A practical fluorous benzylidene acetal protecting group for a quick synthesis of disaccharides

Article abstract of DOI:10.1016/j.tetlet.2007.04.106

A new fluorous benzylidene acetal protecting group was regioselectively introduced into carbohydrates, deprotected under acidic conditions, and reused. Oligosaccharides were synthesized via regioselective conversion of the fluorous acetal group to the ben

Full text of DOI:10.1016/j.tetlet.2007.04.106

Tetrahedron Letters 48 (2007) 4431–4436
A practical fluorous benzylidene acetal protecting group
for a quick synthesis of disaccharides
Masaru Kojima, Yutaka Nakamura and Seiji Takeuchi*
Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan
Received 6 March 2007; revised 2 April 2007; accepted 13 April 2007
Available online 4 May 2007
Abstract—A new fluorous benzylidene acetal protecting group was regioselectively introduced into carbohydrates, deprotected
under acidic conditions, and reused. Oligosaccharides were synthesized via regioselective conversion of the fluorous acetal group
to the benzyl group by traditional reaction conditions. The fluorous compounds were easily separated from non-fluorous by-prod-
ucts by fluorous solid phase extraction.
Ó 2007 Elsevier Ltd. All rights reserved.
Fluorous protecting groups have become increasingly
popular in organic synthesis because they not only fulfill
all the requirements for traditional protecting groups1
but they are also readily separated from non-fluorous
by-products by solid phase extraction with a fluorous
reverse-phase silica gel column (Fluorous solid phase
extraction; FSPE).2 In order to apply the technologies
to total, parallel and combinatorial syntheses of com-
plex molecules, various fluorous protecting groups for
alcohols,3 amines,4 carboxylic acids5 and aldehydes or
ketones6 have been synthesized so far, and some of them
are commercially available. Utilizing these protecting
groups, many researchers have accomplished quick
and efficient synthesis of natural products including
oligosaccharides, oligonucleotides, peptides7 and chemo-
enzymatic synthesis of sialidase inhibitor.8 Recently, we
have also reported a synthesis and utilization of fluorous
dimethylthiocarbamate (FDMTC) groups as a new
fluorous protecting group for alcohols.9 The FDMTC
groups were easily introduced into simple alcohols and
carbohydrates, and selectively removed with m-CPBA.
benzyl group by ring opening oxidation11 or reduc-
tion,12 respectively. Especially regioselective reduction
of 4,6-O-benzylidene acetal group of hexopyranosides
is useful for syntheses of biologically potent oligosaccha-
rides and glycoconjugates. Therefore, development of a
new fluorous acetal protecting group13 for 1,2 and 1,3-
diols is still a challenging target. We describe herein a
synthesis of fluorous benzaldehydes as a reagent for
4,6-O-protection of hexopyranosides and its application
to an oligosaccharide synthesis via the regioselective ring
opening reaction of the fluorous cyclic acetal groups.
Fluorous protecting reagents, 4-(3-perfluoroalkyl)
propyl benzaldehydes 4a–c, were prepared by the route
shown in Scheme 1. We chose the Wittig reaction for
introducing perfluoroalkyl chains onto aromatic rings,
because the reaction conditions are very mild and
suitable for large-scale synthesis. Fluorous phospho-
nium salts 1a–c (Fig. 1) were synthesized according to
Gladyz’s method14 from the corresponding CnF2n+1
-
CH2CH2I (n = 6,8,10). Salts 1a–c were reacted with
methyl 4-formylbenzoate in the presence of potassium
carbonate to give the corresponding alkenes 2a–c.
Compounds 2a–c were hydrogenated with 10% Pd–C
in EtOAc to give fluorous benzoates 3a–c. The benzo-
ates 3a–c were converted into fluorous benzaldehydes
4a–c in high yields with a pyrrolidine-modified alumi-
num hydride reagent according to Abe’s procedure.15
Regioselective protection of hydroxyl groups of poly-
hydroxy compounds plays a crucial role in syntheses
of natural products. The benzylidene acetal group is
often used for protection of 1,3-diol compounds,10
because it can also be transformed into the benzoyl or
Keywords: Benzylidene acetal group; Regioselective reduction;
Oligosacchrides; Fluorous solid phase extraction.
We next examined introduction of Fbenzylidene acetal
groups into 4,6-hydroxyl groups of hexopyranosides
using fluorous benzaldehydes 4a–c (Table 1).
*
Corresponding author. Tel.: +81 250 25 5165; fax: +81 250 25
5021; e-mail: takeuchi@nupals.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.106

4432
M. Kojima et al. / Tetrahedron Letters 48 (2007) 4431–4436
Fluorous phosphonium salts
1a-c (1.0 equiv)
COOMe
K2CO3
COOMe
Rf
OHC
1,4-dioxane−H2O, reflux
2a
(Rf = C6F13) : quant.
2b (Rf = C8F17) : y. 95%
2c (Rf = C10F21) : y. 92%
10% Pd-C, H2 gas
EtOAc, rt
Red-Al, Pyrrolidine,
t-BuOK
COOMe
CHO
Rf
Rf
THF, -20 oC then 0 o
C
3a (Rf = C6F13) : quant.
3b (Rf = C8F17) : quant.
3c (Rf = C10F21) : y. 99%
(Rf = C6F13) : y. 95%
(Rf = C8F17) : quant.
(Rf = C10F21) : y. 96%
4a
4b
4c
Red-Al: Sodium bis (2-methoxyethoxy) aluminium hydride
Scheme 1. Preparation of Fbenzaldehydes 4a–c.
trated to give Fbenzylidene acetal compound 5a in
87% yield (entry 1). Similarly, Fbenzaldehydes 4a–c were
reacted with hexopyranosides. After purification of the
crude products by FSPE, Fbenzylidene acetal com-
pounds 5b, 5c and 6a–c were obtained in good yields
(Table 1).
Ph3P
RfCH2CH2I
+
[Ph3PCH2CH2Rf]+I−
DMF, 105 oC, 24h
Rf = C6F13
Rf = C8F17
Rf = C10F21
1a (Rf = C6F13) : quant.
1b (Rf = C8F17) : quant.
1c (Rf = C10F21) : y. 96%
Figure 1. Preparation of fluorous phosphonium salts 1a–c.
Since Fbenzylidene acetal groups were successfully intro-
duced into 4,6-hydroxyl group of hexopyranosides, we
next tried to deprotect the fluorous acetal groups (Table
2). 4,6-O-FBenzylidene acetal derivatives 7a–c obtained
by acetylation of 5a–c were hydrolyzed in 90% aq AcOH
at room temperature. After the reaction was completed,
the aq AcOH solvent was removed and then the residue
was treated with FSPE as described above. The 80% aq
MeOH fraction gave the corresponding alcohol 9 in
quantitative yield in each case. FBenzaldehydes 4a–c
were quantitatively recovered from the MeOH fraction
(entries 1–3), and the recovered compound 4b was re-
used as the protecting agent (Table 1, entry 3). Another
method of deprotection was carried out by hydrogena-
tion of Fbenzylidene acetal groups with 10% Pd–C.
After purification of the crude products by FSPE,
Benzaldehyde 4a (1.0 equiv) was reacted with trimethyl
orthoformate (2.0 equiv) in the presence of p-TsOHÆ
H2O (0.2 equiv) at room temperature. After monitoring
the complete conversion of Fbenzaldehyde 4a into the
F
corresponding dimethyl acetal 4a0 on TLC, methyl a-
D-glucopyranoside (2.5 equiv) was added to the reaction
mixture. After the reaction was completed, the reaction
was quenched with Et3N. The reaction mixture was
filtered off and then the filtrate was concentrated. To
separate the fluorous product from non-fluorous by-
products, the crude product was loadeÒd onto a fluorous
reverse-phase silica gel (FluoroFlash )16 column and
then the column was eluted successively with 80% aq
MeOH and MeOH. The MeOH fraction was concen-
Table 1. Introduction of Fbenzylidene acetal groups into hexopyranosides
O
OMe
OH
HO
HO
OH
Alcohol
CH(OMe)3
OMe
O
OMe
OH
O
.
p
-TsOH H2O
(2.5 equiv)
CHO
O
Rf
OMe
a)
Rf
Na2SO4
Rf
OH
FSPE
FBenzaldehydes: 4a-c
4a'-c'
CH3CN, rt
i) 80% MeOH aq
ii) MeOH
(1.0 equiv)
5a-6c
Entry
FProtecting reagent
Alcohol
Yield (%)
O
OMe
OH
1
2
3
4
4a
4b
4b
4c
5a (Rf = C6F13): 87
5b (Rf = C8F17): 85
5b (Rf = C8F17): 85b
5c (Rf = C10F21): 94
HO
HO
OH
Methyl α-D-glucopyranoside
O
OMe
OH
5
6
7
4a
4b
4c
6a (Rf = C6F13): 95
6b (Rf = C8F17): 88
6c (Rf = C10F21): 67
HO
HO
OH
Methyl α-D-galactopyranoside
a Na2SO4 (200 mg) as a dehydrating reagent was added to Fbenzaldehydes 4a–c (200 mg).
b Recovered F17benzaldehyde 4b of entry 2 in Table 2 was used.

M. Kojima et al. / Tetrahedron Letters 48 (2007) 4431–4436
Table 2. Deprotection of Fbenzylidene acetal groups
4433
O
OMe
OAc
70 or 80% MeOH aq
HO
HO
Hydrolysis
OAc
or
O
OMe
OR
Hydrogenation
FSPE
O
Alcohols: 9-10
O
Rf
OR
5a-6c: R = OH
7a-8c: R = Ac
CHO
CH3
Ac2O, Py.
or
Rf
FBenzaldehydes: 4a-c
Rf
FToluenes: 11a-c
MeOH
Fluorous compounds
Entry
Substrate
Reaction condition
Yield (%)
Alcohol
Fluorous compound
9: quant.a
9: quant.
9: quant.
4a (Rf = C6F13): quant.a
4b (Rf = C8F17): quant.
4c (Rf = C10F21): quant.
O
OMe
OAc
1
2
3
7a (D-Gluco)
7b (D-Gluco)
7c (D-Gluco)
90% aq AcOH, rt
90% aq AcOH, rt
90% aq AcOH, rt
HO
HO
OAc
9
10: 99a
10: 91
10: 94
11a (Rf = C6F13): 88a
11b (Rf = C8F17): 87
11c (Rf = C10F21): 88
O
OMe
OAc
4
5
6
8a (D-Galacto)
8b (D-Galacto)
8c (D-Galacto)
10% Pd–C, H2 gas/EtOAc, rt
10% Pd–C, H2 gas/EtOAc, rt
10% Pd–C, H2 gas/EtOAc, rt
HO
HO
OAc
10
a The crude product was loaded onto a fluorous reverse-phase silica gel column and then the column was eluted successively with 70% aq MeOH and
MeOH.
deprotected alcohol 10 was obtained in high yields from
the 80% aq MeOH fraction, and fluorous toluenes 11a–c
were obtained from the MeOH fraction in 88%, 87%
and 88% yields, respectively (entries 4–6). The lower
boiling point of 11a–c must have resulted in the lower
recoveries compared to those of 4a–c.17 The conversion
of Ftoluenes 11a–c into Fbenzaldehydes 4a–c for reuse is
now in progress.
hand, using PhBCl2 as an acid, the corresponding 4-
O-F17benzyl-6-O-hydroxyl derivative 14b was obtained
in 96% yield. The isolation of these F17Bn-protected
products (13b and 14b) by FSPE was very easy and
quick.
Using 13b and 14b as acceptors, we tried to synthesize
disaccharides by Schmidt’s trichloroacetoimidate18 and
thioglycoside19 methods. The results of the 4-O-glycosi-
dation are shown in Table 3 (entries 1–6). Unexpectedly,
the glycosidation of 13b with galactosyl trichloroaceto-
imidate 1520 in the presence of a catalytic amount of
TMSOTf (0.1 equiv) in anhydrous CH2Cl2 gave sugar–
sugar orthoester 20b21 in 92% yield (entry 1). However,
the desired disaccharide 21b was obtained in 75%
yield (b only) when 0.25 equiv of TMSOTf was used
(entry 2). To avoid the formation of the orthoester,
As mentioned above, the regioselective ring opening of
the benzylidene acetal group is very useful in carbo-
hydrate chemistry. Therefore, we examined the reductive
cleavage of 4,6-O-F17benzylidene acetal group into the
F17
12b
benzyl group using Et3SiH-TFA12a or PhBCl2
(Scheme 2). When TFA was used as an acid, compound
7b was converted into the corresponding 6-O-F17benzyl-
4-O-hydroxyl derivative 13b in 98% yield. On the other
O
OMe
OAc
O
OMe
OAc
Et3SiH, TFA, MS-4 Å
CH2Cl2, -78 oC to rt
O
O
C8F17
O
HO
C8F17
OAc
OAc
Ac2O, Py., rt
FSPE
i) 80% MeOH aq
ii) MeOH
7b: quant.
13b: y. 98%
O
OMe
OH
O
O
C8F17
OH
5b
BnBr, KOH
O
OMe
OBn
O
OMe
OBn
Et3SiH, PhBCl2, MS-4 Å
O
O
HO
O
Toluene, reflux
CH2Cl2, -78 o
C
OBn
C8F17
C8F17
OBn
FSPE
12b: quant.
14b: y. 96%
i) 80% MeOH aq
ii) MeOH
Scheme 2. Regioselective ring opening reaction of the F17benzylidene acetal group with Et3SiH-TFA or PhBCl2.

4434
M. Kojima et al. / Tetrahedron Letters 48 (2007) 4431–4436
Table 3. Glycosidation of acceptors 13–14b with various donors 15–19
80% MeOH aq
X
O
R3O
R3O
Non-fluorous compounds
OR3
OR3
O
OMe
OR
15-19: donors (3.0 equiv)
FSPE
R2O
R1O
Activator, MS-4 Å
CH2Cl2
OR
Acceptors
13b: R = Ac, R1 = H, R2
14b: R = Bn, R1
F17Bn, R2 = H
=
F17Bn
=
Fluorous disaccharides: 20b-27b
F17Bn =
MeOH
C8F17
O
OMe
OAc
F17BnO
O
OMe
OAc
F17BnO
O
OMe
OBn
O
O
OMe
O
O
O
O
O
AcO
AcO
O
O
O
R3O
R3O
O
F17BnO
OR3
O
F17BnO
OBn
R3O
R3O
AcO
AcO
OAc
OAc
OBn
OBn
OR3
O
OAc
OR3
OR3
OAc
24b
25b: (R3 = Ac)
26b: (R3 = Bz)
27b: (R3 = Bn)
20b
21b: (R3 = Ac)
22b: (R3 = Bz)
23b: (R3 = Bn)
Entry
Acceptor
Donor
Activator
Reaction temperature
Yield (%)
X
R3
1
2
3
4
5
6
13b
15: OC(NH)CCl3
15: OC(NH)CCl3
16: OC(NH)CCl3
17: OC(NH)CCl3
18: SPh
Ac
Ac
Bz
Bn
Ac
Bz
TMSOTf (0.1 equiv)
TMSOTf (0.25 equiv)
TMSOTf (0.25 equiv)
TMSOTf (0.1 equiv)
TfOH (0.3 equiv)/NIS (4.0 equiv)
TfOH (0.3 equiv)/NIS (4.0 equiv)
ꢀ20 °C
20b: 92
ꢀ40 °C then 0 °C
ꢀ40 °C then rt
ꢀ40 °C
21b: 75 (b only)a,b
22b: 73 (b only)a
23b: 86 (a/b = 10:1)c
21b: 64 (b only)a,b
22b: 75 (b only)a
ꢀ20 °C
19: SPh
ꢀ20 °C
7
8
9
10
11
12
13
14b
15: OC(NH)CCl3
15: OC(NH)CCl3
16: OC(NH)CCl3
17: OC(NH)CCl3
17: OC(NH)CCl3
18: SPh
Ac
Ac
Bz
Bn
Bn
Ac
Bz
TMSOTf (0.1 equiv)
TMSOTf (0.25 equiv)
TMSOTf (0.25 equiv)
TMSOTf (0.1 equiv)
TMSOTf (0.1 equiv)
TfOH (0.3 equiv)/NIS (4.0 equiv)
TfOH (0.3 equiv)/NIS (4.0 equiv)
ꢀ20 °C
24b/25b: 94 (4:1)c
ꢀ40 °C then 0 °C
ꢀ40 °C then rt
ꢀ40 °C
25b: 50 (b only)c,d
26b: 70 (b only)c
27b: quant. a/b = 1:1c
27b: quant. a/b = 1:10c,d
25b: 36 (b only)a,e
ꢀ40 °C
ꢀ20 °C
19: SPh
ꢀ20 °C
26b: quant. (98)f (b only)c
a After separated by FSPE, purified by flash column chromatography.
b Acceptor 13b resulting from rearrangement of sugar–sugar orthoester intermediate was isolated.21b–d
c Determined by 1H NMR spectrum.
d CH3CN was used instead of CH2Cl2.
e 6-O-Acetylated derivative of acceptor 14b resulting from rearrangement of sugar–sugar orthoester was isolated.21b–d
f Isolated yield.
perbenzoylated galactosyl imidate 1622 was reacted with
acceptor 13b under similar reaction conditions to give
the corresponding disaccharide 22b (b only) in 73% yield
(entry 3). In order to improve the yield of the disaccha-
ride, perbenzylated galactosyl imidate 1723 was reacted
with acceptor 13b in the presence of catalytic amounts
of TMSOTf (0.1 equiv) to give disaccharide 23b (a/b =
10:1) in 86% yield (entry 4). Glycosidation of 13b with
thioglycoside 1824 and 1925 in the presence of N-iodo-
succinimide (NIS, 4.0 equiv) and trifluoromethansul-
fonic acid (TfOH, 0.3 equiv) in CH2Cl2 at ꢀ20 °C
smoothly gave the corresponding disaccharides 21b
and 22b in 64% and 75% yields, respectively (entries 5
and 6). Similarly, the results of the 6-O-glycosidation
are shown in Table 3 (entries 7–13). The glycosidations
of 14b with perbenzylated imidate 17 and thiogalacto-
side 19 gave disaccharides 27b (a/b = 1:1) and 26b (b
only), respectively, in excellent yields (entries 10 and
13). When CH3CN was used instead of CH2Cl2, the ano-
meric stereoselectivity was dramatically changed to a/
b = 1:10 (entry 11).26 The glycosidation of peracetylated
imidate 15 and thioglycoside 18 gave the corresponding
disaccharide 25b in 50% and 36% yields, respectively,
together with 6-O-acetylated derivative of acceptor 14b
resulting from a rearrangement of sugar–sugar ortho-
ester 24b (entries 8 and 12).21b–d
Finally, we examined deprotection of the F17Bn group of
disaccharide 21b and 25b (Scheme 3). Compounds 21b
and 25b were hydrogenated with 10% Pd–C in EtOAc
and MeOH, respectively. After purification of the crude
products by FSPE, disaccharides 28 and 29 were ob-
tained in excellent yields from 80% aq MeOH fractions
and fluorous toluene 11b was recovered in 83% and 80%
yields, respectively, from MeOH fractions.
In conclusion, we have developed a new fluorous benzyl-
idene acetal protecting group of polyhydroxy com-

M. Kojima et al. / Tetrahedron Letters 48 (2007) 4431–4436
4435
O
OMe
OR
80% MeOH aq
R2O
R1O
OR
28 (R = Ac, R1 = Gal, R2 = H)
y. 92% from 21b
O
OMe
OR
10% Pd-C, H2 gas
FSPE
R2O
R1O
29 (R = H, R1 = H, R2 = Gal)
y. 93% from 25b
rt
OR
21b: EtOAc
25b: MeOH
21b (R = Ac, R1 = Gal, R2
25b (R = Bn, R1
F17Bn, R2 = Gal)
=
F17Bn)
CH3
=
C8F17
MeOH
O
F17Toluene: 11b
y. 83% from 21b
y. 80% from 25b
AcO
F17Bn =
Gal =
C8F17
AcO
OAc
OAc
Scheme 3. Deprotection of F17benzyl group with 10% Pd–C.
Chiva, G.; Sanz-Cervera, J. F.; del Pozo, C.; Acena, J. L.
˜
J. Org. Chem. 2006, 71, 3299–3302.
pounds. It was attached and detached under common
reaction conditions for a non-fluorous benzylidene ace-
tal group. Using the fluorous acceptors, disaccharides
were synthesized under traditional reaction conditions.
The isolation of the fluorous intermediates by FSPE
was very easy and quick, although the fluorine atom
content was just about 21% at the final stage. The fluor-
ous compounds were also purified by standard silica gel
column chromatography, if necessary. Considering
these attributes, the Fbenzylidene acetal groups may find
valuable and versatile use in carbohydrate synthesis.
Optimization of the glycosidation conditions and
further application to syntheses of several bioactive
carbohydrates are now in progress.
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1
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