Cesium trifluoroacetate or silver oxide mediated acyl migration for the construction of disaccharide building blocks

Article abstract of DOI:10.1055/s-2006-933105

A convenient method for the selective differentiation of the 2-OH and 3-OH of pyranosides, based on the CsO₂CCF₃- or Ag ₂O-mediated acyl migration, has been established. The 2-OH and 3-OH can be sequentially glycosylated b

Full text of DOI:10.1055/s-2006-933105

756
LETTER
Cesium Trifluoroacetate or Silver Oxide Mediated Acyl Migration for the
Construction of Disaccharide Building Blocks
C
onstructiono
h
f
Disacchari
e
de
B
uilding
n
Blocks glou Deng, Cheng-Wei Tom Chang*
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
Fax +1(435)7973390; E-mail: chang@cc.usu.edu
Received 28 November 2005
Among these multistep processes, differentiation of the
Abstract: A convenient method for the selective differentiation of
the 2-OH and 3-OH of pyranosides, based on the CsO2CCF3- or
Ag2O-mediated acyl migration, has been established. The 2-OH and
3-OH can be sequentially glycosylated by the desired carbohydrate
equatorial O-2/O-3 trans-diol is one of the most challeng-
ing tasks in carbohydrate protecting group manipulation.
The presence of vicinal axial heteroatoms, such as O and
generating disaccharides of biological interest. A mechanism in- S, will enhance the nucleophilicity of the corresponding
volving either acid- or base-assisted acyl migration is proposed.
vicinal equatorial OH. For instance, the 3-OH in b-D-ga-
lacto configurations will be more nucleophilic than the 2-
OH. Such an enhanced nucleophilicity has led to the de-
velopment of many methods for the differentiation of 2-
OH and 3-OH, like metal-mediated protection,5 direct
acylation,6 reductive cleavage,7 and enzyme catalysis8
(Scheme 1). On the other hand the regioselective expo-
sure of 3-OH is rather indirect often involving sequential
protection and deprotection. To alleviate such an inconve-
nience and to facilitate oligosaccharide synthesis, we wish
to report a facile acyl migration that will allow regioselec-
tive exposure of the desired hydroxyl groups in a trans-
diol configuration and the application of such acyl migra-
tion to the synthesis of disaccharides.
Key words: ABO blood group antigens, silver oxide, cesium tri-
fluoroacetate, acyl migration, migration mechanisms
Carbohydrates are widely recognized for their remarkable
biological relevance. Thus, the synthesis of oligosaccha-
rides has long been a goal pursued by many researchers.1
For example, the minimal determinant oligosaccharides
of the ABO blood group antigens play essential roles in
blood transfusion, cell differentiation, and cell recogni-
tion, and are, therefore, the focus of great interest
(Figure 1).2 Research in these areas requires access to
these oligosaccharides, which has been accomplished via
chemical synthesis3 or biosynthesis.4 For the approach us-
ing chemical synthesis, regioselective protection and gly-
cosylation of both O-2 and O-3 hydroxy groups of the
core galactopyranose are the crucial steps that often re-
quire tedious protection and deprotection processes. Un-
like the O-4 and O-6 hydroxy groups that can be readily
protected using benzylidene, a multistep process is often
needed for regioselective exposure of the desired O-2 or
O-3 hydroxy groups, and the following glycosylation to
take place. Hence, for the synthesis of oligosaccharides,
such as the oligosaccharides of the ABO blood group
antigen, it is preferable that such a multistep process can
be as concise as possible.
Ph
Ph
O
O
O
O
one step
O
O
2
SPh
SPh
HO
PO
1
3
HO
HO
Phenylthiogalactopyranoside
P = protecting group
One step
Ph
protection
Ph
O
O
O
O
deprotection
O
O
SPh
SPh
HO
PO
P'O
P'O
OH
OH
HO
O
P' = protecting group
O
O
R
O
O
oligosaccharide
Scheme 1 Strategy for the differentiation of O-2/O-3 on galacto-
pyranose
HO
NHAc
O
O
H3C
OH
A type, R = α-GalNAc
B type, R = α-Gal
O type, R = H
OH
OH
Recently, Ye and co-workers reported a method for the re-
gioselective protection of 2-OH or 3-OH where the selec-
tivity seems to be governed by differences in the pyranose
scaffold.9 However, no detailed explanation to predict the
regioselectivity was given. In the mean time, we discov-
ered that, in the presence of Lewis acids (or bases) and
catalyst, an acyl group can migrate from the 3-OH to the
2-OH of a galacto-configured disaccharide as shown in
the transformation from 15a to 25a (Table 1). To make such
Figure 1 Examples of carbohydrate blood group antigens.
SYNLETT 2006, No. 5, pp 0756–0760
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933105; Art ID: S11705ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Construction of Disaccharide Building Blocks
757
an acyl migration compatible with acid- or base-labile acyl migration under alkaline conditions (pyridine,
functional groups we have also examined various Lewis NaOMe or NaOH),12 however, pyridine is harmful and
acids and bases for their capability of initiating acyl mi- toxic which may cause environmental problems. More-
gration. We found Ag2O and CsO2CCF3 were the best over, a long reaction time is usually required for the acyl
Lewis base and acid for performing acyl migration migration to go to completion (seven days). Other alkalis,
(Table 1, entries 1 and 10). We have also discovered that such as NaOMe and NaOH, may be not suitable when the
the presence of tetrabutylammonium iodide (TBAI) as a substrates contain base-sensitive functionalities. In con-
catalyst is important. Without the catalyst (TBAI) the mi- trast, application of a Lewis base (Ag2O) and Lewis acid
gration occurs at a much slower rate (Table 1, entry 13), (CsO2CCF3) proved to be a good solution to circumvent
however, TBAI alone cannot trigger the acyl migration these problems. The convenience and simplicity of em-
(Table 1, entry 14). We reasoned that protection of the hy- ploying Ag2O- and CsO2CCF3-mediated acyl migration as
droxy group vicinal to an axial group, for example, the 3- well as the good yields of desired products render this
OH of benzylidene-protected phenylthiogalactoside, is ki- protocol more attractive and applicable.
netically controlled. Migration of the acyl group to the
Besides the benzoyl group, the migration protocol can
other hydroxy group (for example, the 2-OH of compound
also be applied to other acyl groups, such as 4-chloroben-
1) is thermodynamically controlled, and is governed by
zoyl, 4-methoxybenzoyl, decanoyl, and acetyl groups
(Table 2). Under the optimized conditions [Ag2O (1
equiv)/TBAI (0.1 equiv) or CsO2CCF3 (1 equiv)/TBAI
the steric hindrance of the axial group (for example, the 4-
OR of compound 2).
Acyl migration is a common phenomenon that has been (0.1 equiv)], the (substituted and unsubstituted) benzoyl
observed in carbohydrate chemistry.10 For example, group seems to be more susceptible to migration than the
Bourne11 reported that alkaline hydrolysis (aq NaOH) of acetyl counterpart under similar conditions. It should be
2-O-benzoyl-a-D-glucoside could give the 3-O-benzoated noted that temperatures higher than those indicated in
isomer. Similarly, 3-O-benzoyl-b-D-galactoside could be Table 2 led to complicated results, for example, the 2,3-
converted into the 2-O-benzoated isomeric product by diacyl and 2,3-diol products could be generated; longer
Table 1 Conditions Examined for Optimizing Acyl Migration
Ph
Ph
O
O
conditions
DMF, r.t.
O
O
O
O
SPh
SPh
HO
BzO
BzO
HO
1
2
Entry
1
Reagent (equiv)
Ag2O (1)
Ag2CO3 (1)
AgOTf (1)
ZnI2 (1)
Catalyst (equiv)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
TBAI (0.1)
–
Time (h)
48
Products
Yields (%)
2
95
40
–
2
8
2
3
48
N.R.a
4
48
2
30
24
13
–
5
Cu(OAc)2 (1)
ZnCl2 (1)
FeCl3 (1)
72
2
6
72
2
7
72
N.R.
N.R.
2
8
FeCl2 (1)
72
–
9
BaO (1)
72
50
67
33
–
10
11
12
13
14
CsO2CCF3 (1)
CuCl (1)
72
2
72
2
Cu(OTf)2 (1)
Ag2O (1)
–
72
N.R
2
72
30
N.R.
TBAI (1)
72
2
a No reaction.
Synlett 2006, No. 5, 756–760 © Thieme Stuttgart · New York

758
S. Deng, C.-W. T. Chang
LETTER
Table 2 Migration of Different Acyl Groupsa
both tosyl and acyl groups favor the formation of kinetic
products then the acyl groups migrate to the thermo-
dynamically more favored hydroxy group.
Ph
Ph
O
O
O
O
Interestingly, moderate to excellent selectivity for the acyl
migration was obtained even when pyranoses containing
multiple hydroxy groups were employed (Scheme 2). For
example, the 3-O-pivaloyl group compound 7 migrates
predominately to the 2-OH, suggesting that 4-OH is steri-
cally more hindered. The 2-O-pivaloyl group of com-
pound 8 migrates to the 3-OH, affording the more stable
regioisomer. We attempted to optimize the reaction con-
ditions, however, in both cases, heating the reaction to
higher temperatures generated complicated results.
O
O
SPh
SPh
4a–d
RO
HO
HO
RO
3a–d
Compd
R
Method
Temp
Time (h) Yield (%)
3a
4-ClBz
A
B
75 °C
75 °C
7
8
80
83
3b
3c
3d
4-MeOBz
C9H19CO
Ac
A
B
40 °C
50 °C
10
12
77
79
A
B
60 °C
50 °C
7
12
76
76
Ag2O, TBAI, DMF
60 °C, 12 h, 58%
HO
PivO
PivO
PivO
O
O
HO
HO
HO
PivO
or
A
B
r.t.
45 °C
48
24
68
71
CsO2CCF3, TBAI, DMF
8
7
SPh
SPh
55 °C, 10 h, 67%
a Method A: Ag2O, TBAI, DMF; Method B: CsO2CCF3, TBAI,
DMF.
PivO
HO
Ag2O, TBAI, DMF
r.t., 48 h, 49%
PivO
O
O
HO
HO
PivO
reaction times caused the same problem. Therefore, the
reaction was monitored by TLC and quenched immediate-
ly when a side-product appeared. Typically, the regioiso-
mers formed were more polar than the starting materials
so they could be easily separated by column chromato-
graphy.
HO
PivO
10
OMe
9
OMe
Scheme 2 Migration of acyl groups on pyranoses with diols
In the absence of steric preference as in compound 11, a
mixture of starting material and migrated compound 12
(1:1 ratio) was obtained when Ag2O/TBAI was used to ef-
fect migration at room temperature (30 hours), although it
was found that 2-OH is more reactive toward benzoyla-
tion (Scheme 3).9
Differentiation of the O-2 or O-3 hydroxy groups on
benzylidene-protected a-D-glucoside can be achieved in a
similar fashion (Table 3). For the a-D-glucoside scaffold
the 2-OH is kinetically favored, while the 3-OH is thermo-
dynamically more stable. The tosyl group failed to under-
go migration (5e), which may, in part, explain the results
observed by Ye; the tosyl and acyl groups appear to have
the opposite regioselectivity. We propose that, initially,
It was suggested that the acyl migration might proceed
through an intermediate cyclic orthoester.11 The forma-
tion of such a transitory intermediate would initiated by
Table 3 Migration of Acyl Groups on Benzylidene-Protected a-D-Glucoside
O
O
O
Ph
O
Ph
O
O
HO
RO
RO
HO
R'
R'
5a–d
6a–d
Compd
R
R¢
Methoda
Temp
Time (h)
Yield (%)
5a
Bz
OMe
A
B
75 °C
50 °C
7
17
74
78
5b
Ac
OMe
A
B
r.t.
r.t.
48
24
60
67
5c
Bz
Ac
SPh
SPh
A
r.t.
48
70
5d
A
B
50 °C
50 °C
24
12
71
72
5e
Ts
OMe
A
B
60 °C
60 °C
48
48
–
–
a Method A: Ag2O, TBAI, DMF; Method B: CsO2CCF3, TBAI, DMF.
Synlett 2006, No. 5, 756–760 © Thieme Stuttgart · New York

LETTER
Construction of Disaccharide Building Blocks
759
Ag2O
TBAI
necessary. For example, hydrolysis of the benzoyl group
of compound 16 yields 17. Further glycosylation of the
2-OH with a glycosyl donor like 1814 will lead to the
synthesis of a B-type antigen.
O
O
O
O
Ph
Ph
O
O
SPh
SPh
BzO
HO
DMF
r.t.
HO
BzO
11
12
Scheme 3 Acyl migration on glucopyranose
Ph
O
O
SPh
OBn
O
H3C
nucleophilic addition of the hydroxyl group at C-2 to the
vicinal carbonyl functionality. Then ring scission would
give the more stable acyl group at C-2. Based on this
mechanism, we proposed a possible involvement of
iodide (from TBAI) to explain our acyl migration
(Scheme 4). In the proposed mechanism, the iodide
functions as a catalyst and facilitates the orthoester ring
scission, which leads to the migrated product.
O
O
SPh
OBn
BzO
15
OBn
1
a
67%
O
H3C
OBn
16
OBn
OBn
α/β = 10/1
Ph
O
O
O
O
SPh
Ph
Ph
b
HO
O
O
O
O
75%
O
O
O
O
O
H3C
SPh
SPh
B
OBn
17
O
O
R
OBn
OBn
R
H
A
H
O
B
O
Ph
A
BnO
BnO
OBn
O
Ph
H
Ph
O
O
SPh
O
O
O
B
OBn
O
O
O
O
OBn
B
SPh
18
O
O
O
O
BnO
O
SPh
2
SPh
R
BnO
O
BzO
HO
a
65%
R
BnO
19
α/β = 6/1
O
I
Ph
A
A
I
O
O
Scheme 4 Proposed mechanism of acyl migration
OBn
O
O
b
SPh
BnO
O
BnO
After the successful acyl migration in pyranosides, we
proceeded to investigate the compatibility of other sub-
strate such as sphingosine derivative 1313 under similar
conditions (Scheme 5). The desired product 14 was ob-
tained in good yields (77% and 74%, respectively) under
both conditions; any unreacted starting material was re-
covered.
91%
HO
BnO
20
Scheme 6 Reagents and conditions: (a) PhSCl, AgOTf, 2,6-di-tert-
butyl-4-methylpyridine (DTBMP), molecular sieves (AW300),
CH2Cl2, –78 °C; (b) LiOH, H2O, THF, r.t.
Glycosylation using rhamnose and other carbohydrate
moieties has also been successfully attempted (Schemes 7
and 8). Even though both donors (15, 18, and 21) and
acceptors (1 and 2) in one-pot glycosylation reactions are
thioglycosides, the chemoselective glycosylation was
achieved successfully in the presence of PhSCl/AgOTf as
promoter, affording good yields of disaccharides as an
a/b-anomeric mixture. Pure a-anomers were obtained
by recrystallization from diethyl ether–hexane (1:3). No-
tably, such disaccharide products contain an anomeric
phenylthio group that can serve as a glycosyl donor, thus
broadening the application of this procedure.
N3
N3
(a) or (b)
BzO
C13H27
HO
C13H27
OH
14
OBz
13
Scheme 5 3,1-Acyl migration on sphingosine. Reagents and condi-
tions: (a) Ag2O (1 equiv), TBAI (0.1 equiv), DMF, r.t., 20 h, yield:
77%; (b) CsO2CCF3 (1 equiv), TBAI (1 equiv), DMF, 50 °C, 6 h,
yield: 74%.
Having achieved the regioselective acyl migration, we
began to explore its application in the synthesis of several
biologically important disaccharides, for example, the
minimal determinant oligosaccharides of the ABO blood
group antigen. As shown in Scheme 6, the 2-OH and 3-
OH can be glycosylated leading to the synthesis of various
disaccharides. Compound 16, precursor of an O-type
antigen, can be prepared by the glycosylation of 1 with
15.14 One of the advantages of using the acyl group is that
it can be easily removed allowing further glycosylation if
In conclusion, we have developed two general and com-
parable protocols for the differentiation of 2,3-trans-diol
in various pyranoses, which will allow further modifica-
tions such as glycosylation of desired carbohydrates.15,16
To demonstrate the building block synthesis, several di-
saccharides were prepared. Another advantage of our acyl
migration protocol is the use of acyl groups that can be re-
moved conveniently, thus allowing further modifications
if desired. In addition, our protocols can be applied to the
Synlett 2006, No. 5, 756–760 © Thieme Stuttgart · New York

760
S. Deng, C.-W. T. Chang
LETTER
Ph
SPh
Acknowledgment
O
O
H3C
BnO
O
We acknowledge Frontier Scientific Inc. for generous financial
support.
BnO
OBn
O
O
SPh
21
BzO
1
a
61%
References and Notes
H3C
BnO
O
α/β = 8/1
22
(1) (a) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem. Int. Ed.
2001, 40, 1576. (b) Koeller, K. M.; Wong, C.-H. Chem. Rev.
2000, 100, 4465. (c) Lindhorst, T. K. Essentials of
Carbohydrate Chemistry and Biochemistry; Wiley-VCH:
Weinheim, 2003.
BnO
OBn
Ph
O
O
O
O
SPh
b
(2) Feizi, T. Nature (London) 1985, 314, 53.
HO
86%
(3) (a) Lemieux, R. U.; Driguez, H. J. Am. Chem. Soc. 1975, 97,
4069. (b) Love, K. R.; Seeberger, P. H. J. Org. Chem. 2005,
70, 3168.
H3C
BnO
O
23
BnO
OBn
(4) Yi, W.; Shao, J.; Zhu, L.; Li, M.; Singh, M.; Lu, Y.; Lin, S.;
Li, H.; Ryu, K.; Shen, J.; Guo, H.; Yao, Q.; Bush, C. A.;
Wang, P. G. J. Am. Chem. Soc. 2005, 127, 2040.
(5) (a) Gangadharmath, U. B.; Demchenko, A. V. Synlett 2004,
2191. (b) David, S. In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker Inc.: New York, 1997,
69–83. (c) Gridley, J. J.; Osborn, H. M. I.; Suthers, W. G.
Tetrahedron Lett. 1999, 40, 6991. (d) Osborn, H. M. I.;
Brome, V. A.; Harwood, L. M.; Suthers, W. G. Carbohydr.
Res. 2001, 332, 157.
(6) (a) Garegg, P. J. Pure Appl. Chem. 1984, 56, 845. (b)Jiang,
L.; Chan, T.-H. J. Org. Chem. 1998, 63, 6035.
(7) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Fan, H.-F.; Pai, C.-L.;
Yang, W.-C.; Lu, L.-D.; Hung, S.-C. Angew. Chem. Int. Ed.
2002, 41, 2360.
SPh
H3C
BnO
O
O
O
O
Ph
BnO
O
OBn
BzO
21
OMe
24
6a
a
H3C
BnO
O
71%
α/β = 11/1
BnO
OBn
Scheme 7 Reagents and conditions: (a) PhSCl, AgOTf, DTBMP,
molecular sieves (AW300), CH2Cl2, –78 °C; (b) LiOH, H2O, THF,
r.t.
SPh
(8) Gridley, J. J.; Hacking, A. J.; Osborn, H. M. I.; Spackman,
D. G. Tetrahedron 1998, 54, 14925.
(9) Wang, H.; She, J.; Zhang, L.-H.; Ye, X.-S. J. Org. Chem.
2004, 69, 5774.
(10) Haines, A. H. Adv. Carbohydr. Chem. Biochem. 1976, 33,
11.
(11) Bourne, E. J.; Huggard, A. J.; Tatlow, J. C. J. Chem. Soc.
1953, 735.
O
H3C
BnO
O
BnO
21
O
Ph
OBn
O
O
5a
BzO
a
OMe
H3C
BnO
O
93%
BnO
OBn
25
α only
(12) Chittenden, G. J. F.; Buchanan, J. G. Carbohydr. Res. 1969,
11, 379.
O
SPh
OBn
H3C
BnO
O
O
Ph
O
OBn
15
BzO
(13) Qiu, D.; Schmidt, R. R. Liebigs Ann. Chem. 1992, 217.
(14) (a) Li, J.; Wang, J.; Czyryca, P. G.; Chang, H.; Osak, T. W.;
Evanson, R.; Chang, C.-W. T. Org. Lett. 2004, 6, 1381.
(b) Wang, J.; Li, J.; Chang, C.-W. T. unpublished results
(15) Acyl Migration Using Ag2O; General Procedure. A
solution of starting material (0.12 mmol) and TBAI (4.2 mg,
0.012 mmol), Ag2O (0.12 mmol) in anhyd DMF (5 mL) was
stirred at the indicated temperature. The reaction was
monitored by TLC. When the side product appeared, the
reaction mixture was subsequently filtered then
concentrated. The filtrate was subject to flash column
chromatography to yield the desired product. The unreacted
starting material was recovered.
O
OMe
OBn
6a
a
91%
O
H3C
OBn
BnO
26
α/β = 15/1
BnO
BnO
OBn
O
O
O
O
SPh
Ph
O
BzO
OBn
18
OMe
6a
OBn
a
O
91%
BnO
OBn
(16) Acyl Migration Using CsO2CCF3; General Procedure. A
mixture of starting material (0.20 mmol), CsO2CCF3 (0.20
mmol), and TBAI (8 mg, 0.02 mmol) in anhyd DMF (10
mL) was stirred at the indicated temperature. The reaction
was monitored by TLC. When the side product appeared, the
reaction mixture was filtered then concentrated. The filtrate
was subject to flash column chromatography to yield the
desired product. The unreacted starting material was
recovered.
BnO
α/β = 10/1
27
Scheme 8 Reagents and conditions: (a) PhSCl, AgOTf, DTBMP,
molecular sieves (AW300), CH2Cl2, –78 °C.
3,1-acyl migration of sphingosine. The mechanism for the
acyl migration has been elaborated, which may clarify the
role of TBAI and the effect of DMF. Furthermore, the
extension of acyl migration methodology to other poly-
hydroxyl substrates has also been undertaken.
Synlett 2006, No. 5, 756–760 © Thieme Stuttgart · New York