A high-yielding, one-pot preparation of unsymmetrical glycosyl disulfides using 1-chlorobenzotriazole as an in situ trapping/oxidizing agent

Article abstract of DOI:10.1016/j.tetlet.2010.07.176

A high-yielding, one-pot methodology for preparing unsymmetrical glycosyl disulfides derived from sugar, alkyl/aryl or cysteine thiols is reported using 1-chlorobenzotriazole (BtCl) as the oxidant. The highlight of the method is the low temperature of coupling (-78 °C) as well as the in situ trapping of the sulfenyl intermediate, which ensures that no homodimer of R¹SH (R¹SSR¹) is formed. The coupling efficiency is independent of sugar type, thiol position in the sugar, sugar-protecting groups, and the various products serve to illustrate the rapid synthetic access to a number of model systems in glycobiology.

Full text of DOI:10.1016/j.tetlet.2010.07.176

Tetrahedron Letters 51 (2010) 5309–5312
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A high-yielding, one-pot preparation of unsymmetrical glycosyl disulfides
using 1-chlorobenzotriazole as an in situ trapping/oxidizing agent
a
b
Nashia Stellenboom a, Roger Hunter a, , Mino R. Caira , László Szilágyi
*
a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
b Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A high-yielding, one-pot methodology for preparing unsymmetrical glycosyl disulfides derived from
sugar, alkyl/aryl or cysteine thiols is reported using 1-chlorobenzotriazole (BtCl) as the oxidant. The high-
light of the method is the low temperature of coupling (ꢀ78 °C) as well as the in situ trapping of the sul-
fenyl intermediate, which ensures that no homodimer of R1SH (R1SSR1) is formed. The coupling efficiency
is independent of sugar type, thiol position in the sugar, sugar-protecting groups, and the various prod-
ucts serve to illustrate the rapid synthetic access to a number of model systems in glycobiology.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 June 2010
Revised 19 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Keywords:
Unsymmetrical disulfide synthesis
Diglycosyl disulfide
BtCl
Sugar thiols
14
The unsymmetrical disulfide functionality R1SSR2 plays a broad
range of roles in Nature. For instance, it has long been known that
S-allylmercaptocysteine and allicin, which are both present in
freshly crushed garlic are responsible for the anti-infective proper-
ties of this vegetable.1 Similarly, simple aryl–alkyl disulfides were
recently shown to inhibit the growth of methicillin-resistant S. aur-
eus and B. anthracis in vitro.2 Use of the disulfide motif to connect a
glycosyl unit to an alkyl or aryl chain3 or to a different sugar has
been shown to afford a novel class of disaccharide mimic,4 while
some neoglycoproteins represent further examples of interesting
hybrid structures in which glycosyl units are attached to proteins
through S–S linkages.5 Mixed alkyl–glycosyl disulfides have been
proposed as glycosyl donors in oligosaccharide synthesis,6a,b while
phosphine-mediated mono-desulfurization of the disulfide linkage
has been shown to produce thioglycosides.7a–c Diglycosyl disul-
fides have been shown to act as biologically active ligands in hu-
man tumor cell lines,8 while specific binding of oligovalent
aromatic mannosyl disulfide derivatives to the lectin, concanavalin
A has also been recently reported.9
glycosylsulfenyl halogenides,13 glycosyl selenylsulfides, and
alkyl- and arylthiosulfonates,15 via disulfide exchange16 or by using
diethyl azodicarboxylate as a glycosylsulfenyl transfer reagent.17 By
comparison, synthesis of the more challenging unsymmetrical
diglycosyl disulfides was first reported by Szilágyi et al. through
nucleophilic substitution of glycosyl methanethiosulfonates (MTS)
with glycosyl thiolates.4a Pinto and co-workers prepared diglycosyl
disulfides and selenosulfides using a similar approach,4b while
diethyl azodicarboxylate (DEAD), a reagent introduced by Mukaiy-
ma18 for unsymmetrical disulfide synthesis back in the late 1960s,
was demonstrated recently to be suitable for the synthesis of both
symmetrical and unsymmetrical diglycosyl disulfides.19
Recently, we reported20 an efficient one-pot method for synthe-
sizing unsymmetrical disulfides that relied on the interception of a
reactive sulfenyl derivative in situ generated using 1-chlorobenzo-
triazole (BtCl) as the oxidant. Thus, treatment of an alkyl, aryl or
heteroaryl thiol R1SH at ꢀ78 °C in CH2Cl2 with BtCl (1.5 equiv)
together with benzotriazole BtH (1 equiv) to maximize trapping
of the sulfenyl chloride intermediate as described previously20a,c
produces a high yield of R1SBt with virtually no trace of the corre-
sponding homodimer of R1SH (R1SSR1). Substitution of R1SBt with
a second thiol R2SH at around ꢀ20 °C generates the desired unsym-
metrical disulfide R1SSR2 together with small amounts of the
homodimer R2SSR2 from reaction of the excess R2SH with the ex-
cess BtCl used to drive the reaction to full conversion of R1SH,
Scheme 1.
With regard to synthesis, a range of methods is available for
disulfides containing at least one sugar unit. Thus, symmetrical
diglycosyl disulfides can be readily obtained by oxidation of glyco-
syl thiols10 or thiol equivalents such as glycosyldithiocarbamates,11
or via reaction of benzyltriethylammonium tetrathiomolybdate
with glycosyl halides.12 Disulfides containing only one sugar unit
such as glycosyl–alkyl/aryl disulfides can be prepared from
Usually, the heterodisulfide can be separated chromatographi-
cally from the R2SSR2 homodimer by-product. This new method
has been shown to work efficiently with a range of alkyl-, aryl-,
* Corresponding author. Tel.: +27 21 650 2544; fax: +27 21 650 5195.
E-mail address: Roger.Hunter@uct.ac.za (R. Hunter).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.176

5310
N. Stellenboom et al. / Tetrahedron Letters 51 (2010) 5309–5312
R2SH (1.5 equiv), -20 °C, 0.5 h
BtCl (1.5 equiv), BtH (1 equiv),
CH2Cl2, -78 °C, 2 h
R1SH
R1SBt
R1SSR2
(1 equiv)
Scheme 1. General reaction scheme using the BtCl coupling methodology.
R2SH (1.5 equiv), -78 °C, 2 h
BtCl (1.5 equiv), BtH (1 equiv),
CH2Cl2, -78 °C, 2 h
R1SH
R1SBt
R1SSR2
(1 equiv)
Scheme 2. Conditions for efficient coupling of sugar thiols.
and heteroarylthiols20a,c as well as biologically relevant cys-
teine.20b Generally, it was found that the reaction of aliphatic thiols
was fast at ꢀ78 °C, and for the coupling of protected cysteines to
afford unsymmetrical cystine derivatives it was found20c to be
imperative to maintain the temperature at ꢀ78 °C throughout both
the addition steps. In this Letter we report that our new mild meth-
od can also bring about an efficient coupling of different sugar thi-
ols in a one-pot reaction that avoids the use of toxic activating or
chlorinating agents, and in which the only by-product is the
homodimer of R2SH.
Thereafter, a range of sugar thiols21,22 was selected to probe the
influence of the coupling partner, the position of the sulfhydryl
group as well as the hydroxy-protecting group. In each case, the
reaction proceeded smoothly to furnish the desired disulfide in
good to excellent yield, see Table 1.
Entries 13 and 14 revealed that reversing the order of addition
of the sugar thiols in this case had no effect on the overall outcome
of the coupling in terms of yield. In the other entries the order of
addition was not varied, but generally, results demonstrate that a
particular sugar may act nucleophilically toward either the electro-
philic BtCl reagent in the first step or the R1SBt intermediate in the
second (compare entries 5 and 7 for b-GlcSH and 6 and 8 for Gal-
6SH). The only case where the yield was a little depressed (75%)
was the diglycosyl disulfide involving the 4-SH of a protected glu-
cose derivative (entries 13 and 14 in which the order of addition
was varied), where steric considerations may have played a role.
Similarly, the efficiency of the coupling was found to be indepen-
dent of the protecting groups used in terms of electron-withdraw-
ing (acetate) or electron-releasing (ketal), or the C-2 group
(acetoxy or acetamido). However, it was found from the purifica-
tion point of view that each sugar thiol R1SH and R2SH needed to
Initially, for optimization purposes, 2,3,4,6-tetra-O-acetyl-1-
thio-b-D
-glucopyranose21 was reacted with either n-propylthiol
or p-anisylthiol using the conditions described in Scheme 1 to re-
turn a modest yield of coupled heterodisulfide after chromatogra-
phy. Mindful of the temperature aspect alluded to previously in the
case of coupling cysteine derivatives,20c gratifyingly it was found
that reducing the temperature in the second step to ꢀ78 °C and
maintaining it at this temperature for two hours gave excellent
yields (>80%) of the desired product. In the cases involving ali-
phatic or aromatic thiols (entries 1–4), the sugar thiol was added
first. The full conditions are shown in Scheme 2.
Table 1
One-pot diglycosyl disulfide synthesis using BtCla
Entry
1
R1SH
R2SH
R1SSR2
Yieldb
92
AcO
AcO
AcO
HS
OMe
O
O
AcO
AcO
OMe
OMe
AcO
SH
SH
SH
S
S
S
S
S
S
OAc
OAc
O
AcO
HS
AcO
O
AcO
AcO
AcO
2
3
4
5
89
90
89
86
AcO
AcO
OAc
O
OAc
O
AcO
HS
HS
OMe
AcO
AcO
AcO
AcO
NHAc
NHAc
Ac
Ac
AcO
AcO
O
O
O
O
AcO
AcO
AcO
SH
SH
AcO
S
S
AcO
OAc
AcO
AcO
OAc
OAc
O
O
O
O
AcO
AcO
AcO
AcO
S
S
AcO
SH
OAc
OAc
OAc
O
NHAc
AcHN
AcO
O
AcO
O
HS
O
AcO
AcO
AcO
AcO
S
SH
O
O
O
S
O
OAc
OAc
6
88
O
O
O
O

N. Stellenboom et al. / Tetrahedron Letters 51 (2010) 5309–5312
5311
Table 1 (continued)
Entry
R1SH
R2SH
R1SSR2
Yieldb
AcO
AcO
O
AcO
O
O
HS
O
O
AcO
AcO
S
O
AcO
SH
O
O
S
O
NHAc
NHAc
7
89
O
O
O
O
Ac
Ac
O
O
AcO
AcO
HS
O
O
O
O
AcO
AcO
AcO
AcO
O
O
SH
S
O
8
80
O
O
S
O
O
O
OAc
O
OAc
O
AcO
AcO
AcO
AcO
O
O
HS
SH
S
O
O
O
S
OAc
OAc
9
93
80
O
O
O
O
AcO
AcO
Ac
Ac
AcO
AcO
O
O
O
O
O
AcO
AcO
AcO
AcO
AcO
SH
AcHN
10
NHAc
OAc
OAc
S
S
SH
O
OAc
AcO
O
AcO
O
O
O
AcO
AcO
AcO
HS
O
AcO
SH
11
12
S
NHAc
83
88
S
S
O
NHAc
NHBoc
NHBoc
O
AcO
O
AcO
O
O
AcO
AcO
AcO
HS
O
AcO
SH
NHAc
S
NHAc
O
NHCBz
NHCbz
AcO
BnO
AcO
O
O
O
AcO
HS
AcO
AcO
BnO
AcO
SH
AcO
S
O
13
75
75
S
NHAc
NHAc
AcO
AcO
OMe
AcO
OMe
OMe
BnO
AcO
AcO
O
O
O
HS
AcO
AcO
AcO
AcO
AcO
BnO
SH
NHAc
S
O
14
S
NHAc
AcO
AcO
OMe
AcO
a
See Refs. 21,22 for the preparation of the sugar thiols.
Isolated yield after chromatography.
b
have a reasonably different Rf on TLC by virtue of having a different
set of protecting groups (acetate or ketal), or a different C-2 substi-
tuent (OAc vs NHAc). This ensured that the unsymmetrical disul-
fide could be efficiently separated chromatographically from the
homodimer R2SSR2 by-product. Finally, efficient coupling could
be achieved by varying the position of the thiol group (positions
1, 4, and 6) as well as using different sugar configurations (glucose,
mannose, galactose). Coupling was also independent of the thiol
anomeric configuration and in all cases, the thiol group of R1SH
was carried through with retention of configuration into the disul-
fide product as reflected in the product anomeric coupling con-
stants. Cysteine derivatives (entries 11 and 12) could also be
coupled as models for glycopeptide conjugate synthesis. All prod-
ucts gave satisfactory analytical and spectral data, two examples
of which are given.23,24
In conclusion, our BtCl technology, involving a low reaction
temperature, small excess of reagent and with only one of the
homodimers observed as a by-product, offers a much milder
coupling protocol for sugar disulfide synthesis compared to other
methods. The extremely mild conditions of coupling bode

5312
N. Stellenboom et al. / Tetrahedron Letters 51 (2010) 5309–5312
ElOualid, F.; Claridge, T. D. W.; Davis, B. G. Angew. Chem., Int. Ed. 2008, 47,
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well for achieving oligosaccharide coupling via
linkage.
a disulfide
General experimental procedures: To a stirred solution of 1-chlo-
robenzotriazole (0.058 g, 0.375 mmol) and benzotriazole (0.030 g,
0.250 mmol) in CH2Cl2 (3 mL) under N2 at ꢀ78 °C was added drop-
wise a solution of R1SH (0.250 mmol) dissolved in CH2Cl2 (1 mL).
The solution was allowed to stir for 2 h at ꢀ78 °C. R2SH
(0.375 mmol) in CH2Cl2 (1 mL) was then added slowly at ꢀ78 °C
and the solution stirred for a further 2 h. The reaction was
quenched with a solution of Na2S2O3 (0.10 g in 3 mL of H2O).
CH2Cl2 (25 mL) was added together with saturated aq Na2CO3
(10 mL) and the solution stirred rapidly for 20 min. The CH2Cl2
layer was then separated and the aqueous fraction extracted with
CH2Cl2 (2 ꢁ 25 mL). TLC analysis showed that the organic layer
contained no BtH. The combined organic extracts were dried over
anhydrous MgSO4, filtered, and evaporated under reduced pres-
sure. The crude residue was purified by silica gel column chroma-
tography using petroleum ether/EtOAc mixtures to afford the
corresponding unsymmetrical disulfide.
9. Murthy, B. N.; Sinha, S.; Surolia, A.; Jayaraman, N.; Szilágyi, L.; Szabó, I.; Kövér,
K. E. Carbohydr. Res. 2009, 344, 1758–1763.
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11. Huerzeler, M.; Bernet, H.; Vasella, A. Helv. Chim. Acta 1992, 75, 557–588.
12. (a) Prabhu, K. R.; Devan, M.; Chandrasekaran, S. Synlett 2002, 1762–1778; (b)
Sridhar, P. R.; Prabhu, K. R.; Chandrasekaran, S. Eur. J. Org. Chem. 2004, 4809–
4815.
13. (a) Bell, R. H.; Horton, D.; Miller, M. J. Carbohydr. Res. 1969, 9, 201–214; (b)
Hürzeler, M.; Bernet, H.; Vasella, A. Helv. Chim. Acta 1992, 75, 557–588.
14. Gamblin, D. P.; Garnier, P.; van Kasteren, S.; Oldham, N. J.; Fairbanks, A. J.;
Davis, B. G. Angew. Chem., Int. Ed. 2004, 43, 828–833.
15. (a) Gamblin, D. P.; Garnier, P.; Ward, S. J.; Oldham, N. J.; Fairbanks, A. J.; Davis,
B. G. Org. Biomol. Chem. 2003, 1, 3642–3644; (b) Kim, E. J.; Knapp, S.; Hanover, J.
A. J. Am. Chem. Soc. 2007, 129, 14854–14855.
16. McIndoe, W. M.; van Oijen, A. H.; Boons, G. J. Chem. Commun. 1998, 847–848.
17. Hummel, G.; Hindsgaul, O. Angew. Chem., Int. Ed. 1999, 38, 1782–1784.
18. Mukaiyama, T.; Takahashi, K. Tetrahedron Lett. 1968, 9, 5907–5908.
19. Morais, G. R.; Falconer, R. A. Tetrahedron Lett. 2007, 48, 7637–7641.
20. (a) Hunter, R.; Caira, M.; Stellenboom, N. J. Org. Chem. 2006, 71, 8268–8271; (b)
Hunter, R.; Caira, M. R.; Stellenboom, N. Synlett 2008, 252–254; (c) Hunter, R.;
Caira, M. R.; Stellenboom, N. Tetrahedron 2010, 66, 3228–3241.
Acknowledgements
ˇ
ˇ
ˇ
21. Cerny´, M.; Vrkoc, J.; Stanek, J. Collect. Czech. Chem. Commun. 1959, 24, 64–69.
22. R1SH-entry 1: see Ref. 21; R1SH-entry 3: see: Akagi, M.; Haga, M. Chem. Pharm.
Bull. 1961, 9, 360–366; R1SH-entry 4: see: Matta, K. L.; Girotra, R. N.; Barlow, J.
J. Carbohydr. Res. 1975, 43, 101–109; Haque, M. B.; Roberts, B. P.; Tocher, D. A. J.
Chem. Soc., Perkin Trans. 1 1998, 2881–2889; R2SH-entry 6: see: Alho, M. A. M.;
R.H. and M.R.C. thank the University of Cape Town, the Claude
Leon Foundation and the South African National Research Founda-
tion for a Fellowship to N.S. as well as financial support. L.Sz.
thanks NKTH and OTKA (Project Nos. NK-68578 and ZA-20/2008)
for the financial support in Hungary. The help of Ambati Ashok Ku-
mar (Debrecen) with the preparation of the 4- and 6-thiosugar
derivatives is acknowledged.
D’Accorso, N. B.; Thiel, I. M. E. J. Heterocycl. Chem. 1996, 33, 1339–1343; R2SH-
ˇ
ˇ
entry 9: see: Cerny´, M.; Stanek, J.; Pacák, J. Monatsh. Chem. 1963, 94, 267–290;
R2SH-entry 13: see: Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801–805.
23. Entry 9: (0.149 g, 93%) as a clear oil; ½a D20
ꢀ16.0 (c 1.0, CHCl3); IR mmax (CH2Cl2)/
ꢂ
cmꢀ1 1751 (C@O), 1370 (C(CH3)2), 499 (S–S); dH (400 MHz, CDCl3), dashed
assignments refer to the ketal sugar: 1.27 (6H, s, CH3), 1.36 (3H, s, CH3), 1.52
(3H, s, CH3), 1.91 (3H, s, CH3), 2.00 (6H, s, CH3), 2.10 (3H, s, CH3), 2.91 (1H, dd, J
7.6 Hz and 13.5 Hz, H-6’), 3.02 (1H, dd, J 5.8 Hz and 13.5 Hz, H-6’), 3.93 (1H, t, J
6.4 Hz, H-5), 4.07 (3H, m, H-6 and H-5’), 4.21 (1H, d, J 8.0 Hz, H-2’), 4.25 (1H,
dd, J 3.0 and 5.0 Hz, H-4’), 4.58 (2H, m, H-1 and H-3’), 5.01 (1H, dd, J 3.0 Hz and
10.0 Hz, H-3), 5.24 (1H, t, J 10.0 Hz, H-2), 5.36 (1H, d, J 3.0 Hz, H-4), 5.45 (1H, d,
J 5.2 Hz, H-1’); dC (100.58 MHz, CDCl3): 20.3 (CH3), 20.4 (CH3), 20.4 (CH3), 20.5
(CH3), 24.3 (CH3), 24.9 (CH3), 25.8 (CH3), 26.0 (CH3) 39.4 (C-6’), 61.5 (C-6), 66.1
(C-5’), 66.9 (C-2), 67.2 (C-4), 70.4 (C-2’), 70.9 (C-3’), 71.7 (C-4’ and C-3), 74.7 (C-
5), 91.2 (C-1), 96.5 (C-1’), 108.6 (C(CH3)2), 109.1 (C(CH3)2), 169.2 (C@O), 169.7
(C@O), 169.9 (C@O), 170.2 (C@O); HRMS: m/z 661.1626 (M++Na),
References and notes
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C
26H38NaO14S2 requires 661.1601.
24. Entry 12: (0.142 g, 88%) as a colourless solid, mp 183–185 °C (EtOH); ½a D20
ꢂ
ꢀ52.6 (c 1.0, CHCl3); IR mmax (CH2Cl2)/cmꢀ1 3337 (NH), 1744 (C@O), 1694
(C@O), 1660 (C@O), 495 (S–S); dH (400 MHz, CDCl3): 1.22 (3H, t, J 7.2 Hz, CH3),
1.87 (3H, s, CH3), 1.97 (3H, s, CH3), 1.99 (6H, s, CH3), 3.07 (1H, dd, J 7.6 Hz and
13.8 Hz, SCH2), 3.30 (1H, dd, J 4.2 Hz and 13.8 Hz, SCH2), 3.75 (1H, m, H-5), 4.14
(5H, m, H-2, H-6 and OCH2), 4.65 (1H, br s, CHN), 4.73 (1H, d, J 10.4 Hz, H-1),
5.07 (3H, m, Bn and H-4), 5.23 (1H, t, J 9.8 Hz, H-3), 5.72 (1H, d, J 8.0 Hz, NH),
6.04 (1H, d, J 8.8 Hz, NH), 7.28 (5H, m, Ar-H)); dC (100.58 MHz, CDCl3): 14.0
(CH3), 20.5 (CH3), 20.5 (CH3), 20.5 (CH3), 23.0 (CH3), 42.5 (SCH2), 52.5 (C-2),
53.7 (CN), 61.9 (C-6), 62.1 (OCH2), 67.0 (Bn), 68.2 (C-4), 73.4 (C-3), 76.1 (C-5),
89.3 (C-1), 128.0 (Ar), 128.1 (Ar), 128.4 (Ar) 136.2 (Ar), 155.7 (C@O), 169.2
(C@O), 170.2 (C@O), 170.4 (C@O), 170.5 (C@O), 170.7 (C@O); HRMS: m/z
667.1622 (M+Na)+, C27H36NaN2O12S2 requires 667.1607; Found: C, 49.98; H,
5.41; N, 4.07; S, 9.66. C27H36NaN2O12S2 requires C, 50.30; H, 5.63; N, 4.35; S,
9.95.
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Bernardes, G. J. L.; Grayson, E. J.; Thompson, S.; Chalker, J. M.; Errey, J. C.;