Fast and selective oxidation of thioglycosides to glycosyl sulfoxides using KF/m-CPBA

Article abstract of DOI:10.1016/j.tetlet.2005.09.132

A very fast and selective oxidation of thioglycosides to glycosyl sulfoxides has been achieved using KF/m-CPBA in CH₃CN-H₂O. This protocol has many advantages compared to the currently available methodologies for this transformation

Full text of DOI:10.1016/j.tetlet.2005.09.132

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8113–8116
Fast and selective oxidation of thioglycosides to glycosyl
sulfoxides using KF/m-CPBAq
Geetanjali Agnihotri and Anup Kumar Misra*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226 001, UP, India
Received 11 August 2005; revised 16 September 2005; accepted 21 September 2005
Available online 7 October 2005
Abstract—A very fast and selective oxidation of thioglycosides to glycosyl sulfoxides has been achieved using KF/m-CPBA in
CH3CN–H2O. This protocol has many advantages compared to the currently available methodologies for this transformation in
terms of selectivity, yield, reaction time, control of temperature, etc. The yields obtained were excellent in all cases.
Ó 2005 Elsevier Ltd. All rights reserved.
Selective and oxyfunctionalization of organic sulfides is
a pivotal reaction in many organic syntheses of biologi-
cally active molecules.1 Organic sulfoxides are an impor-
tant class of synthetic intermediates used for C–C
bond formation, and stereocontrolled functional group
transformations.2 In carbohydrate chemistry, the use
of glycosyl sulfoxides as novel glycosyl donors in
oligosaccharide syntheses was introduced by Kahne
et al.3 Currently, glycosyl sulfoxides hold a distinct posi-
tion in synthetic carbohydrate chemistry in synthesizing
oligosaccharides4 and glycoconjugates5 because of the
mild reaction conditions under which they react,6 their
good to excellent anomeric stereo control7 and their
adaptabilities to both solution8 and solid phase synthe-
sis.9 Moreover, the stereochemical outcome of glycosyl-
ation using glycosyl sulfoxides as glycosyl donors is
independent of the configuration of sulfur atom, which
eliminates the need to prepare diastereomerically pure
glycosyl sulfoxide donors for their use in glycosylation
reactions. Apart from being used as glycosyl donors,
they have also been used to generate glycosyl carbanions
for the synthesis of C-glycosides10 and for the prepara-
tion of 2-hydroxy glycals.11 In view of the importance
of glycosyl sulfoxides, several oxidizing agents have been
employed for the selective oxidation of thioglycosides to
the corresponding glycosyl sulfoxides, which include, m-
chloroperbenzoic acid (m-CPBA),3 hydrogen peroxide–
acetic anhydride–SiO2,12 oxone,13 selectfluor,14 magne-
sium monoperoxyphthalate (MMPP),15 and tert-butyl
hydroperoxide.16 In general, the oxidation of thioglyco-
sides to sulfoxides has been achieved most successfully
using m-CPBA. However, this method suffers from a
number of shortcomings including a requirement for
strict control of temperature (below ꢀ38 °C), over-oxi-
dation to sulfone, partial solubility of m-CPBA in
dichloromethane and difficulty in removing the by-prod-
uct (m-chlorobenzoic acid) from the sulfoxide. Other re-
cently developed methods for the selective oxidation of
thioglycosides to glycosyl sulfoxides also have notable
drawbacks such as over-oxidation, requirement of a so-
lid support,12 controlling of temperature and oxidant
and controlled microwave irradiation.15 Therefore, there
is still a need to develop a less stringent selective meth-
odology for the transformation of thioglycosides to gly-
cosyl sulfoxides. As a part of our ongoing program, we
needed to prepare several glycosyl sulfoxides for their
use in various glycosylation reactions towards the syn-
thesis of oligosaccharides. In our hands, the use of
m-CPBA and other oxidizing agents gave a mixture of
glycosyl sulfoxide and sulfone in every case. We noted
a few recent reports, which described an easy conversion
of azides into nitro compounds using HOFÆCH3CN
and the electrophilic oxygen atom of HOFÆCH3CN
Keywords: Glycosyl sulfoxide; Thioglycoside; KF; m-CPBA; Selective;
Fast.
q C.D.R.I Communication No. 6848.
*
Corresponding author. Tel.: +91 522 2612411/18; fax: +91 522
2623938; e-mail: akmisra69@rediffmail.com
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.132

8114
G. Agnihotri, A. K. Misra / Tetrahedron Letters 46 (2005) 8113–8116
was also used for oxidation of sulfides.17 In another
report, KF/m-CPBA complex was successfully
employed for the selective oxidation of indolyl methyl
sulfides to the corresponding sulfoxides, avoiding the
formation of over-oxidized products.18 Earlier, a KF/
m-CPBA complex was successfully employed for the
preparation of glycal epoxides.19 We reasoned that
KF/m-CPBA in CH3CN–H2O could produce KO-
FÆCH3CN, which could selectively oxidize glycosyl
sulfides to the corresponding sulfoxides utilizing the
a
Table 1. Oxidation of thioglycosides to glycosyl sulfoxides using KF/m-CPBA in CH3CN–H2O
Entry
Thioglycosides (1)
Glycosyl sulfoxides (2)
Time (min)
5
Yield (%)a
90
d/rb
1:1
Ref.
12
OAc
OAc
a
AcO
AcO
AcO
AcO
O
O
SPh
SOPh
OAc
OAc
OAc
OAc
OAc
OAc
O
O
b
c
5
5
5
4
92
90
87
92
1:1
—
—
—
—
AcO
BzO
AcO
BzO
SOPh
SOPh
SPh
OAc
OAc
OBz
O
OBz
O
11:9
2.5:1
1:0
BzO
BzO
SPh
OBz
OBz
OBz
OBz
OBz
OBz
O
O
d
e
BzO
AcO
BzO
AcO
SOPh
SOPh
SPh
OBz
O
OBz
O
AcO
AcO
SPh
OAc
OAc
SPh
OBn
SOPh
OBn
O
Me
O
Me
f
2
5
95
85
1:0
1:0
8b
—
OBn
OBn
OBn
OBn
SPh
SOPh
O
O
Me
AcO
Me
AcO
g
AcO
O
AcO
OAc
OAc
Ph
Ph
O
O
O
h
5
88
1:1
—
O
O
AcO
AcO
SPh
SOPh
OAc
OAc
OTBDPS
O
OTBDPS
O
BzO
BzO
BzO
BzO
i
5
3
5
85
95
90
2:1
2:1
2:1
—
—
12
SEt
SOEt
OBz
OBz
O
O
O
O
OBn
OBn
O
O
j
SOPh
SPh
OBn
OAc
OBn
OAc
AcO
AcO
AcO
AcO
O
O
k
SPh
SOPh
NPhth
OAc
NPhth
OAc
O
O
AcO
AcO
AcO
AcO
OAc
OAc
l
5
88
2:1
—
O
O
AcO
AcO
O
O
SPh
SOPh
AcO
AcO
OAc
OAc
a Isolated yield.
b Diastereomeric ratio based on the ration of integration values of anomeric protons in the 1H NMR spectra.

G. Agnihotri, A. K. Misra / Tetrahedron Letters 46 (2005) 8113–8116
8115
electrophilic nature of oxygen atom of KOFÆCH3CN. In
this letter, we disclose our findings on the treatment of
the KF/m-CPBA combination with thioglycosides for
a rapid generation of glycosyl sulfoxides with high selec-
tivity and efficiency (Scheme 1).
syl sulfoxides in oligosaccharide synthesis is currently in
progress.
Acknowledgements
Instrumentation facilities from SAIF, CDRI is grate-
fully acknowledged. G.A. thanks CSIR, New Delhi,
for providing a senior research fellowship. This project
was funded by the Department of Science and Technol-
ogy (DST), New Delhi (SR/FTP/CSA-10/2002), India.
The KF/m-CPBA combination has been employed to
synthesize a series of glycosyl sulfoxides having a wide
range of protecting groups, which are presented in Table
1. In every case, the reaction was exceptionally fast and
exclusive formation of sulfoxide was observed in excel-
lent yield without any trace of sulfone, in a few minutes.
Acid-labile functional groups such as benzylidene acetal,
isopropylidene, TBDPS groups remained intact under
the reaction conditions. The rate of oxidation depends
on the nature of the protecting group linked to C-2.
ꢀArmed sugarsꢁ having an electron-donating group, such
as a benzyl group at C-2 were oxidized at a faster rate
than ꢀdisarmed sugarsꢁ having an electron-withdrawing
group, such as acetyl or benzoyl group at C-2. In most
of the cases, a diastereomeric mixture of sulfoxides
was formed. The diastereomeric ratio was determined
from a comparison of integration value of H-1 in their
1H NMR spectra. It is worth noting that among most
frequently used solvents such as dichloromethane,
dichloroethane, nitromethane, THF, CH3CN used for
this transformation, CH3CN–H2O was found to be the
most effective in producing a high yield and a cleaner
reaction. Since the reaction was carried out in
CH3CN–H2O, there was no need to use anhydrous con-
ditions and m-CPBA was completely soluble in the reac-
tion mixture.
References and notes
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A typical experimental procedure is as follows: To a
solution of KF (117 mg, 2.0 mmol) in CH3CN–H2O
(4.0 ml; v/v 5:1), 70% m-CPBA (345 mg, 2.0 mmol)
was added and the reaction mixture was stirred at 0 °C
for 30 min. To the ice-cooled reaction mixture was
added phenyl 2,3,4,6-tetra-O-acetyl-1-thio-b-D-gluco-
pyranoside (1a; 440 mg, 1.0 mmol) and the mixture
was stirred at 0 °C for the appropriate time as specified
in Table 1. After completion of the reaction, it was
quenched with aq FeSO4 solution and extracted with
CH2Cl2. The organic layer was washed with aq NaH-
CO3 and water successively, dried (Na2SO4) and concen-
trated under reduced pressure. The crude reaction
mixture was purified over SiO2 using hexane–EtOAc
as eluant to furnish pure phenyl 2,3,4,6-tetra-O-acetyl-
1-sulfinyl-b-D-glucopyranoside as a diastereomeric mix-
ture. The ratio of isomers was determined from the inte-
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spectra.20
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In conclusion, fast and exclusive generation of various
glycosyl sulfoxides from the corresponding thioglyco-
sides was achieved using KF/m-CPBA in CH3CN–
H2O. The reaction is highly selective and efficient. Use
of cheap, commonly available reagents, the exception-
ally fast reaction rate, the absence of a need for strict
control of temperature, high selectivity and no forma-
tion of over-oxidized product make this protocol an
attractive alternative to the existing methodologies.
The exploration of the synthetic utility of several glyco-

8116
G. Agnihotri, A. K. Misra / Tetrahedron Letters 46 (2005) 8113–8116
14. Vincent, S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.;
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20. Spectral data of phenyl 2,3,4,6-tetra-O-acetyl-1-sulfinyl-
b-D-glucopyranoside 2a: d/r 1:1; Rf 0.35 (hexane–EtOAc,
25
1:1); ½aꢁD ꢀ43.8 (c 1.6, CHCl3); IR (KBr): 3021, 1754, 1371,
1218, 1044, 766, 669 cmꢀ1; 1H NMR (300 MHz, CDCl3): d
7.66–7.54 (m, 5H, aromatic protons), 5.36–5.21 (m, 2H),
5.03–4.96 (m, 1H), 4.43 (d, J = 9.1 Hz, 0.5H), 4.29 (d,
J = 9.1 Hz, 0.5H), 4.14–4.01 (m, 2H), 3.72–3.69 (m, 0.5H),
3.62–3.59 (m, 0.5H), 2.01, 2.00, 1.96, 1.91 (4s, 12H,
4COCH3); ESI-MS: 479 [M+Na]; Anal. Calcd for
C20H24O10S (456): C, 52.62; 5.30. Found: C, 52.40; H, 5.50.