Fluorous thiols in oligosaccharide synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.04.116

A new, almost odorless fluorous thiol is synthesized, which is utilized to prepare highly fluorinated thioglycosyl donors. These thioglycosides showed excellent reactivities in glycosylation reactions. The fluorous chain, stable under esterification, etherification, deacetylation, and glycosylation conditions, allowed facile purification of the thioglycosides by solid-phase extraction through fluorous silica gel. The fluorous thiol was readily recycled.

Full text of DOI:10.1016/j.tetlet.2004.04.116

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4615–4618
Fluorous thiols in oligosaccharide synthesis
Yuqing Jing and Xuefei Huang*
Department of Chemistry, University of Toledo, 2801 W. Bancroft Street, Toledo, OH43606-3390, USA
Received 30 March 2004; revised 21 April 2004; accepted 21 April 2004
Abstract—A new, almost odorless fluorous thiol is synthesized, which is utilized to prepare highly fluorinated thioglycosyl donors.
These thioglycosides showed excellent reactivities in glycosylation reactions. The fluorous chain, stable under esterification,
etherification, deacetylation, and glycosylation conditions, allowed facile purification of the thioglycosides by solid-phase extraction
through fluorous silica gel. The fluorous thiol was readily recycled.
Ó 2004 Elsevier Ltd. All rights reserved.
Traditional oligosaccharide synthesis is a time-consum-
ing process mainly due to tedious chromatographic
purification of multiple synthetic intermediates.1 Resin
based solid-phase carbohydrate syntheses2 can help
alleviate this problem but it suffers several disadvantages
such as reduced reactivity, lack of a general method for
real time monitoring of the reaction3 and difficulty in
purification of attached intermediates. Recently, fluor-
ous chemistry has become an attractive alternative to
solid-phase synthesis.4 A highly fluorinated compound
is readily separated from nonfluorinated substances by
either binary fluorous/organic phase extraction or solid-
phase extraction (SPE) through fluorous silica gel.5
Fluorous technologies have been applied to carbo-
hydrate synthesis,6 primarily in development of highly
fluorinated protective groups such as ester, acetal, silyl,
and benzyl, where purification of desired products are
greatly facilitated by fluorous moieties in the molecule.
odorless. Moreover, the fluorous moiety significantly
aids the purification of corresponding thioglycosides
and the fluorous thiol 1a can be readily regenerated for
further uses.
CH3
N
C8F17
C8F17
HS
HS
1b
O
1a
1c
BzO
BzO
H
N
O
C8F17
HS
S
BzO
C8F17
OBz
O
2
In designing the fluorous thiol, a suitable linker should
be installed between the highly electron withdrawing
fluorous chain and the nucleophilic sulfur atom. Crich
and co-workers have demonstrated that a two methy-
lene group spacer was enough to insulate the electron
withdrawing power of the fluorous chain from the
sulfoxide sulfur in the fluorous dimethylsulfide reagent
for fluorous Swern oxidation reactions.8 Our initial
studies were carried out using the commercially avail-
able 1H,1H,2H,2H-perfluorodecane thiol 1b with a two
methylene linker.8;9 The two methylene spacer in 1b was
found not sufficiently insulating as we failed to activate
the disarmed thioglycoside 2 even with one of the most
powerful promoters, p-toluenesulfenyl triflate (p-Tol-
SOTf)10 formed in situ by p-toluenesulfenyl chloride (p-
TolSCl) and AgOTf. In order to increase the length of
the linker, a fluorous p-amido thiophenol 1c was pre-
pared. However, the secondary amide moiety underwent
undesirable benzoylation or benzylation under standard
protective group manipulation conditions carried out on
Thioglycosides are one of the most popular glycosyl
donors due to its high stability and high reactivities
toward thiophilic promoters, which have been exten-
sively utilized in stepwise and one-pot syntheses of
complex oligosaccharides.7 However, one drawback is
the extremely unpleasant odor of thiols employed for
thioglycoside formation, especially with the increasing
environmental consciousness. We report here the
development of a newfluorous thiol 1a, which is almost
Keywords: Fluorous thiol; Odorless; Glycosylation; Thioglycosides;
Solid-phase extraction.
* Corresponding author. Tel.: +1-419-530-1507; fax: +1-419-530-4033;
e-mail: xuefei.huang@utoledo.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.116

4616
Y. Jing, X. Huang / Tetrahedron Letters 45 (2004) 4615–4618
O
a
S
S
C8F17
NH
S
NH2
HO
C8F17
75%
H2N
4
2
O
3
5
CH3
N
O
CH3
N
b
c
C8F17
S
C8F17
S
H3C
H3C
70-85%
95-100%
O
O
7
6
CH3
N
d
C8F17
HS
70-75 %
O
1a
Scheme 1. Synthesis of fluorous thiol 1a. Reagents and conditions: (a) BOP (1 equiv), TEA, DMF, 80 °C, 10 h; (b) CH3I (20 equiv), KOH (20 equiv),
tetrabutylammonium bromide (1 equiv), 1:1 THF–H2O, rt, 15 h; (c) Selectfluor (1 equiv), 20:1 CH3CN–H2O, rt, 20 min; (d) TFAA, 40 °C, 50 min; 2 N
NaOH, 0 °C, 2 h; 6 N HCl.
the corresponding thioglycosides. This led to the syn-
thesis of the fluorous p-methylamido thiophenol 1a
(Scheme 1).
tetraacetyl-a-D-glucosyl bromide 10a by thiol 1a under
PTC followed by removal of acetate produced the
thioglucoside 11a in quantitative yield (Scheme 2a).
Benzoylation of 11a with benzoyl chloride gave the
disarmed thioglucoside 8a (83%). Excess of benzoyl
chloride (20 equiv) was necessary to drive the reaction
to completion. Compound 11a was successfully ben-
zylated under PTC15 to form armed donor 9 (76%)
(Scheme 2b). Benzylation with sodium hydride and
benzyl bromide in DMF gave lowyield of the desired
product presumably due to the amphiphilic nature of
11a. Disarmed thiogalactoside 8b was obtained in a
similar fashion as the corresponding thioglucoside 8a
in 85% yield. All fluorinated compounds synthesized
maintain normal chromatographic behavior on stan-
dard silica gel, allowing easy monitoring of the course
of reactions by TLC. Purification of the desired gly-
cosyl donor obtained from the multiple step syntheses
was significantly aided by the fluorous moiety. The
reaction mixture was subjected to solid-phase extrac-
tion (SPE) on fluorous silica gel. Excess reagents and
side products were readily removed by washing with
80% methanol and water mixture, followed by elution
of the fluorous compounds with pure acetone. The
fluorous compounds can also be purified by normal
silica gel chromatography if necessary, which is
advantageous compared to solid-phase synthesis. The
NMR signals originating from the fluorous chain
do not interfere with the carbohydrate region,
thus allowing facile characterization of the desired
product.
Mono-amidation of p-aminophenyl disulfide 3 with
a fluorous carboxylic acid 4 in the presence of
benzotriazol-1-yloxy tris(dimethylamino-phosphonium
hexafluorophosphate) (BOP) and triethylamine (TEA)
in N,N-dimethylformamide (DMF) gave disulfide 5
(75%), which was subsequently methylated with methyl
iodide and potassium hydroxide under phase transfer
conditions (PTC) to produce thioether 6 in 70–85%
yield. In order to cleave the thiomethyl group, a two-
step procedure was adopted. Oxidation by Selectfluor
led to quantitative formation of sulfoxide 7.11 The usage
of the popular oxidant m-chloroperoxybenzoic acid
(mCPBA) formed substantial amount of undesired sul-
fone even with carefully controlled amount of oxidant at
lowtemperature. Refluxing sulfoxide 7 in trifluoroacetic
anhydride (TFAA),12 followed by base and acid treat-
ments yielded the desired fluorous thiol 1a (70–75%),13
which is almost odorless.
With the fluorous thiol 1a in hand, disarmed (i.e.,
8a,b) and armed thioglycoside donors14 (i.e., 9) were
prepared (Scheme 2). Displacement of bromide from
R2
OH
a)
R1
O
R2
OAc
O
S
a, b
HO
O
R1
1a
HO
AcO
N
C8F17
AcO
Br
CH3
10a: R1= OAc, R2 = H
10b: R1= H, R2 = OAc
11a: R1= OH, R2 = H
11b: R1= H, R2 = OH
100%
100%
The reactivities of these newhighly fluorinated thiogly-
coside donors were examined next using acceptors 12
and 13 as examples of primary and secondary hydroxyl
groups. Both disarmed donors 8a,b and armed donor 9
underwent smooth glycosylation with 12 and 13 to form
disaccharides 15 to 20 in excellent yields (Table 1).
Promoter systems such as N-iodosuccinimide (NIS)/
AgOTf, NIS/TfOH, and p-TolSCl/AgOTf10 gave similar
results indicating these highly fluorinated donors are
compatible with multiple common glycosylation condi-
tions.
R2
OBz
R1
BzO
O
S
O
c
BzO
N
C8F17
CH3
8a: R1= OBz, R2 = H
8b: R1= H, R2 = OBz
83%
85%
OBn
d
BnO
BnO
O
b)
S
11a
O
76%
BnO
N
C8F17
9
CH3
Scheme 2. Syntheses of fluorinated thioglycosyl donors. Reagents and
conditions: (a) 1 M aq Na2CO3, EtOAc, rt, 2 h; (b) CH3ONa, CH3OH,
rt, 5 h; (c) BzCl (20 equiv), DMAP (1 equiv), pyridine, rt, 15 h; (d)
benzyl bromide, aq 50% NaOH, tetrabutylammonium bromide
(1 equiv), CH2Cl2, rt, 20 h.
OH
O
OBn
O
CH3
N
BzO
BzO
HO
BnO
C8F17
S
BzO
BnO
OCH3
OCH3
O
2
14
12
13

Y. Jing, X. Huang / Tetrahedron Letters 45 (2004) 4615–4618
Table 1. Results of glycosylation using highly fluorinated donors
4617
Entry
Donor+acceptor
Product
Yield (%)
Disulfide 14 recovered (%)
OBz
BzO
BzO
O
O
1
8a+12
93a
75
BzO
BzO
BzO
O
BzO
OCH3
15
OBz
BnO
BzO
BzO
O
2
3
8a+13
8b+12
87b
O
O
BnO
BzO
BnO
OCH3
16
OBz
OBz
O
O
BzO
91a
95b
86
60
BzO
BzO
BzO
O
BzO
OCH3
17
OBz OBz
O
BnO
O
O
4
5
8b+13
9+12
88a
BzO
BnO
OBz
BnO
OCH3
18
OBn
O
α : β ~ 1:2d
O
BnO
BnO
92c
80
75
BnOBzO
O
BzO
BzO
OCH3
19
OBn
α : β ~ 2 :1d
BnO
BnO
O
OBn
6
9+13
85a
BnO
O
O
BnO
BnO
OCH3
20
a Reagents and condition: NIS (2 equiv), AgOTf (0.2 equiv), CH2Cl2, MS-AW300, ꢀ78 °C.
b Reagents and condition: p-TolSCl (1 equiv), AgOTf (1 equiv), CH2Cl2, MS-AW300, ꢀ78 °C.
c Reagents and condition: NIS (2 equiv), TfOH (0.03 equiv), CH2Cl2, MS-AW300, ꢀ78 °C.
dAnomeric ratios were determined after comparison with literature data.16
The side product fluorous disulfide 14 from glycosyla-
tion reactions was facilely recovered by SPE with flu-
orous silica gel in 60–86% yields. Thiol 1a can be
regenerated (65–70%) through reduction of disulfide 14
with zinc dust (Scheme 3), which can be utilized further
to form thioglycosyl donors.
sides, fluorous thiols can be potentially utilized in
preparation of fluorinated glycosyl sulfoxide donors and
as a ligand for metal catalysts. Further work is in pro-
gress to extend the application of fluorous thiols.
Acknowledgements
In conclusion, we have prepared a new, almost odorless
fluorous thiol 1a, from which thioglycosyl donors were
synthesized in good yields. Purification of glycosyl
donors were greatly facilitated by fluorous moieties
through SPE. Both armed and disarmed fluorinated
thioglycoside donors showed excellent reactivities in
glycosylation with primary and secondary acceptors.
Fluorous group utilized was found compatible with
etherification, esterification, deacetylation, and glyco-
sylation conditions. The fluorous disulfide formed in
glycosylation reactions was easily recycled to regenerate
the fluorous thiol 1a. Besides formation of thioglyco-
We thank The University of Toledo for supporting this
research.
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CH3
CH3
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a
C8F17
C8F17
S
HS
N
65-70%
O
O
1a
14
2
Scheme 3. Reagents and conditions: (a) Zn (10 equiv), AcOH, 60–
70 °C, 15 h.

4618
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