack n ow led gm en t. We thank the Analytical Center
of Dainippon Pharmaceutical Co., Ltd. for elemental
analyses, Dr. N. Okuda of the Research Department of
Osaka Organic Chemical Ind., Ltd. for measurement of
specific rotations, and Dr. M. Morita of the Mass
Spectroscopy Laboratory, Kinki University, for mea-
surement of mass spectra. This work was supported
by the Environmental Science Program, Environmental
Institute of Kinki University, and by a Grant-in-Aid for
Science Research from the J apan Private School Promo-
tion Foundation.
J O961376R
Exp er im en ta l Section
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Gen er a l Meth od s. Uncorrected melting points (and mixed
melting points with authentic samples) were determined on a
hot-stage apparatus. 1H NMR spectra were recorded with a
J EOL J NM GX-400 spectrometer at 400 MHz (solutions in TMS/
DMSO-d6 or TSP/D2O). FAB-HRMS were determined with a
J EOL HX-100 spectrometer in the negative ion mode. UV
spectra were obtained with a Hitachi U-3000 spectrophotometer
(solutions in MeOH). Specific rotations were determined with
(9) In the case of 13, elevated reaction temperatures and/or longer
reaction times resulted in increased formation of byproducts (TLC).
(16) Robins, M. J .; Mengel, R.; J ones, R. A.; Fouron, Y. J . Am. Chem.
Soc. 1976, 98, 8204.