Regioselective oxidative cleavage of benzylidene acetals of glycopyranosides with periodic acid catalyzed by tetrabutylammonium bromide

Article abstract of DOI:10.1055/s-0033-1340056

A combination of periodic acid, tetrabutylammonium bromide, and wet alumina in dichloromethane efficiently oxidized benzylidene acetals of carbohydrates to the corresponding hydroxybenzoates in excellent yields (>90%). Under these conditions, other protec

Full text of DOI:10.1055/s-0033-1340056

LETTER
▌115
lRetteergioselective Oxidative Cleavage of Benzylidene Acetals of Glycopyranosides
with Periodic Acid Catalyzed by Tetrabutylammonium Bromide
Regioselective Cleavage of Glucopyranoside Benzylidene Acetals
Jean-Michel Vatèle*
Université Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR 5246 CNRS, Equipe SURCOOF,
bât. Raulin, 43, Bd. du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
E-mail: vatele@univ-lyon1.fr
Received: 03.09.2013; Accepted after revision: 01.10.2013
Dedicated to the memory of Professor André Lubineau
Here, we describe a new procedure for high-yielding regi-
Abstract: A combination of periodic acid, tetrabutylammonium
oselective cleavage of benzylidene-protected glycosides
bromide, and wet alumina in dichloromethane efficiently oxidized
to give the corresponding hydroxybenzoates by using a
periodic acid, tetrabutylammonium bromide and wet alu-
benzylidene acetals of carbohydrates to the corresponding hydroxy-
benzoates in excellent yields (>90%). Under these conditions, other
protecting groups, such as tert-butyl(dimethyl)silyl, tert-butyl(di- mina system.
phenyl)silyl, and functional groups, such as epoxide, were unaffect-
In continuation in our interest in the development of novel
ed. By varying the nature of the protecting group at the C3 position,
good to high regioselectivity toward 4- or 6-benzoates was ob-
tained.
synthetic applications of systems consisting of (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) and co-oxi-
dants,13 and encouraged by reports on oxidative deprotec-
tion of O-benzyl ethers by TEMPO and sodium
hypochlorite14 or its oxoammonium salts,15 we examined
the oxidative cleavage of the 4,6-O-benzylidene deriva-
tive 1 with TEMPO and various co-oxidants. However,
regardless of the conditions that we used, such as
TEMPO, iodosylbenzene and Lewis acid13b,c,f or TEMPO,
copper(II) bromide and dioxygen,13d either no reaction oc-
curred or partial hydrolysis of the benzylidene group was
observed.
Key words: acetals, carbohydrates, oxidation, cleavage, regio-
selectivity, protecting groups
It is well known that carbohydrates play important roles,
not only as partial structures of various biologically active
compounds, but also as inexpensive starting materials for
total syntheses of natural products.1 Regioselective pro-
tection of individual hydroxy groups of carbohydrates is
an essential step in the synthesis of oligosaccharides.2
Discrimination among the various secondary hydroxy
groups of a carbohydrate is often a difficult task. The re-
gioselective cleavage of benzylidene acetals is an appeal-
ing approach to attaining this goal. These acetals are
widely used as protecting groups for 1,2- and 1,3-diols in
organic synthesis because of their ease of preparation and
their tolerance to a wide variety of reagents and reaction
conditions. Although many methods are available for the
reductive opening of benzylidene acetals to give O-benzyl
ethers,3 this is not the case with regard to their oxidative
cleavage to form hydroxybenzoates. Benzylidene acetals
can be oxidatively cleaved by using trityl tetrafluoro-
borate,4 ozone,5 palladium(II) acetate or copper(II)
chloride/tert-butyl hydroperoxide,6 N-bromosuccinimide
and water,7 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
and water,8 bipyridinium chlorochromate and 4-chloro-
peroxybenzoic acid,9 sodium or potassium bromate and
sodium dithionite,10 cobalt(II) acetate, N-hydroxysuccin-
imide, and dioxygen,11 or dimethyldioxirane.12a,b These
methods are not frequently used because they require
harsh conditions, long reaction times, or ecologically un-
friendly reagents, and because most of them give only
moderate to low regioselectivities.
With the aim of overcoming the drawbacks of existing
methods, we screened a number of oxidizing systems that
might promote the transformation of compound 1 into the
corresponding hydroxybenzoates 1a,b, and our most sig-
nificant results are listed in Table 1.
Hypervalent iodine reagents in conjunction with bromide
salts have been used for the oxidative cleavage of simple
acetals.16 1,2-Dihydroxy-1,2-dihydro-3H-1λ3-benziodol-
3-one 1-oxide (IBX) or diacetyl(phenyl)-λ3-iodane
[PhI(OAc)2] in the presence of tetrabutylammonium bro-
mide in aqueous acetonitrile at 65 °C gave the desired 4-
and 6-O-benzoates in acceptable yields, but with long re-
action times and modest degrees of regioselectivity (Table
1, entries 1 and 2). Marcotullio and co-workers have re-
ported an oxidative cleavage of acetals with Oxone sup-
ported on wet alumina.17 Under their conditions, we found
almost no reaction occurred, and a mixture of benzoates
was obtained in low yield (entry 3). Conversely, in the
presence of 0.5 equivalents of tetrabutylammonium bro-
mide, supported Oxone gave a roughly 1:1 mixture of
regioisomers in good yield (entries 4 and 5). Interestingly,
the use of 1,2-dichloroethane as the solvent instead of
acetonitrile reversed the regioselectivity to give the 6-O-
benzoate 1a as the main product in 60% yield (entry 6).
Replacing Oxone with periodic acid18 and performing the
reaction in dichloromethane allowed the cleavage to pro-
ceed efficiently (90 min, r.t.) to give a mixture of diastereo-
SYNLETT 2014, 25, 0115–0119
Advanced online publication: 08.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340056; Art ID: ST-2013-D0847-L
© Georg Thieme Verlag Stuttgart · New York

116
J.-M. Vatèle
LETTER
Table 1 Optimization of Conditions for the Oxidative Cleavage of Acetal 1
OBz
O
OH
O
oxidant
solvent
Ph
O
O
BzO
AcO
HO
O
AcO
AcO
AcO
AcO
AcO
OMe
OMe
OMe
1
1a
1b
Entry
Oxidant (equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
6-O-Bz/4-O-Bz
1
2
3
4
5
6
7
8
IBXb,c (2)
MeCN–H2O (1:1)
MeCN–H2O (1:1)
CH2Cl2
65
65
r.t.
r.t.
50
50
r.t.
r.t.
14
24
24
8
77
74
10e
84
83
85
96
67f
63:37
65:35
-
PhI(OAc)2c (2)
Oxoned (3)
Oxonec,d (3)
Oxonec,d (3)
Oxonec,d (3)
H5IO6c,d (3)
H5IO6c,d (3)
MeCN
46:54
45:55
71:29
64:36
26:74
MeCN
1
DCE
3
CH2Cl2
1.5
1
MeCN
a Isolated yield.
b IBX = 1,2-dihydroxy-1,2-dihydro-3H-1λ3-benziodol-3-one 1-oxide.
c In the presence of TBAB (0.5 equiv).
d In the presence of wet Al2O3 (2.2 g/mmol of substrate).
e Starting material was recovered (74%).
f Partial hydrolysis of the 4,6-O-benzylidene group was observed.
mers in excellent yield (96%), but with a moderate idative cleavage of 4,6-benzylidene acetals (entries 11–
regioselectivity (64:36) in favor of the 6-O-benzoate 1a. In 13). As seen in the manno and galacto series, the regiose-
acetonitrile, the reverse regioselectivity in favor of the 4- lectivity was not affected by the configuration at C4 or C2
O-benzoate 1b was observed, showing that, as in the case (entries 14–16). Oxidative cleavage of the exo- and endo-
of Oxone as oxidant, the solvent has a significant effect on dibenzylidene mannopyranoside 17 (entries 17 and 18)
the regioselectivity of the cleavage of the 4,6-O-benzyli- gave two products, both having a 2-O-benzoate group, in-
dene moiety of 1 (entry 8).
dicating that cleavage of the 2,3-O-benzylidene group of
17 led to the formation of the axially oriented benzoate
group, in agreement with the regioselectivity observed
with the potassium bromate/sodium dithionite system.10b
Cleavage of the acid-sensitive 4,6-(4-methoxybenzyli-
dene) acetal 18 gave an equal mixture of the two regioiso-
mers in 75% yield, along with 20% of methyl 2,3-di-O-
acetyl-α-D-glucopyranoside (entry 19). Oxidation of com-
pound 19, bearing an epoxy function, gave a 1:1 mixture
of regioisomers in high yield, although periodic acid is
known to cleave epoxides to form carbonyl derivatives
(entry 20).21 In the presence of the periodic acid/bromide
system, compound 20, bearing two benzyl groups, under-
went concomitant oxidative cleavage of the benzyl and
benzylidene groups to give several products, as observed
by TLC.22 By using Oxone and tetrabutylammonium bro-
mide in aqueous acetonitrile, the two deprotected regio-
isomers 20a and 20b could be obtained in 68% yield
(entry 22).
We next examined the scope of the oxidative cleavage of
various benzylidene acetals and the effects of the nature of
protecting groups on the regioselectivity of the reaction of
various monosaccharides with periodic acid/tetrabutyl-
ammonium bromide/wet alumina in dichloromethane.19,20
As can be seen in Table 2, the yield of the oxidative cleav-
age was in excess of 90% with most substrates. We first
studied the effect of the nature of the protecting groups at
C-2 and C-3 on the regioselectivity of the reaction of
methyl 4,6-O-benzylidene-α-D-glucopyranoside deriva-
tives. Among the esters screened (entries 1–3), the dichlo-
roacetyl group gave the best regioselectivity in favor of
the 6-O-benzoate 3b (entry 3), in a similar manner to the
corresponding reaction with dimethyldioxirane.12a Bulky
electron-donating groups in the 3-position, such as tert-
butyl(dimethyl)silyl, tert-butyl(diphenyl)silyl, or tosyl,
induced a reversal of the selectivity, with a high prefer-
ence for the formation of the secondary benzoate (entries
6, 8, and 9), once again in agreement with the correspond- To elucidate the mechanism of our oxidative cleavage of
ing reaction with dimethyldioxirane.12a Protected methyl benzylidene acetals, we conducted some additional exper-
2-deoxy-2- phthalimido-β-D-glucopyranoside derivatives iments on compound 1. We found that oxidation of 1 was
gave similar regioselectivities to those obtained in the α- inhibited by galvinoxyl free radical or TEMPO (0.1
glucopyranoside series, confirming the predominant role equiv), or by performing the reaction in darkness. To trap
of the substituent at O-3 on the regioselectivity of the ox- a putative hemi-orthoester or oxonium ion, we carried out
Synlett 2014, 25, 115–119
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Cleavage of Glucopyranoside Benzylidene Acetals
117
the reaction in the presence of a large excess of methanol homolytic cleavage under visible light to generate a bro-
and, in addition to 1a,b (40% yield), we obtained the or- mine radical. Benzylic hydrogen abstraction gives radical
thoester 21 in 24% yield (Scheme 1). The structure and A which is trapped by the bromine radical to give the bro-
configuration of 21 were assigned by means of NMR ex- mo acetal intermediate B.24 Disproportionation B to ben-
periments (COSY, HSQC, and NOE). Under our reaction zoxonium ion C and bromide ion, followed by attack by
conditions, pure hydroxybenzoate 1b was not converted water, gives hemi-orthoester D, which collapses to pro-
to any extent into its regioisomer 1a by equilibration. On vide the 4- and 6-O-benzoates. In the presence of metha-
the basis of these results, we propose a plausible mecha- nol, the oxocarbenium ion C gives the isolable orthoester
nism for the cleavage of benzylidene acetals with periodic E, which is hydrolyzed to form hydroxybenzoates. The
acid and tetrabutylammonium bromide, which is shown in role of alumina is probably in buffering the acidity of the
Scheme 1. Oxidation of bromide ion by periodic acid periodic acid, thereby preventing hydrolysis of the ben-
gives molecular bromine,23 as evidenced by the orange zylidene acetal, and in mediating the reaction by disper-
color of the suspension. The bromine molecule undergoes sion of the oxidant on its surface.25
Table 2 Oxidative Cleavage of Benzylidene Acetals of Carbohydrate Derivatives with the Periodic Acid/Tetrabutylammonium Bromide/Wet
Alumina System
Entry
Substrate
Product (ratio)a
Yieldb (%)
OBz
OH
O
Ph
O
O
O
O
R1O
HO
BzO
R1O
R1O
R2O
R2O
OMe
R2O
OMe
OMe
1
2
1: R1 = R2 = Ac
2: R1 = R2 = Bz
1a (62)
2a (40)
3a (81)
4a (45)
5a (36)
6a (5)
1b (38)
2b (60)
3b (19)
4b (55)
5b (64)
6b (95)
7b (77)
8b (94)
9b (95)
10b (64)
96
99
92
98
96
97
96
97
98
95
3
3: R1 = R2 = COCHCl2
4: R1 = Ac; R2 = H
5: R1 = Ac; R2 = TBS
6: R1 = TBDPS; R2 = Ac
7: R1 = R2 = Ms
8: R1 = R2 = Ts
4
5
6
7
7a (23)
8a (6)
8
9
9: R1 = R2 = TBS
10: R1 = R2 = Me
O
9a (5)
10
10a (36)
OH
O
OBz
O
Ph
O
O
OMe
HO
RO
BzO
RO
OMe
RO
OMe
NPhth
NPhth
NPhth
11
12
13
11: R = Ac
11a (69)
12a (79)
11b (31)
12b (21)
90
96
98
12: R = COCHCl2
13: R = TBS
13a (3)
13b (97)
Ph
OH
OBz
OBz
OH
O
O
O
O
RO
RO
RO
RO
O
OMe
OMe
RO
RO
OMe
14
15
14: R = Ac
15:R = TBS
14a (37)
15a (4)
14b (63)
15b (96)
92
95
OH
OAc
OBz
OAc
OAc
O
Ph
O
O
O
O
AcO
BzO
AcO
HO
AcO
OMe
OMe
OMe
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 115–119

118
J.-M. Vatèle
LETTER
Table 2 Oxidative Cleavage of Benzylidene Acetals of Carbohydrate Derivatives with the Periodic Acid/Tetrabutylammonium Bromide/Wet
Alumina System (continued)
Entry
16
Substrate
Product (ratio)a
Yieldb (%)
95
16
16a (36)
16b (64)
Ph
OBz
O
OBz
BzO
HO
O
BzO
HO
O
O
HO
HO
Ph
O
O
OMe
OMe
O
OMe
17
17
18
exo
17a (39)
17b (61)
91
88
endo
17a (45)
17b (55)
O
MBzO
HO
p-MeOC6H4O
O
O
O
O
HO
MBzO
AcO
AcO
AcO
AcO
AcO
AcO
OMe
OMe
OMe
19
20
18
18a (52)
18b (48)
75c
94
O
O
O
O
HO
BzO
BzO
HO
Ph
O
OMe
OMe
OMe
O
O
O
19
19a (52)
19b (48)
O
BzO
HO
Ph
O
O
O
O
HO
BzO
HO
HO
BnO
HO
HO
OMe
OMe
BnO
OMe
d
21
22
20
–
–
–
20a (30)
20b (70)
68e
a The ratio of the two regioisomers was determined by 1H NMR spectroscopy of the pure mixture.
b Isolated yield.
c The product of p-anisylidene hydrolysis was isolated (20%).
d An intractable mixture of products was formed.
e Reaction conditions: substrate (1 mmol), Oxone (3 g, 5 equiv), TBAB (0.32 g, 0.5 equiv), wet alumina (3.8 g), MeCN (10 mL), r.t., 10 h.
2H+ + IO4– + 2Br–
In summary, we have shown that the periodic acid/tetra-
butylammonium bromide/wet alumina system is an effi-
cient reagent system for regioselective oxidative cleavage
of a variety of benzylidene acetals of carbohydrates, and
that the reaction is controlled by the nature of the protect-
ing group at the C3 position. Because the reaction in-
volves mild conditions, requires cheap reagents, is
chemoselective, has short reaction times, and involves
simple workup, this protocol represents a valuable alter-
native to existing methods. Studies of other uses of this
new supported oxidizing system are currently under way.
Br2 + IO3– + H2O
visible light
•
Br2
2Br
•
•
O
O
Br
Ph
Ph
O
X
O
X
O
O
OMe
OMe
RO
RO
A
.
•
Br
Br
O
O
– Br–
Ph
Ph
O
X
Ph
Ph
O
X
O
OMe
OMe
O
OMe
OMe
RO
RO
C
B
H2O
OH
OMe
O
Acknowledgment
O
O
X
O
X
O
We thank Dr. Dominique Lafont for a gift of 1,3,4,6-tetra-O-acetyl-
2-deoxy-2-phthalimido-β-D-glucopyranose.
O
RO
RO
D
E
21 R = Ac, X = OAc
α-OMe
Supporting Information for this article is available online at
BzO
HO
RO
HO
BzO
RO
O
X
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
O
X
OMe
OMe
+
Scheme 1 Proposed mechanism for oxidative cleavage of benzyl-
idene acetals mediated by periodic acid, tetrabutylammonium bro-
mide, and wet alumina
Synlett 2014, 25, 115–119
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Cleavage of Glucopyranoside Benzylidene Acetals
119
(16) (a) Kuhakarn, C.; Panchan, W.; Chiampanichayakul, S.;
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(20) Oxidative Cleavage of Benzylidene Acetals; General
Procedure
Wet alumina was prepared by mixing neutral alumina (50 g,
Fluka ref. 06300; Brockmann activity 1) with H2O (10 g) and
shaking until a free-flowing homogeneous powder was
obtained. The wet Al2O3 (2.2 g), TBAB (0.16 g, 0.5 equiv),
and H5IO6 (0.68 g, 3 equiv) were added successively to a
solution of the benzylidene acetal (1 mmol) in CH2Cl2 (10
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