Trifluoroethylsulfonate protected monosaccharides in glycosylation reactions

Article abstract of DOI:10.1016/j.tetlet.2004.06.131

A variety of sulfo-protected monosaccharide donors and acceptors were investigated in glycosylation reactions. Trifluoroethylsulfonate (SO ₃TFE) group was compatible with a wide range of activation conditions commonly used with fluoride, imidat

Full text of DOI:10.1016/j.tetlet.2004.06.131

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6433–6437
Trifluoroethylsulfonate protected monosaccharides in
glycosylation reactions
Nathalie A. Karst,a Tasneem F. Islam,a Fikri Y. Avcia,b and Robert J. Linhardta,b,
*
aDepartment of Chemistry, University of Iowa, Iowa City, IA 52242, USA
bDepartments of Chemistry and Chemical Biology, Biology and Chemical and Biological Engineering,
Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Received 19 December 2003; revised 25 May 2004; accepted 30 June 2004
Available online 19 July 2004
Abstract—A variety of sulfo-protected monosaccharide donors and acceptors were investigated in glycosylation reactions. Trifluoro-
ethylsulfonate (SO3TFE) group was compatible with a wide range of activation conditions commonly used with fluoride, imidate, and
sulfide donors. In addition, the influence of a SO3TFE group, at the critical 2-position in glycosyl donor, on the stereoselectivity of the
glycosylation reaction was studied.
Ó 2004 Elsevier Ltd. All rights reserved.
Glycosaminoglycans (GAGs) are linear, polydisperse
acidic polysaccharides that occur ubiquitously in animal
tissues, membranes, intracellularly in secretory granules
or extracellularly in the matrix. GAGs contain repeating
units of hexosamine, either glucosamine (GlcNp) or gal-
actosamine (GalNp), and uronic acid, either glucuronic
acid (GlcAp) or iduronic acid (IdoAp). The biological
significance of these sulfated oligosaccharides have
made them the object of numerous studies for synthetic
carbohydrate chemists for several decades.1 However,
due to their structural complexity, GAG synthesis has
remained an important challenge. Recent advances in
oligosaccharide preparation, such as automated solid
phase synthesis, have shown promising results, allowing
faster access to the molecules of interest.2,3 Nevertheless,
these approaches still require preparation of suitably de-
signed monomers. Positions that will ultimately contain
sulfo groups must be masked with temporary protecting
groups, deprotected after assembly of the oligosaccha-
ride and sulfonated. Thus, such strategies require long
multi-step synthetic sequences and intensive protecting
group manipulation. Additionally, sulfonation reactions
can be troublesome and often sluggish at the higher
oligosaccharide level.4 Sulfo esters are highly polar,
making the products of sulfonation reactions difficult
to manipulate and to purify. The protection of sulfo
esters offers an attractive alternative to solve these prob-
lems. The introduction of protected sulfo esters, into
monosaccharide or disaccharide building blocks at the
early stages of the synthesis, should reduce protecting
group manipulation and decrease the polarity of these
molecules, making them easier to handle and purify.
Phenylsulfonate and trifluoroethylsulfonate derivatives
were introduced as sulfo-protection groups in carbohy-
drates in 1981 and 1997 by Penney and Perlin5 and
Flitsch and co-workers.6 With the exception of our
recently reported use of trifluoroethylsulfonate group
in the preparation of sulfo-protected hexosamine build-
ing blocks,7 no further reports of sulfo protection in
oligosaccharide synthesis can be found. In the current
study, we have extended the application of this protec-
tion chemistry to the synthesis of different hexosamine
and uronic acid precursors and studied their behavior
in glycosylation reactions.
The syntheses of 6-sulfo protected fluorides 1 and 2 and
4-sulfo protected trichloroacetimidate 3 (Fig. 1) have
been described in our previous report.7 In the course
of these studies, we found that the trifluoroethylsulfo-
nate (SO3TFE) group at the primary 6-position, could
act as a good leaving group under basic conditions,
affording 1,6-anhydro derivatives. As a result prepara-
tion of 6-SO3TFE trichloroacetimidate donors was
Keywords: Trifluoroethylsulfonate; Glycosylation; Glycosaminogly-
cans.
*
Corresponding author. Address: Departments of Chemistry and
Chemical Biology, Biology and Chemical and Biological Engineer-
ing, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. Tel.:
+1-518-276-3404; fax: +1-518-276-3405; e-mail: linhar@rpi.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.131

6434
N. A. Karst et al. / Tetrahedron Letters 45 (2004) 6433–6437
intermediate 12 was synthesized from commercially
OSO3TFE
BnO OSO3TFE
O
available 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose
as described in literature,11 and submitted to the two
steps sequence of sulfonation/sulfo-protection, affording
compound 13 in 87% yield (Scheme 2). Regioselective
opening of the benzylidene ring in 13 afforded 14
(93%), which was subsequently 6-O-acetylated to give
compound 15. The activation of 13 and 15 proved to
be troublesome in both cases and imidates 10 and 11
were obtained in modest 40% and 34% yield, respec-
tively. The limiting step of activation was found to be
the oxidative removal of the MP group with CAN.
NMR studies of the major side-product recovered from
the reaction revealed the presence of SO3TFE group,
which withstood the oxidative conditions of the reac-
tion, and showed perturbation of the MP aromatic sig-
nals. No formal identification of this intermediate
could be achieved.
O
PMBO
BnO
F
F
BzO
N3
1
N3
2
OBn
O
TFEO3SO
BzO
N3
OC(NH)CCl3
3
Figure 1. TFE-protected donors 1–3.
found difficult, thus we decided to investigate other
types of activation. In the GlcNp series, the a-thiophen-
ylglycosyl donor 4 was synthesized since it could either
be directly used in glycosylation or transformed into a
more reactive sulfoxide donor 5 (Scheme 1). Differen-
tially protected thiophenylglycoside 4 was synthesized
from the known thiophenylglycoside 6.8 After deacetyla-
tion and introduction of a p-methoxybenzylidene acetal
at the 4,6-positions, the remaining 3-hydroxyl was benz-
ylated, to give 8 in 80% yield. Regioselective opening of
the benzylidene acetal by treatment with Bu2BOTf9
afforded the expected 6-hydroxyl derivative 9 in 91%
yield. Selectivity was confirmed by NMR studies and
subsequent acetylation of the primary position. Intro-
duction of SO3TFE at the 6-position was achieved in
two steps, sulfonation and sulfo protection with a
freshly prepared solution of trifluorodiazoethane10 in
presence of citric acid, affording donor 4 in 70% yield.
Subsequent oxidation of 4 with mCPBA afforded the
corresponding sulfoxide donor 5.
Donors 1–4, 10, and 11 were investigated under a variety
of glycosylation conditions with acceptors 17, 18,7 19,12
and 2012 (Fig. 2). The strong electron-withdrawing char-
acter of the SO3TFE group was an initial concern in the
glycosylation reactions. Its presence contributed to dis-
arm the sugar, and it was expected that the reactivity
of both donors and acceptors would be lowered. To
our satisfaction, glycosylation of a reactive acceptor
17, with fluorides, sulfide, and imidate donors gave good
to excellent results (Table 1, entries 1–5, 7–8). Partial
loss of the PMB protection was observed under Ag-
ClO4/Cp2ZrCl2 initiation used with fluoride donor 1.
The use of acid scavenger, norbornylene,13 did not
The uronic acid residues in GAGs, both GlcAp (chon-
droitin sulfate D) and IdoAp (heparin, dermatan sul-
fate) units can contain 2-O-sulfo groups. For example,
IdoA2SO3 is an essential saccharide residue in the hepa-
rin pentasaccharide structure that binds to antithrom-
bin, promoting its anticoagulant activity. Thus, we
next directed our studies toward the preparation of the
2-sulfo protected uronic acid precursors glucose (Glcp).
2-SO3TFE protected Glcp derivatives 10 and 11 were
prepared to study the influence of SO3TFE protecting
group, in the critical 2-position, on the outcome of the
glycosylation reaction stereoselectivity. The common
O
O
Ph
Ph
O
a
O
O
O
OMP
c
BnO
BnO
TFEO3SO
OR
OC(NH)CCl3
12 R = H
b
10
13 R = SO3TFE
OR6
O
OAc
O
a
BnO
BnO
TFEO3SO
BnO
BnO
OMP
OC(NH)CCl3
OSO3TFE
14 R6 = H
15 R6 = Ac
11
d
Scheme 2. Reagents and conditions: (a) (i) CAN, MeCN, PhMe, H2O;
(ii) Cl3CCN, DBU, DCM 10 40%, 11 34%; (b) (i) Me3NÆSO3, D MF,
50°C; (ii) TFEN2, citric acid, MeCN 87% (two steps); (c) BH3ÆTHF,
Bu2BOTf 93%; (d) Ac2O, pyridine 99%.
OAc
O
O
R3O
7: R3 = H
PhOMe
O
a
O
AcO
AcO
N3
N
SPh
3 SPh
6
b
8: R3 = Bn
c
OH
O
COOMe
O
O
OSO3TFE
O
OH
O
ClAcO
BnO
O
d
PMBO
BnO
PMBO
BnO
BzO
O
OC(NH)CCl3
O
16
17
N
3 R
N3
SPh
9
4: R = SPh
e
OSO3TFE
O
OTBDMS
O
COOMe
O
5: R = SOPh
HO
HO
HO
OTDS
OBn
OMP
BnO
BzO
BnO
Scheme 1. Reagents and conditions: (a) (i) MeONa, MeOH; (ii)
MeOPhCH(OMe)2, CSA, MeCN 82% (two steps, a:b 7:1); (b) NaH,
BnBr, DMF 80%; (c) BH3ÆTHF, Bu2BOTf 91%; (d) (i) Me3NÆSO3,
DMF, 50°C; (ii) TFEN2, citric acid, MeCN 70% (two steps); (e)
mCPBA, DCM 86%.
N3
OBz
OSO3TFE
18
19
20
Figure 2. Donor 16 and acceptors 17–20 employed in the glycosylation
reactions.

N. A. Karst et al. / Tetrahedron Letters 45 (2004) 6433–6437
Table 1. Glycosylation of SO3TFE donors and acceptors
6435
Entry
Donora
Acceptora
Disaccharide
OSO3TFE
Promoter (equiv)
Yield, a:b ratio
R4O
O
OH
O
O
BnO
OSO3TFE
AgClO4 (2.0)
Cp2ZrCl2 (2.0)
71%
a only
N3
O
O
O
PMBO
BnO
1
O
F
O
O
O
O
N3
4
4
O
21 R = PMB
O
22 R = H
OSO3TFE
O
OSO3TFE
COOMe
O
HO
BnO
O
HO
PMBO
BnO
COOMe
2
AgClO4 (2.0)
Cp2ZrCl2 (2.0)
50%
a only
OBn
F
N
3O
BzO
O
OBn
OBz
BzO
N3
23
OBz
BnO OSO3TFE
O
OH
O
O
O
OSO3TFE
O
BnO
BzO
O
BzO
O
3b
AgClO4 (3.0)
Cp2ZrCl2 (3.0)
64%
a:b 4:1
N3
O
O
O
O
N
3 F
O
24
O
OSO3TFE
O
OH
O
PMBO
BnO
O
O
OSO3TFE
O
NIS (2.5)
72%
O
O
4c
PMBO
BnO
TfOH (0.5)
Ph2SO (2.8)
Tf2O (1.4)
a only
64%
N3
O
O
O
O
N3
SPh
21
O
a:b1:2
O
TFEO3SO OBn
O
OH
O
O
O
OBn
O
TFEO3SO
BzO
O
BzO
O
5b
BF3ÆEt2O
(0.45)
49%
b only
N3
O
O
O
O
N3
OC(NH)CCl3
O
O
25
OBn
O
TFEO3SO
BzO
OBn
O
TFEO3SO
BzO
OTBDMS
O
OTBDMS
O
O
HO
OMP
6
7
BF3ÆEt2O
(0.2)
10%
b only
OMP
OSO3TFE
BnO
BnO
N3
OSO3TFE
N3
OC(NH)CCl3
26
O
Ph
O
O
OH
O
O
O
O
O
TMSOTf
(0.2)
76%
a:b 1:1.1
75%
BnO
O
O
Ph
O
TFEO3SO
O
BnO
O
BF3ÆEt2O
(0.2)
O
O
TFEO3SO
OC(NH)CCl3
O
27
a:b 1:5.7
O
OAc
O
OH
O
BnO
BnO
O
O
TMSOTf
(0.2)
91%
a:b 1.2:1
90%
O
OAc
O
O
BnO
BnO
TFEO3SO
8
9
O
BF3ÆEt2O
(0.2)
O
O
O
TFEO3SO
OC(NH)CCl3
a:b 1:2
O
28
O
OSO3TFE
O
COOMe
O
OSO3TFE
O
COOMe
O
ClAcO
BnO
O
ClAcO
BnO
OTDS
HO
TMSOTf
(0.25)
44%
b only
BnO
OTDS
BnO
BzO
N3
BzO OC(NH)CCl3
N3
29
a All glycosylation reaction were carried on in DCM, except for entry 6 conducted in toluene, and with 1equiv of donor and excess acceptor (1.2–
1.5equiv) except where otherwise specified.
b Referred to Ref. 7 for characterization of disaccharides 24 and 25.
c See Ref. 15, DTBMP (3.0equiv) was used as a base.
improve the outcome of the reaction. In the case of sul-
fide 4, activation under the traditional NIS/TfOH condi-
tions using 0.5equiv of catalyst14 was complete in less
than 30min. However, when the amount of catalyst

6436
N. A. Karst et al. / Tetrahedron Letters 45 (2004) 6433–6437
Ph
Ph
O
O
O
a
O
O
O
OMP
OMP
BnO
O3-SO
BnO
TFEO3SO
31
13
O3-SO OBn
TFEO3SO OBn
b
O
O
O
O
HO
N3
BzO
N3
O
O
O
O
O
O
O
32
O
O
25
O
-
OSO3
O
OSO3TFE
O
c
HO
HO
BnO
BnO
COOH
COOMe
O
N
3O
N
O
3O
OBn
OBn
HO
BzO
OH
OBz
33
23
OBn
O
OBn
TFEO3SO
BzO
O3-SO
HO
OTBDMS
O
OTBDMS
O
d
e
O
O
O
OMP
OMP
BnO
BnO
N3
N3
OSO3TFE
OSO3TFE
26
34
O
3-SO
HO
OBn
O
OTBDMS
3-SO
HO
OBn
O
O
OH
O
O
OMP
OSO3TFE
O
O
BnO
OH
BnO
N3
-
N3
OSO3
34
35
Scheme 3. Reagents and conditions: (a) t-BuOK, t-BuOH 82%; (b) MeONa, MeOH 70%; (c) (i) MeONa, MeOH; (ii) t-BuOK, t-BuOH 60% (two
steps); (d) MeONa, MeOH 90%; (e) t-BuOK, t-BuOH 50%.
was decreased (0.2equiv), the overnight reaction was
incomplete and a large amount of unreacted donor
was recovered. The use of less reactive acceptors, such
as 4-OH containing GlcAp methyl ester 20 or 2-SO3TFE
Glcp derivative 19, resulted in a drop of reactivity, low
to poor yields and the recovery of a large amount of
unreacted acceptors (Table 1, entries 2 and 6). This
trend was confirmed by glycosylation studies with donor
16, prepared as described in literature,4b and acceptor
18, affording 29 in a modest 44% yield (Table 1, entry
9). Glycosylation performed with 2-SO3TFE donors 10
and 11 under TMSOTf conditions resulted in an equal
amount of products in the a- and b-anomeric form.
Lowering the reaction temperature (À15°C) did not
improve stereo selectivity, suggesting that SO3TFE
group at the 2-position acted as a nonparticipating
group. An increase of the b-selectivity could, however,
be achieved using BF3ÆEt2O as a catalyst (Table 1,
entries 7 and 8).
32 yield of 70%. Deprotection of the 6-sulfo compound
23 also posed the greatest challenge, as the major prod-
uct formed on treating 23 under standard conditions6
was desulfonated. Removal of the OBz groups in 23, fol-
lowed by standard deprotection conditions6 resulted in
only minor loss of sulfo group, affording 33 in 60%
yield. To remove the 2- and 4-sulfo groups from 26, a
stepwise approach was required. Treatment under
sodium methoxide/methanol resulted in 4-sulfo group
deprotection affording 34, followed by t-BuOÀK+/
t-BuOH to deprotect the 2-sulfo group. The 2,4-disulfo
product 35 was obtained in a 45% overall yield with
partial decomposition resulting in loss of the 6-
OTBDMS and OMP protecting groups. Further optimi-
zation studies on the deprotection of these groups will
be required to make the sulfo-protection strategy useful
in glycosaminoglycan synthesis.
In summary, the SO3TFE protecting group proved to be
compatible under a wide range of activation conditions.
The 6-, 4-, and 2-SO3TFE glycoside fluoride, sulfide,
and imidate donors showed satisfactory results in the
glycosylation of reactive acceptors. Glycosylation
proved more difficult with less reactive acceptors, such
as uronic acids, presumably due to the strong electron-
withdrawing character of the SO3TFE group. Investiga-
tion of highly reactive donors, such as sulfoxide, is now
underway to improve glycosylation yields.
Preliminary studies aimed at the deprotection of these
products focused on compounds 13, 23, 25, and 26
(Scheme 3). The 2-sulfo protected monosaccharide 13
was deprotected using standard conditions, t-BuOÀK+/
t-BuOH affording 82% yield of 31.6 Similar conditions
proved too harsh resulting in decomposition of the
4-sulfo protected disaccharide 25. The use of milder con-
ditions, 1equiv sodium methoxide/methanol, afforded

N. A. Karst et al. / Tetrahedron Letters 45 (2004) 6433–6437
6437
7. Karst, N.; Islam, T.; Linhardt, R. J. Org. Lett. 2003, 5,
4839–4842.
Supplementary data
8. Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118,
9239–9248.
9. Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998, 39,
355–358.
Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tet-
let.2004.06.131.
10. 2,2,2-Trifluorodiazoethane solution in MeCN was pre-
pared as described in Ref. 6. Caution: This reagent should
be considered as potentially explosive and highly toxic.
11. Karst, N.; Jacquinet, J.-C. J. Chem. Soc., Perkin Trans. 1
2000, 2709–2717.
12. Compound 19 was obtained from 12: (1a) EtSH, p-TsOH,
DCM, 94%; (1b) TBDMSCl, imidazole, DMF, 92%.
Compound 20 was synthesized from known methyl
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