Glycosyldisulfides: A new class of solution and solid phase glycosyl donors

Article abstract of DOI:10.1039/b008734n

Mixed glycosyl disulfides are not only glycomimetics but also glycosyl donors that may be readily constructed in either armed ether-protected or disarmed ester-protected and in soluble or solid-supported forms from corresponding glycosyl methanethiosulfonates and used in the glycosylation of a variety of representative acceptors.

Full text of DOI:10.1039/b008734n

Glycosyldisulfides: a new class of solution and solid phase glycosyl donors†‡
Benjamin G. Davis,* Sarah J. Ward and Phillip M. Rendle
Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK.
E-mail: Ben.Davis@durham.ac.uk
Received (in Liverpool, UK) 24th October 2000, Accepted 22nd November 2000
First published as an Advance Article on the web 8th January 2001
Mixed glycosyl disulfides are not only glycomimetics but also
glycosyl donors that may be readily constructed in either
armed ether-protected or disarmed ester-protected and in
soluble or solid-supported forms from corresponding glyco-
syl methanethiosulfonates and used in the glycosylation of a
variety of representative acceptors.
Scheme 1
Oligosaccharides and glycopeptides are essential tools for the
investigation of the enormous variety of biological functions
that require specific carbohydrate-containing structures.1 Fur-
prepared a representative range of glycosyl disulfides 2a–e
(Scheme 1) in which the structure of the coupling thiol 4 was
thermore, their potential as therapeutic agents is clear.2 As a
result, the formation of the glycosidic linkage continues to be a
varied. Thus, addition of ethanethiol 4a to equimolar glucoMTS
dominant theme in carbohydrate chemistry.3 Yet despite the
3a14 gave ethyl glucosyl disulfide 2a† in an excellent 96%
development of many elegant strategies, there is still no
generally efficient and stereoselective method available. To this
end, a number of glycosyl donor systems have been developed
in which differences in their anomeric leaving groups have an
often critical effect upon reactivity. Of the variety of glycosyl
donor systems available, thioglycosides 1 have proved one of
yield. Similarly, more complex dipeptide glucosyl disulfide
2b15 (62% yield), as a potential glycopeptide mimic, or
galactosyl glucosyl disulfide 2c (60% yield), as a potential
trehalose analogue, were also prepared in fair yield simply by
reaction of the appropriate thiol 4b,c, respectively, with 3a. It
should be noted that in all cases the b anomeric stereochemistry
of the glucoMTS was preserved in the product disulfides. This
also demonstrated the compatibility of this method with
partially-, 4b, or even un-protected, 4c, thiols. To investigate the
effect of protecting groups in the glucoMTS 3, we prepared
perbenzylated glucoMTS 3b, which also reacted smoothly with
the most popular.4 Strategies for tuning their reactivity,
including armed/disarmed5 donors, active/latent donors6 or the
use of bulky leaving groups,7 have culminated in elegant one-
pot glycosylation systems.8
ethanethiol to give 2d (78% yield).16
Having demonstrated the efficient synthesis of several
different glucosyl disulfides 2a–d, we chose ethyl glycosyl
disulfides 2a,d as model systems in which to investigate their
utility as glycosyl donors with the representative selection of
glycosyl acceptors 5a–c (Scheme 2). As Table 1 shows,
glucosyl disulfide 2a allowed the successful preparation of
simple 6a, disaccharide 6b17 and glycopeptide 6c18 O-gluco-
sides. In all three cases exclusive b-stereoselectivity was
observed. However, consistent with the disarmed and peracety-
lated nature of 2a, moderate yields and acetyl migration side-
products19 were obtained under a variety of conditions. The
disarmed nature of 2a was further confirmed by the lack of
reactivity with I2 but the efficient conversion of 2a to
acetobromoglucose 7 using IBr.20 With the aim of improving
efficiencies, the activation of armed perbenzylated glucosyl
disulfide 2d was investigated next. We were delighted to find
that under the optimal conditions elucidated for the activation of
2a (NIS, TESOTf, CH2Cl2), 2d rapidly and smoothly21 gave
methyl glucoside 8a in an excellent 90% yield. Furthermore,
reaction of 2d with more hindered acceptors 5b,c gave good
yields of disaccharide 8b22 and glycopeptide 8c23 O-glucosides,
respectively.
With the goal of extending the scope of glycosyl donor
reagents with sulfur at the anomeric centre, we have examined
the utility of glycosyl disulfides 2. These appeared attractive for
several reasons: (i) the mixed disulfide linkage is a flexible one
that may be cleaved for ready aglycon adjustment in reactivity
tuning methods.9 (ii) If used as a linker in solid-supported
glycosylations, the anomeric mixed disulfide linkage would
allow bidirectional (reductive or hydrolytic) cleavage, that
would be of great advantage in both the analysis and use of solid
supported glycosylation systems. (iii) The coordination of a
potential thiophile by both sulfur atoms may offer enhanced
reactivity over single sulfur thioglycoside systems.10
Remarkably, despite these positive indications and the high
utility of thioglycosides 1, the use of glycosyl disulfides 2 as
glycosyl donors in O-glycoside bond formation is unexplored.11
This neglect of glycosyl disulfides may in part be due to the lack
of efficiency in existing syntheses.12 We therefore set ourselves
the goals of (a) developing efficient and general methods for the
construction of glycosyl disulfides and (b) exploring their utility
as glycosyl donors in O-glycoside formation.
Methanethiosulfonate (MTS) reagents allow the rapid and
efficient formation of mixed disulfides.13 We have previously
demonstrated the utility of glycosyl methanethiosulfonates in
the site-selective glycosylation or proteins.14 In order to test
fully the efficiency and scope of their use as reagents we
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b0/b008734n/
‡ Some of this work was presented at a joint meeting of the RSC
Carbohydrate and Bioorganic groups, Warwick, July 6 2000 and at the 20th
International Carbohydrate Symposium, Hamburg, August 30, 2000.
Scheme 2
DOI: 10.1039/b008734n
Chem. Commun., 2001, 189–190
This journal is © The Royal Society of Chemistry 2001
189

Table 1 Results of glycosylation reactions using dithioglycosides 2 as
donors
funding and the EPSRC for a quota studentship (S. J. W.), and
access to the Mass Spectrometry Service at Swansea and the
Chemical Database Service at Daresbury.
Reac-
tion
time/h
Accep- Pro-
tor
Donor Conditionsa
duct Yields (%)b
Notes and references
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2d
2d
2d
2e
NIS, reflux
NIS, TfOH
24
22
24
4.5
6
2
168
30 min
15 min 5a
24 5c
40 min 5b
1
1.5
4
5b
5b
5b
5b
5b
5b
5b
—
6b
6b
6b
6b
6b
6b
—
7
6a
6c
8b
8a
8c
8a
32c (b only)
26c (b only)
2c (b only)
30c (b only)
16c (b only)
36c (b only)
—
82 (a only)
24c (b only)
34c (b only)
75 (9+11 a+b)
90 (9+15 a+b)
73d (1+1 a+b)
67e (1+2 a+b)
1 A. Varki, Glycobiology, 1993, 3, 97; R. A. Dwek, Chem. Rev., 1996, 96,
683; B. G. Davis, J. Chem. Soc., Perkin Trans. 1, 1999, 3215.
2 J. C. McAuliffe and O. Hindsgaul, Chem. Ind., 1997, 170; B. G. Davis,
Chem. Ind., 2000, 134; K. M. Koeller and C.-H. Wong, Nature
Biotechnol., 2000, 18, 835.
3 H. Paulsen, Angew. Chem., Int. Ed. Engl., 1982, 21, 155; K. Toshima
and K. Tatsuta, Chem. Rev., 1993, 93, 1503; G. J. Boons, Contemp. Org.
Synth., 1996, 3, 173; G. J. Boons, Tetrahedron, 1996, 52, 1095; B. G.
Davis, J. Chem. Soc., Perkin Trans. 1, 2000, 2137.
4 P. J. Garegg, Adv. Carbohydr. Chem. Biochem., 1997, 52, 179.
5 D. R. Mootoo, P. Konradsson, U. Udodong and B. Fraser-Reid, J. Am.
Chem. Soc., 1988, 110, 5583; G. J. Boons, P. Grice, R. Leslie, S. V. Ley
and L. L. Yeung, Tetrahedron Lett., 1993, 34, 8523.
NIS, TfOH, CH3CN
NIS, TMSOTf
NIS, TMSOTf, CH3CN
NIS, TESOTf
I2
IBr
NIS, TESOTf
NIS, TESOTf
NIS, TESOTf, 0 °C
NIS, TESOTf 0 °C
NIS, TESOTf, 0 °C
NIS, TESOTf
5a
5c
5a
a All reactions at rt in CH2Cl2 unless otherwise stated. b All yields are for
isolated products. c See ref. 19. d See ref. 23. e Yield over two steps:
mercaptomethylpolystyrene 4e with 3b then glycosylation.
6 R. Roy, F. O. Andersson and M. Letellier, Tetrahedron Lett., 1992, 33,
6053.
7 G. J. Boons, R. Geurtsen and D. Holmes, Tetrahedron Lett., 1995, 36,
6325.
8 S. V. Ley and H. W. M. Priepke, Angew. Chem., Int. Ed. Engl., 1994, 33,
2292; P. Grice, S. V. Ley, J. Pietruszka, H. M. I. Osborn, H. W. M.
Priepke and S. L. Warriner, Chem. Eur. J., 1997, 3, 431; Z. Y. Zhang,
I. R. Ollmann, X. S. Ye, R. Wischnat, T. Baasov and C. H. Wong, J. Am.
Chem. Soc., 1999, 121, 734; X. S. Ye and C.-H. Wong, J. Org. Chem.,
2000, 65, 2410.
9 Advantageously, 1-thiohexoses do not mutatrotate in basic or neutral
conditions [see W. Schneider and H. Leonhardt, Ber. Dtsch. Chem.
Ges., 1929, 62, 1384] and in glycosyl disulfides the aglycon may be
exchanged without loss of anomeric configuration.
10 For enhanced reactivity of disulfides as Lewis bases see H. Böhme and
H.-P. Steudel, Justus Liebigs Ann. Chem., 1969, 730, 121. Since
thio(sulfenyl) halides are more stable than corresponding sulfenyl
halides (see ref. 11), halonium activation preequilibrium followed by
glycosyl cation formation via a late transition state of significant product
character would lead to enhanced reactivity. Glycosylthio(sulfonium)
intermediates are implicated in thioglycoside activation: F. Dasgupta
and P. J. Garegg, Carbohydr. Res., 1990, 202, 225.
To test the applicability of glycosyl disulfides to solid-
supported glycosylation strategies we used mercaptomethylpo-
lystyrene 4e as a suitable thiolfunctionalized support (Scheme
3). Such was the reactivity of 3b that even with solid-supported
thiol 4e reaction proceeded rapidly (1 h) to give solid-supported
glycosyl disulfide 2e.24 The cleavage of 2e as a representative
disulfide-linked glycoside from the support in a bidirectional
manner was then demonstrated. Firstly, a small portion of 2e
was taken and treated with tributylphosphine to yield configura-
tionally stable tetrabenzyl 1-thio-b- -glucose 9. The potential
D
ability to retune 9 in a latent/active manner to create a glycosyl
donor bearing an alternative aglycon (in this case bearing a
methyl) was demonstrated by smooth conversion into 1025
using methyl methanethiosulfonate. This also showed the
release of solid-supported glycosyl disulfide glycosyl donor 2e
from the resin in the form of a solution phase glycosyl donor 10,
thereby demonstrating the potential of the resin as a platform for
the creation of solution-phase donors. Next, the ability of 2e to
act as a solid-supported glycosyl donor was clearly demon-
strated by activation with NIS, TESOTf in the presence of
glycosyl acceptor 5a to yield methyl glycoside 8a in a good
overall yield (67% over 2 steps). This is also a traceless
cleavage method that installs reducing end functionality.
In summary, we have demonstrated the ready and efficient
preparation of a wide range of glycosyl disulfides using
differently protected glycosyl methanethiosulfonates. Fur-
thermore, we have shown for the first time that glycosyl
disulfides may be used as efficient glycosyl donors in both
solution- and solid-phase systems for the preparation of O-
glycosides including disaccharides and glycopeptides. The
disulfide linkage offers enhanced utility in aglycone alteration,
use as a linker to solid supports and higher activation rates, the
full potential of which is the subject of current investigations.
We thank Dr L. Oates, Mr J. P. Marston for technical
assistance, the Mitzutani Foundation for Glycoscience for
11 For one example of N-glycoside formation see: M. Hürzeler, B. Bernet
and A. Vasella, Helv. Chim. Acta, 1992, 75, 557.
12 Large excess of aglycon thiol under oxidising conditions allows
glycosyl disulfide synthesis. Also see G. Hummel and O. Hindsgaul,
Angew. Chem., Int. Engl., 1999, 38, 1782. Unfortunately, these methods
are not compatible with the efficient use of sensitive or scarce thiols or
with solid supported thiols, respectively.
13 R. Wynn and F. M. Richards, Methods Enzymol., 1995, 201, 351.
14 B. G. Davis, R. C. Lloyd and J. B. Jones, J. Org. Chem., 1998, 63, 9614;
B. G. Davis and J. Bryan Jones, Synlett, 1999, 1495; B. G. Davis,
M. A. T. Maughan, M. P. Green, A. Ullman and J. B. Jones,
Tetrahedron: Asymmetry, 2000, 11, 245.
15 We are exploring such peptide glycosyl disulfide systems in intra-
molecular glycosylations: details will be published in due course.
16 A 10+1 mixture of 3b with its a-anomer also gave exclusively pure b-
linked 2d and recovered MTS enriched in the a-anomer. We are
investigating the nature of this apparently stereospecific coupling.
17 K. Freudenberg, A. Noë and E. Knopf, Chem. Ber., 1927, 60, 238.
18 M. G. Vafina, V. A. Derevitskaya and N. K. Kochetkov, Bull. Acad. Sci.
USSR Div. Chem. Sci. (Engl. Transl.), 1965, 1777.
19 Mass balance of 1,3,4,6-tetra-O-acetyl-a-D-glucose and acetylated
acceptor indicated successful activation of donor but subsequent acetyl
migration. See R. U. Lemieux and A. R. Morgan, Can. J. Chem., 1965,
43, 2190; T. Nukada, A. Berces, M. Z. Zgierski and D. M. Whitfield,
J. Am. Chem. Soc., 1998, 120, 13291.
20 K. P. R. Kartha and R. A. Field, Tetrahedron Lett., 1997, 38, 8233.
21 2d is in fact more rapid than the corresponding ethyl thioglucoside. We
are currently investigating other reactivity ratios.
22 R. J. Ferrier, R. W. Hay and N. Vethaviyasar, Carbohydr. Res., 1973,
27, 55.
23 J. M. Lacombe, A. A. Pavia and J. M. Rocheville, Can. J. Chem., 1981,
59, 473. N-glucosylated succinimide (21%) was also isolated.
24 Ellman’s reagent showed lack of thiol: G. L. Ellman, K. D. Courtney, V.
Andres and R. M. Featherstone, Biochem. Pharmacol., 1961, 7, 88.
25 M. Hürzeler, B. Bernet and A. Vasella, Helv. Chim Acta, 1993, 76,
995.
Scheme 3 Reagents and conditions: i, Et3N, CH2Cl2; ii, PBu3, CH2Cl2; iii,
MeSSO2Me, Et3N, CH2Cl2; iv, MeOH, CH2Cl2, NIS, TESOTf.
190
Chem. Commun., 2001, 189–190