cosylation of peracetylated sugars catalyzed by I2/HMDS (60
mol % each) in the presence of MeSSMe or thiols has been
demonstrated.13 So far, only ZrCl4 can mediate thioglyco-
sylation of peracetylated glycosides with complete 1,2-trans
selectivity at 0 °C in stoichiometric sense.14 However, only
a 1:1 mixture of R/â anomers was obtained when the reaction
was carried out at ambient temperature. Therefore, a new
mild, water-tolerant, and stereoselective catalyst to fulfill such
a transformation remains to be explored.
applicable to three different 4- and 2-substituted-benzenethi-
ols (Table 1). In general, the sterically encumbered 2-sub-
Table 1. Effects of Thiol Substrates on the
R-Thioglycosylation of â-Anomer 1 Catalyzed by MoO2Cl2
As part of our ongoing projects by using vanadyl and
oxometallic species in catalyzing C-C and C-X bond
formation,15 asymmetric aerobic oxidative dehydrogenation16
and coupling,17 and photoinitiated DNA cleavage,18 we eval-
uated the feasibility of catalyzing the thioglycosylation event
by using amphoteric and water-tolerant oxometallic species.
Herein we disclose our preliminary finding toward this
end.
R1SH
time, h
product
yield,a %
PhSH
14
16
10
16
10
20
20
8
10
12
64
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
94
90
95
86
94
47
64
88b
81b
76b
71b
68b
71b
64b
4-MeC6H4SH
4-ClC6H4SH
4-MeOC6H4SH
2-NpSH
2-MeOC6H4SH
2-MeC6H4SH
CH3CH2SH
PhCH2SH
c-C6H11SH
t-BuSHc
HS(CH2)3SH
HS(CH2)10CO2Me
HS(CH2)2OTBS
We started out by using penta-O-acetyl-â-D-glucose 1 and
thiophenol (1.3 equiv) as a test thioglycosylation system with
a diverse array of oxometallic species (1-5 mol %) in
optimal solvent CH2Cl2 at ambient temperature. Among 18
different oxometallic species examined,19 MoO2Cl2 (1 mol
%) was found to be the most reactive and efficient catalyst,
leading only to the â-anomer 2a in 88% yield along with
the recovery of the starting R-anomer 1 (7-8%). Some of
the â-anomer 1 is isomerized into R-anomer 1 during the
catalytic conditions, suggesting the involvement of an
oxocarbenium ion intermediate. Notably, no desired product
was obtained when MoCl5 was employed as the catalyst,
indicating the participating role of the oxometallic unit(s) in
MoO2Cl2. Molybdenum species have been recognized as
competent oxidative sulfur-transfer catalysts in episulfide
formation of strained cyclic alkenes and transsulfidation of
isonitriles (RNtC) to isothiocyanates (RNdCdS).20a,b No-
tably, nonoxidative thiol group transfer of the current study
has never been documented.20c,d
8
12
a Isolated yields after chromatographic purification. b 5 mol % of catalyst
was used. c 3 equiv of tert-butylmercaptan was used.
stituted-benzenethiols are less reactive (20 h) and lower
yielding (47-64% yields) than the corresponding 4-substi-
tuted ones (16 h; 86-90% yields). In addition, thiols bearing
electron-donating substituents (e.g., CH3 and OCH3) are less
reactive (16 h) and lower yielding (86-90% yields) than
those (10 h and 94-95% yields) bearing electron-withdraw-
ing substituents (e.g., Cl and benzo-fused 2-Np). Notably,
about 44% and 32% of the isomerized substrate (i.e.,
R-anomer 1) was recovered respectively in the cases of
slower reacting 2-methyl- and 2-methoxybenzenethiols which
are responsible for the lower isolated yields in the products
2f and 2g.
With the optimal thioglycosylation catalyst MoO2Cl2 in
hand, we started to look at the substrate scope with aromatic
and aliphatic thiols of varying steric and electronic demands.
For the given â-anomer 1, the current catalytic protocol is
Four straight alkanethiols of varying steric attributes were
also examined. The rates of catalytic thioglycosylation were
significantly decreased up to a factor of 8 with increasing
(13) Mukhopadhyay, B.; Ravindranathan Kartha, K. P.; Russell, D. A.;
Field, A. J. Org. Chem. 2004, 69, 7758.
(14) (1) Contour, M. O.; Defaye, J.; Iittle, M.; Wong, E. Carbohydr.
Res. 1989, 193,283. (2) Yili, D. Synth. Commun. 1999, 29, 3541.
(15) (a) Chen, C.-T.; Kuo, J.-H.; Ku, C.-H.; Weng, S,-S.; Liu, C.-Y. J.
Org. Chem. 2005, 70, 1328. (b) Chen, C.-T.; Munot, Y. S. J. Org. Chem.
2005, 70, 8625 and references therein.
(16) (a) Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-
T. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3522. (b) Pawar, V. D.; Weng,
S.-S.; Bettigeri, S.; Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128,
6308.
(17) Barhate, N. B.; Chen, C.-T. Org. Lett. 2002, 4, 2529.
(18) Chen, C.-T.; Lin, J.-S.; Kuo, J.-H.; Weng, S.-S.; Cuo, T.-S.; Lin,
Y.-W.; Cheng, C.-C.; Huang, Y.-C.; Yu, J.-K.; Chou, P.-T. Org. Lett. 2004,
6, 4471.
steric demands of the thiols (i.e., Et > PhCH2 > c-C6H11
>
t-Bu). In addition, the chemical yields dropped from 88%
to 71%. Functionalized alkanethiols like 11-mercaptounde-
canoate and 2-tert-butyldimethylsiloxyethanethiol (TBSO-
(CH2)2SH) are also suitable substrates for the â-thioglyco-
sylation, leading to 2m and 2n in satisfactory yields (64-
71%). Notably, monothioglycosylation can be achieved for
dithiols like 1,3-propanedithiol. The expected 2l can be
isolated in 68% yield, thus allowing for subsequent functional
group manipulation at the remaining thiol unit in 2l. Since
all the recovered starting R-anomer 1 may be readily
converted back to the original â-anomer 1 and the catalyst
can be recovered from the aqueous layer, the current catalytic
protocol is unprecedented and meets the standard of green
chemistry.
(19) See the Supporting Information for details.
(20) (a) Prabhu, K. R.; Sivanand, P. S.; Chandrasekaran, S. Angew.
Chem., Int. Ed. 2000, 39, 4316. (b) Adam, W.; Bargon, R. M.; Bosio, S.
G.; Schenk, W. A.; Stalke, D. J. Org. Chem. 2002, 67, 7037. (c) For
reduction, see: Fernandes, A. C.; Fernandes, R.; Rama˜o, C. C.; Roya, B.
Chem. Commun. 2005, 213. (d) For acylation, see: Chen C.-T.; Kuo, J.-
H.; Pawar, V. D.; Munot, Y. S.; Weng S.-S.; Ku, C.-H.; Liu C.-Y. J. Org.
Chem. 2005, 70, 1188.
5634
Org. Lett., Vol. 8, No. 24, 2006