The S-xanthenyl group: Potential for application in the synthesis of thioglycosides

Article abstract of DOI:10.1016/S0040-4039(02)02070-1

The S-xanthenyl (Xan) group was demonstrated to have potential as a convenient protecting group for 1-thiosugars in the synthesis of thioglycosides. Easily introduced by reaction of a 1-thiosugar with 9-hydroxyxanthene in the presence of catalytic TFA, th

Full text of DOI:10.1016/S0040-4039(02)02070-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8503–8505
The S-xanthenyl group: potential for application in the synthesis
of thioglycosides
Robert A. Falconer*
Department of Pharmaceutical & Biological Chemistry, The School of Pharmacy, University of London,
29–39 Brunswick Square, London WC1N 1AX, UK
Received 7 August 2002; revised 10 September 2002; accepted 20 September 2002
Abstract—The S-xanthenyl (Xan) group was demonstrated to have potential as a convenient protecting group for 1-thiosugars in
the synthesis of thioglycosides. Easily introduced by reaction of a 1-thiosugar with 9-hydroxyxanthene in the presence of catalytic
TFA, the S-Xan group is compatible with a wide range of functionalities and protecting groups. © 2002 Elsevier Science Ltd. All
rights reserved.
Thioglycosides are key intermediates for oligosaccha-
ride assembly1 and are of importance in biological
systems due to their increased chemical and enzymatic
stability.2 They are more stable to the action of glycosi-
dases than their O-linked isosteres, making them candi-
dates as enzyme inhibitors,3 and are a potential means
by which to facilitate the delivery of therapeutic
peptides.4
Protection of the thiol group is generally problematic in
organic synthesis.5 Many of the commonly used pro-
tecting groups suffer from the need for strongly basic
conditions during introduction or strongly acidic,
reductive or basic conditions during deprotection. Vari-
ous thiol-protecting groups have been reported,6 for
example the 4-methoxytrityl (Mmt),7 tert-butyl8 and
acetamidomethyl (Acm)9 groups—all commonly used
in solid-phase peptide chemistry. However, these pro-
tecting groups present some limitations. 1-Thiosugars
have been protected using the acetate group, which
presents difficulties in selective deprotection. Other can-
didates include the 9-fluorenylmethyl (Fm) group,10
which requires basic conditions for its introduction, and
the triphenylmethyl (Trt) group,11 which requires strong
acid for its removal. In addition, reactions to introduce
both the Fm and Trt protecting groups were problem-
atic and generally low yielding in our hands. There is
therefore a need for new alternatives.
The synthesis of complex thio-linked oligosaccharides
and glycoconjugates demands a convenient orthogonal
thiol-protecting group. This group should ideally be
easily introduced and removed, and be able to with-
stand conditions commonly employed in the prepara-
tion of thioglycosides. In addition, the increasing
importance of solid-phase methodologies in the synthe-
sis of complex oligosaccharides and glycopeptides,
means compatibility with conventional solid-phase syn-
thesis protocols (e.g. Fmoc) would be a significant
advantage.
The recently reported S-9H-xanthen-9-yl (Xan) pro-
tecting group,12 used as a temporary cysteine S-protect-
ing group in the synthesis of a-conotoxin,13 has been
successfully applied here for thiol protection in thiogly-
coside synthesis. This represents
a
considerable
improvement over existing options. It is easily intro-
duced under mild conditions and can be selectively
removed in the presence of a wide range of hydroxyl
protecting groups. Another significant advantage is that
it can be introduced cleanly in quantitative yield.14
Figure 1. Introduction of the S-xanthenyl group.
The Xan group is conveniently introduced by reaction
of the 1-thiosugar with 9-hydroxyxanthene, in the pres-
ence of a catalytic quantity of trifluoroacetic acid
* Tel.:
+44-20-7753-5883;
fax:
+44-20-7753-5964;
e-mail:
robert.falconer@ulsop.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02070-1

8504
R. A. Falconer / Tetrahedron Letters 43 (2002) 8503–8505
tides linked via disulphide bridges.13 Application of this
compatibility with standard Fmoc solid-phase synthesis
protocols has provided a potential means by which to
anchor an orthogonally masked thiosugar onto a solid
support.
(TFA), in CH2Cl2 (Fig. 1). 1-Thiosugars (glucose 1a,
galactose 1b, mannose 1c) were synthesised from their
respective bromosugars using the procedure described
for glucose by Horton.15 The reaction proceeds cleanly
to completion within 1 h at room temperature and
isolation of 2a,16 2b and 2c requires only simple
purification.
Glycopeptides in which the sugar component is linked
via an unnatural linkage (e.g. thio-linked glycopeptides)
have potential utility in therapeutic peptide and drug
delivery. In previous work in our laboratory, a glycosyl
azide was immobilised onto a solid support, allowing
extension of the peptide chain via an N-linkage in a
modified Staudinger reaction.18 The versatility of the
S-Xan protecting group is further demonstrated by the
preparation of protected thioglycoside building blocks
9a–c and 10a–c, which were synthesised as a means by
which to anchor the thiosugar to the solid support via
the 6-OH (either directly or via a linker, depending on
the nature of the derivatised resin being used). This
would allow the extension of a peptide chain via a
thioether linkage.
The S-Xan protected derivatives were found to be
stable to a wide variety of reaction conditions, such as
those required to introduce and remove various
hydroxyl-protecting groups (Fig. 2). For example, treat-
ment of 2a with sodium methoxide in methanol led to
the formation of the de-O-acetylated analogue 3a in
excellent yield, with no apparent removal of the S-Xan
group. The reverse, base-catalysed acetylation was simi-
larly high yielding. Benzylation (conversion of 3a to
4a), catalytic hydrogenation (4a to 3a) and benzylidene
acetal formation (3a to 6a) were also successfully
achieved in high yield without loss of the thiol
protection.
Deprotection of the S-Xan group, in for example com-
pound 2a, was easily achieved using 2% TFA in CH2Cl2
to give the free thiol 1a (Fig. 3) in essentially quantita-
tive yield.17
The S-Xan protected derivatives 2a–c were de-O-acetyl-
ated under standard Zemplen conditions. The 6-OH
was then protected with
a tert-butyldimethylsilyl
(TBDMS) group. Introduction of this group to man-
nose derivative 2c proved facile, simply stirring the
S-Xan protected derivative with TBDMS–Cl and imi-
dazole in pyridine at room temperature to give 7c.
Introduction to glucose derivative 2a (Fig. 4) and galac-
tose derivative 2b proved more problematic, requiring
the use of triethylamine and DMAP while refluxing in
1,2-dichloroethane to give 7a and 7b in high yield. This
is most likely to be due to the relative steric inaccessibil-
ity of the primary hydroxyl group in the glucose and
galactose derivatives, where the S-Xan group is in the
b-configuration, as opposed to the predominantly a-
configuration of mannose.19
Barany and co-workers originally used the S-Xan pro-
tecting group as a means by which to de-block cysteine
thiol groups selectively in order to produce cyclic pep-
Following re-O-acetylation (8a–c), the TBDMS group
was removed using tetra-butylammonium fluoride
Figure 2. Reagents and conditions: (i) NaOMe, MeOH, rt,
91%; (ii) Ac2O, pyr, rt, 93%; (iii) NaH, BnBr, DMF, rt, 74%;
(iv) H2, Pd/C, MeOH, rt, 79%; (v) HCOOH, PhCHO, rt,
92%; (vi) Ac2O, pyr, rt, 89%.
Figure 4. Reagents and conditions: (i) NaOMe, MeOH, rt,
91%; (ii) TBDMS–Cl, DMAP, Et3N, ClCH2CH2Cl, reflux,
76%; (iii) Ac2O, pyr, rt, 89%; (iv) TBAF, THF, rt, 93%; (v)
succinic anhydride, DMAP, pyr, rt, 72%.
Figure 3. Reagents and conditions: (i) TFA:Et3SiH:CH2Cl2,
2:1:97, rt, quant.

R. A. Falconer / Tetrahedron Letters 43 (2002) 8503–8505
8505
(TBAF) in THF to give 9a–c, with no apparent loss of
the S-Xan group.
6. (a) Gomez-Martinez, P.; Guibe, F.; Albericio, F. Lett.
Pept. Sci. 2000, 7, 187–194; (b) Zeysing, B.; Gosch, C.;
Terfort, A. Org. Lett. 2000, 2, 1843–1845; (c) Arjona, O.;
Iradier, F.; Medel, R.; Plumet, J. J. Org. Chem. 1999, 64,
6090–6093.
7. Barlos, K.; Gatos, D.; Hatzi, O.; Koch, N.; Koutso-
gianni, S. Int. J. Peptide Protein Res. 1996, 47, 148–153.
8. Eritja, R.; Ziehler-Martin, J. P.; Walker, P. A.; Lee, T.
D.; Legesse, K.; Albericio, F.; Kaplan, B. Tetrahedron
1987, 43, 2675–2680.
9. Veber, D. G.; Milkowski, J. D.; Varga, S. L.; Denkewal-
ter, R. G.; Hirschmann, R. J. Am. Chem. Soc. 1972, 94,
5456–5461.
10. Bodanszky, M.; Bednarek, M. A. Int. J. Peptide Protein
Res. 1982, 20, 434–437.
11. Photaki, I.; Taylor-Papadimitriou, J.; Sakarellos, C.;
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12. Hin, Y.; Barany, G. J. Org. Chem. 1997, 62, 3841–3848.
13. Hargittai, B.; Barany, G. J. Peptide Res. 1999, 54, 468–
479.
14. 2,3,4,6-Tetra-O-acetyl-1-thio-glucopyranose (1 g, 2.75
mmol) was stirred in 4% TFA in abs. CH2Cl2 (50 ml) for
15 min and then treated with 9-hydroxyxanthene (816
mg, 4.12 mmol). After 90 min at rt, the solution was
concentrated, and the residue dissolved in CH2Cl2, (50
ml). The solution was washed with satd NaHCO3 (2×25
ml), dried (MgSO4) and concentrated. Column chro-
matography (hexane:ethyl acetate, 1:2 v/v) gave the pure
product as an oil.
Compounds 9a–c can be directly anchored to a solid
support via the free primary hydroxyl group, or alter-
natively attached through a linker bearing a free car-
boxyl group, such as that formed by reaction with
succinic anhydride to give 10a–c. Once immobilised, the
S-Xan protection is easily removed providing a free
thiol from which to synthesise glycopeptides through a
thioether linkage.20
In conclusion, considering the relative lack of suitable
temporary thiol-protecting groups of use in carbohy-
drate synthesis, the S-Xan protecting group has proved
to be stable to a wide variety of conditions frequently
employed in carbohydrate chemistry, such as acylation,
de-acylation, alkylation, catalytic hydrogenation, acetal
formation, silylation and de-silylation. In addition, it is
compatible with standard solid-phase protocols and can
be selectively cleaved in the presence of commonly used
protecting groups while attached to the solid support.
It is introduced in quantitative yield under mild condi-
tions and can be selectively removed in the presence of
a range of other protecting groups. It is therefore
extremely useful in the synthesis of thio-linked
glycoconjugates.
Acknowledgements
15. Horton, D. Methods Carbohydr. Chem. 1963, 2, 433–437.
16. 1H NMR (500 MHz, assigned using 2D-COSY, CDCl3)
for 2a (gluco): l 1.84, 1.93, 1.98, 2.06 (4×s, 12×H, 4×
OAc), 3.39 (m, 1×H, H-5), 3.85 (m, 1×H, H-6%), 4.14 (m,
1×H, H-6), 4.17 (d, 1×H, H-1, J1,2=9.9 Hz, b), 4.91,
4.99–5.02 (2×m, 3×H, H-2, H-3, H-4), 5.54 (s, 1×H, CH),
7.10–7.14 (m, 4×H, ArH), 7.26–7.31 (m, 2×H, ArH),
7.35–7.40 (m, 2×H, ArH). FAB-MS for 2a (C27H28O10S)
544 m/z (%) 567 [M+Na]+ (100), 677 [M+Cs]+ (40).
17. S-Xan derivative 2a (50 mg, 0.0919 mmol) was stirred in
TFA:Et3SiH:CH2Cl2 (2:1:97, 5 ml) for 60 min at room
temperature. The solution was then concentrated and
purified by column chromatography to give 1a.
18. Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org. Chem.
2000, 65, 5249–5252.
Thanks go to Mr. Mike Cocksedge for MS analysis,
and Dr. Mire Zloh for NMR analyses. This work was
supported by a School of Pharmacy (University of
London) Research and Teaching Fellowship.
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19. 1H NMR (400 MHz, assigned using 2D-COSY, CDCl3)
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tion.