Anomeric activation of thioglycosides and preparation of deoxyglycosides using polymer-bound iodate(I) complexes

Article abstract of DOI:10.1016/S0040-4039(02)02708-9

New thiophilic polymer-bound haloate(I) complexes are presented which are well suited for the polymer-assisted solution-phase activation of 2-deoxythioglycosides. In the presence of alcohols 2-deoxyglycosides are obtained in yields between 60 and 95%. Isolation of the target glycosides is further simplified by removing the byproduct diphenyldisulfide by reductive work-up. Here also a polymer-bound reagent, namely borohydride exchange resin, served as a tool for sequestering the sulfur-containing impurities.

Full text of DOI:10.1016/S0040-4039(02)02708-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 637–639
Anomeric activation of thioglycosides and preparation of
deoxyglycosides using polymer-bound iodate(I) complexes
Janis Jaunzems, Georgia Sourkouni-Argirusi, Martin Jesberger and Andreas Kirschning*
Institut fu¨r Organische Chemie der Universita¨t Hannover, Schneiderberg 1B, D-30167 Hannover, Germany
Received 29 October 2002; revised 27 November 2002; accepted 28 November 2002
Abstract—New thiophilic polymer-bound haloate(I) complexes are presented which are well suited for the polymer-assisted
solution-phase activation of 2-deoxythioglycosides. In the presence of alcohols 2-deoxyglycosides are obtained in yields between
60 and 95%. Isolation of the target glycosides is further simplified by removing the byproduct diphenyldisulfide by reductive
work-up. Here also a polymer-bound reagent, namely borohydride exchange resin, served as a tool for sequestering the
sulfur-containing impurities. © 2003 Elsevier Science Ltd. All rights reserved.
The efficient preparation of oligosaccharides and glyco-
conjugates in solution is still a challenging topic and
various new solution phase techniques have been devel-
oped recently. These include the use of fluorous
phases,1 functionalized polymers,2 scavenging protocols
based on ‘capping and tagging’ protecting groups,3
multienzyme loaded beads for sugar nucleotide
regeneration4 and computer-assisted planning of solu-
tion syntheses.5
of oligodeoxysaccharides and therefrom derived glyco-
conjugates using thioglycosides and polymer-supported
haloate(I) complexes 1 and 2 (Scheme 1). As is shown,
these new polymer-supported reagents are highly thio-
philic. They are prepared in analogy to related
reagents9 as is described in Scheme 2 by oxidative
ligand transfer of the mobile ligands in [bis(trifluoroace-
toxy)iodo]benzene 4 or [hydroxy(tosyloxy)iodo]benzene
5,10 often referred to as the Koser reagent, onto poly-
mer-bound iodide 3.
A solution-phase technique of general importance is the
utilization of polymer-supported reagents and catalysts6
because work-up is minimized to the point that only
filtration is necessary. The activation of glycosyl bro-
mides with silver ions that are immobilized on a solid-
phase was first studied by Paulsen and Lockhoff7 and
later by Capillon et al.8 Recently, we disclosed the
preparation of 2-deoxyglycosides by employing poly-
mer-attached silyltriflate as activating agent for the
corresponding 2-deoxygenated glycosyl acetates.3 In
this communication, we describe the facile preparation
After washing with dry dichloromethane, these new
functionalized polymers can be stored at −20°C for
weeks. Polymer-bound iodide 3 is obtained by treat-
ment of anionic exchange resin IRA-400 or IRA-900
(chloride form) with an excess of an aqueous solution
of HI (3N).
The key step of this project is the glycosidation step.
We employed thioglycosides 6 and 7 as glycosyl donors
which were activated by functionalized polymers 1 and
Scheme 1.
* Corresponding author. Tel.: +49(0)511/762-4613; fax: +49(0)511/
762-3011; e-mail: andreas.kirschning@oci.uni-hannover.de
Scheme 2.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02708-9

638
J. Jaunzems et al. / Tetrahedron Letters 44 (2003) 637–639
2 in the presence of various alcohols (Scheme 3 and
Table 1). The two iodate(I)-complexes 1 and 2 show
differences in reactivity towards thioglycosides.11 While
in the presence of bis-trifluoroacetate 1 thioglycosides
are instantaneously consumed in dichloromethane,
reagent 2 reacts substantially slower (40°C, 24 h). With
both reagents the glycosidation products are not
formed immediately. TLC-analysis revealed rapid for-
mation of a new more polar compound which vanished
as time proceeded while the glycosidation products
appeared. Early work-up allowed us to isolate the
corresponding pyranoses which presumably are the
hydrolysis products of the glycosyl trifluoracetates and
glycosyl tosylates, respectively, or the corresponding
iodine (III) species arising from the reaction of the
iodate(I)-anion and the oxonium cation.
Table 1. Polymer-assisted glycosidation of 2-deoxythio-
glycosides
The reaction is terminated after 2–3 h by addition of
Amberlyst A-21 8 which scavenged trifluoroacetic acid
and toluenesulfonic acid, respectively. After filtration
and concentration the crude product was treated with
polymer-bound borohydride (BER) 11 in iso-propanol
at rt for 12 h. We found that these conditions efficiently
scavenge thiophenol and diphenyldisulfide 9 (Scheme
4).
Thus, the target glycosides were isolated as mixtures of
a/b-anomers and free of disulfide 912 if reagent 1 served
as activating agent (Schemes 3 and 4). This scavenging
system is so effective because iso-propanol is a solvent
which reacts only very sluggishly with borohydride
exchange resin 11.13 Therefore, it is able to reduce
diphenyldisulfide 9 which is followed by the scavenging
of the nucleophilic thiophenol which presumably results
in the formation of resin 12 (Scheme 4). In contrast to
this observation, polymer-bound haloate(I) complex 2
yielded sulfoxide 1014 as byproduct which could not
efficiently be removed by this procedure.
The glycosidation protocol favours a-glycosides when
arabino-configured 2-deoxythioglycosides are employ-
ed. However, the stereoselectivity of the process is
moderate when arabino-configured 2-deoxythioglyco-
sides are employed. In close proximity, this result is
independent of the a/b-ratio of the thioglycoside 6
employed. In contrast, ribo-configured thioglycosides
Scheme 3.

J. Jaunzems et al. / Tetrahedron Letters 44 (2003) 637–639
639
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Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A.
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Polym. Bull. 1985, 13, 185–192.
Scheme 4.
only furnish a-configured glycosidation products in
good to excellent yield. These observations are in accor-
dance with conventional solution-phase glycosidations
of 2-deoxythioglycosides when no stereodirecting group
is present at C-2.15,16
9. (a) Sourkouni-Argirusi, G.; Kirschning, A. Org. Lett.
2000, 2, 3781–3784; (b) Monenschein, H.; Sourkouni-
Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning,
A. Org. Lett. 1999, 1, 2101–2104; (c) Kirschning, A.;
Monenschein, H.; Schmeck, C. Angew. Chem. 1999, 111,
2720–2722; Angew. Chem., Int. Ed. 1999, 38, 2594–2596.
10. Koser, G. F. Aldrichim. Acta 2001, 34, 89–102.
In conclusion, we developed a polymer-assisted solu-
tion-phase approach to 2-deoxyoligosaccharides and
glycoconjugates which uses thioglycosides as glycosyl
donors. For this purpose we developed a new set of
thiophilic reagents and a scavenging protocol which can
be utilized to quantitatively remove disulfides from
solution. Tedious work-up and product isolation are
reduced to a minimum. Hence, this synthetic strategy
has the potential for the automated synthesis of
oligosaccharides in solution.
11. We screened for thiophilicity among a wide range of
−
polymer-bound haloate(I) complexes such as I(OAc)2
,
Br(OAc)2−, Br(O2CCF3)2−, as well reagent mixtures like
Br(OAc)2−/TMSOTf, and I(OAc)2−/TMSOTf which
failed to promote glycosidation.
12. General procedure for the glycosidation of thioglycosides
using polymer-bound reagents 1 and 2 followed by seques-
tration of diphenyldisulfides: To a solution of thiogly-
coside (1 equiv.) in absolute dichloromethane (50
mL×mmol−1) at rt were added the glycosyl acceptor (1.0
equiv.) and resins 1 or 2 (1–3 equiv.; 2.5 mmol×g−1 based
on original loading of commercial resin). The reaction
mixture was shaken at rt or at 40°C (refer to Table 1) 2–4
h at 300 rpm under light protection. The reaction was
monitored by tlc and was terminated by addition of
Amberlyst A-21 8 (3 equiv.; 11 mequiv.×g−1 for dry
resin). Shaking was continued for 30 minutes. After
filtration, the resins were washed with CH2Cl2 and the
combined filtrates were concentrated under reduced pres-
sure to yield the desired glycoside along with diphenyl-
disulfide. The crude material was taken up in iPrOH (30
mL×mmol−1) and borohydride exchange resin (1 g×
mmol−1; 3 mmol×g−1 loading) was added. The reaction
mixture was shaken overnight at rt, filtered and concen-
trated under reduced pressure to yield the pure gly-
cosides. Isolation of each anomeric isomer requires
column chromatography on silica gel.
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft (SFB 416) and the Fonds der Chemischen
Industrie. This project is part of the joint initiative
‘Biologisch aktive Naturstoffe-Chemische Diversita¨t’ at
the University of Hannover. We thank Dr. G. Jas
(CHELONA GmbH, Potsdam) for helpful discussions.
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