Diastereoselective thioglycosylation of peracetylated glycosides catalyzed by in situ generated iron(III) iodide from elemental iodine and iron

Article abstract of DOI:10.1016/j.tetlet.2009.07.077

A facile in situ preparation of Fe(III) iodide from cheap, abundant elemental iodine and iron metal served as an efficient catalyst for the thioglycosylation of peracetylated glycosides with various alkyl and aryl mercaptans. Due to neighboring participation, the anomerically pure β-thioglycosides were obtained in good to high yields with exclusive diastereocontrol.

Full text of DOI:10.1016/j.tetlet.2009.07.077

Tetrahedron Letters 50 (2009) 6414–6417
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective thioglycosylation of peracetylated glycosides catalyzed
by in situ generated iron(III) iodide from elemental iodine and iron
*
Shiue-Shien Weng
Department of Chemistry, R.O.C. Military Academy, Kaohsiung, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile in situ preparation of Fe(III) iodide from cheap, abundant elemental iodine and iron metal served
as an efficient catalyst for the thioglycosylation of peracetylated glycosides with various alkyl and aryl
mercaptans. Due to neighboring participation, the anomerically pure b-thioglycosides were obtained in
good to high yields with exclusive diastereocontrol.
Received 7 June 2009
Revised 12 July 2009
Accepted 16 July 2009
Available online 19 July 2009
Ó 2009 Published by Elsevier Ltd.
Carbohydrate derivatives with anomeric-substituted thiol
groups as stable O-glycoside analogues have attracted considerable
attention in a wide array of biological activity studies.1 In addition,
thioglycosides with different substituted pendants have served as
versatile building block core units to facilitate the rapid synthesis
of complex oligosaccharides, known as ‘Programmable One-Pot
Oligosaccharide Synthesis’.2 The Lewis acid-catalyzed thiolysis of
peracetylated saccharides to produce thioglycosides with predom-
inantly 1,2-trans-product has been the most extensively adopted
method for many years.1b Currently available catalysts such as p-
TSA,3a Amberlyst/Amberlite resin,3b perchloric acid–silica,3c TiCl4,4
BF3–Et2O,5 AlCl3,6 ZrCl4,7 SnCl4,8 TMSOTf,9 ZnI2,10 Et3SiH/I2–thio-
urea,11 Me3SiSiMe3/I2,12 and amphoteric MoO2Cl213 have been suc-
cessfully employed, stoichiometrically or substoichiometrically, for
such transformations. In most instances, the cost of the catalyst,
moisture sensitivity, and toxicity issues have restricted their use
in biological or pharmaceutical applications. Hence, a more simple,
efficient, clean, cost-effective, and safe catalyst to replace toxic
and/or precious ones, such as an iron-containing catalyst to effect
catalytic thioglycosylation, remained to be explored.
Being easily accessible, inexpensive, biologically essential, and
abundant on earth, iron catalysts have become popular and attrac-
tive from an environmental and economic point of view for organic
transformations as well as for catalytic reactions.14 In addition,
FeCl3 has also been employed as an efficient catalyst for O-isopro-
pylidenation, acetolysis, acylation, and activation of the anomeric
acetate of carbohydrates in suprastoichiometric use.15 This in-
spired us to initiate an extensive search for a more sustainable iron
catalyst than FeCl3 in order to meet the standard of green chemis-
try. Herein we describe a new economical, efficient, and handy pro-
tocol for thioglycosylation of peracetylated glycosides by using
cheap, easily available, non-toxic iodine, and iron metal.
In order to find the best iron catalyst for thioglycosylation of
peracetylated saccharides, we initiated catalyst screening of vari-
ous Fe(II) and Fe(III) salts in the presence of 1.0 equiv penta-O-
acetyl-b-D-glucopyranose 1 and 1.3 equiv p-toluenethiol in CH2Cl2
at rt for 24 h. The results indicated that the commercial 5 mol %
FeI2 and freshly prepared Fe(OTf)3 had the highest reactivities,
yielding phenyl-2,3,4,6-tetra-O-acetyl-b-D-1-thio-glucopyranoside
1a (Table 1, entries 3 and 10). Notably, the trivalent ferric salts
Table 1
Effects of iron salts on catalytic thioglycosylation of penta-O-acetyl-b-D-glucopyra-
nose and p-toluenethiola
OAc
O
OAc
O
5 mol%Fe(X)n
+
AcO
AcO
AcO
AcO
SH
STol
OAc
CH Cl2, rt,
2
OAc
OAc
1 eq.
1
1a
1.3eq.
Entry
FeXn
Time (h)
Conversiond (%)
Yielde (%)
f
1
2
3
4
5
FeCl2
FeBr2
FeI2
Fe(OAc)2
Fe(OTf)2
FeCl3
24
24
7
—
9
13
24 (48b)
24
43 (52b)
41 (51b)
f
3
33
12
—
24
24
28
6
9
7
FeBr3
24
27
22
8
9
Fe(ClO4)3
Fe(OTs)3
Fe(OTf)3
FeI2 + 1.0 equiv I2
Fe + 1.6 equiv I2
24
24
33
30
27
31
10
11
12
13
14
24 (48b)
0.7 (1c)
0.7 (1c)
24
48 (61b)
45 (57b)
94 (95c)
95 (97c)
>99 (>99c)
>99 (>99c)
f
Fe
I2
0
0
—
f
24
—
a
b
c
d
e
f
All reactions were performed in CH2Cl2 at rt.
20 mol % catalyst was used.
1 mol % catalyst was used.
Determined by 1H NMR analysis of the reaction mixture.
Isolated yield after column chromatography.
Not determined.
* Tel./fax: +886 7 742 9442.
E-mail address: wengss@mail.cma.edu.tw
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.07.077

S.-S. Weng / Tetrahedron Letters 50 (2009) 6414–6417
6415
Table 2
showed the best reactivities and their catalytic efficiency increased
with a decrease in the basicity of the counteranion bearing the iron
(TfOꢀ > TsOꢀ, ClO4ꢀ > Brꢀ > Clꢀ). In contrast, the ferrous salts were
far less reactive than the ferric ones, except FeI2. On the basis of
these results, the best, Fe(OTf)3 and FeI2, were further examined.
Increasing catalyst loading to 20 mol %, thiol amount to 2.0 equiv
and extending the reaction time to 48 h resulted in only 10–12%
improvement in yield (Table 1, entries 3 and 10, parentheses).
Since the trivalent ferric salts were more reactive than the diva-
lent ferrous competitors and FeI2 showed remarkable catalytic effi-
ciency, in situ prepared FeI3 was thus targeted as the catalyst for
thioglycosylation. The FeI3 could easily be prepared by reacting
Fe metal or FeI2 with 1.5 equiv or an equal amount of iodine in
anhydrous CH2Cl2 and served as an excellent catalyst to accelerate
the asymmetric Diels–Alder addition at low temperature.16 Thus,
FeI3 was prepared in situ by stirring 1.0 equiv FeI2 with 1.0 equiv
I2 in CH2Cl2 or by adding 1.6 equiv I2 to 1.0 equiv Fe metal powder
in CH2Cl2 for 4 h until the metal had totally dissolved. Indeed, FeI3
was found in both reaction mixtures as evidenced by the ESI-MS
spectra.17 Furthermore, both reaction mixtures were diluted to
5 mol % and individually employed as catalysts for the thioglycosy-
lation of glucoside 1 (1.0 equiv) in the presence of 1.3 equiv p-tol-
uenethiol in CH2Cl2 at rt under an N2 atmosphere. Surprisingly,
both reactions were completed in 40 min and the glucoside 1
was totally converted into 1a, as evidenced by the 1H NMR spectro-
scopic analyses of the crude reaction mixtures (entries 11 and 12).
Moreover, even with the catalyst loading decreased to 1 mol %, the
reaction was completed in 1 h and no epimerization side product
Effects of thiols on thioglycosylation of penta-O-acetyl-b-D-glucopyranose catalyzed
by 1 mol % of in situ prepared FeI3
a
OAc
O
OAc
O
1 mol%
FeI3
AcO
AcO
AcO
AcO
R1-SH
1.3eq.
+
OAc
SR1
CH2Cl2, rt,
OAc
1 eq.
OAc
1a-n
1
Entry
R1
Time (h)
Product
Yieldd (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3CH2–
PhCH2–
(CH3)2CH–
Cyclohexyl-
tert-Butyl-
CH3C(O)NHCH2CH2–
–(CH2)10CO2Me
Ph–
4-Me–C6H4–
4-MeO–C6H4–
2-Me–C6H4–
4-Cl–C6H4–
12
6
4
6
1b
1c
1d
1e
1f
1g
1h
1i
1a
1j
1k
1l
87
88
81
76
24 (72b)
24
23(27b)
0
12
0.5
1
1 (4)
1 (4)
0.5
0.5
24
74
97
95
62(69c)
44(56c)
95
2-Naphthyl–
4-NO2–C6H4–
1m
1n
98
0
a
All reactions performed in CH2Cl2 at rt.
5 equiv tert-butyl mercaptan was used.
Yield of isolated product after 4 h.
b
c
d
Isolated yield after column chromatography.
lated b-D-galactose 2, D-xylose 3, D-arabinose 4, and furanosyl D-
ribose 8 were reacted with 1.3 equiv benzenethiol and proceeded
smoothly in the presence of freshly prepared 3 mol % FeI3 under
the optimal condition to afford the desired 1,2-trans products
2a (97%), 3a (94%), 4a (96%), and 8a (97%), respectively. The
(penta-O-acetyl-a-D
-glucopyranose) was found in the crude 1H
NMR spectrum. The control reactions also revealed that I2 or metal
Fe did not catalyze thioglycosylation individually. Finally, the gly-
cosyl donor penta-O-acetyl-a-D-glucopyranose 1 with 2-O-acetyl
group cis- orientated to the anomeric leaving acetate did not effect
this transformation even though 20 mol % catalyst was employed
or the reaction time was prolonged, only traces (<5%) of the prod-
uct were observed.
nearly 1 to 1 anomeric mixture of peracetylated
showed low reactivities and the phenyl 2,3,4,6-tetra-O-acetyl-
-1-thio-mannoside 5a was obtained in only 14% yield. Expect-
edly, the additional control reaction of the less reactive -per-
acetylated mannoside 50 failed to produce the corresponding
thioglycoside. The peracetylated b- -2-deoxy-phthalimido- and
D-mannose 5
a-
D
a-D
D
Ultimately, the cheapest and most convenient combination of
1 mol % I2 and metal Fe in CH2Cl2 to generate FeI3 in situ was cho-
sen as the optimized condition for substrate scope investigation.18
Several alkyl and aryl thiols with different electronic and steric de-
mands were then examined (Table 2). In general, the aliphatic mer-
captans were less reactive than the aryl ones (complete reaction in
4–6 h vs 0.5–1 h) but satisfactory yields were obtained for aliphatic
thiols (23–88%). In the case of tert-butyl mercaptan, even when
5.0 equiv thiol was used or the reaction time was prolonged, only
27% yield of product could be generated. Unsurprisingly, the reac-
tivities of the alkyl mercaptans increased with a decrease in the
steric substitution (Et-, Bn- > i-propyl- > cyclohexyl- ꢁ t-butyl-).
Notably, the amide containing N-acetyl cystamine showed no reac-
tivity (Table 2, entry 6). A similar result was found when the reac-
tion was performed in a strong coordination solvent such as
DMF.17 For aryl thiols the reactivity was influenced by the elec-
tronic nature of the substituents, with electron-withdrawing sub-
acetamido-glucosides 6 and 7 were also tested. In one case, the
strong coordination acetamido (–NHAc) group containing 7 re-
mained unreactive and the starting acetamido precursor was to-
tally recovered. In the other case, the weak coordinative
phthalimido-masked (NPhth) glucosides
reactivity under optimal conditions and afforded the phenyl 2-
phthalimido-2-deoxy-b- -1-thio-glucoside 6a with a 74% yield.
The protocol was also applicable to peracetylated b- -disaccha-
6 showed moderate
D
D
rides derived from lactose 9 and maltose 10. The exclusive 1,2-
trans thioglycosides 9a and 10a were obtained in 90–92% yield
within 2 h and the stereochemistry of the 1–40 glycosidic bond re-
mained intact.
In summary, we developed a handy approach for the thiogly-
cosylation of peracetylated saccharides by using an in situ pre-
pared FeI3 catalyst made from cheap iodine and metal iron in
CH2Cl2 solution. The anchimeric assistance mechanism during
the glycosylation process is suggested due to the exclusive 1,2-
trans diastereoselectivity of the products. The current catalytic
protocol offers an alternative variant that is competitive with sev-
eral existing methods in terms of its low cost, operational simplic-
ity, and compatibility with diverse thiols and sugars, which argues
well for its potential application in carbohydrate chemistry.
stituents giving
a
higher yield than electron-donating
substituents. In addition, the reactivity was affected by steric de-
mand, with the yield dropping to 44% when o-toluenethiol was
employed instead of p-toluenethiol (Table 2, compare entries 9
and 11). Although the electron-withdrawing aryl thiols provided
the best efficiency, the most electron-deficient 4-nitro-benzene-
thiol did not show any reactivity. This above disappointing result
can be postulated that an interaction occurred between FeI3 and
nitro group which hindered the ability of the catalyst to participate
in the formation of a glycosidic linkage (Table 2, entry 14).
Acknowledgments
We acknowledge the National Science Council of the Republic of
China for a generous financial support of this research (97-2113-
M-145-001-MY2). We thank Professor Chien-Tien Chen for gener-
ous support of chemicals and discussion.
To expand the substrate scope, a series of peracetylated b-D-
saccharides were further examined with highly reactive, cheap,
and commercially available benzenethiol, Table 3. The peracety-

6416
S.-S. Weng / Tetrahedron Letters 50 (2009) 6414–6417
Table 3
a
Thioglycosylation of peracetylated saccharides and benzenethiol catalyzed by 1 mol % in situ-prepared FeI3
Glycosides
Time
Product
Yieldc (%)
AcO
AcO
AcO
AcO
OAc
O
OAc
O
1
97
OAc
2
SPh
2a
OAc
OAc
O
O
AcO
AcO
AcO
AcO
OAc
3
SPh
1
1
94
96
3a
OAc
OAc
OAc
OAc
AcO
O
O
OAc
4
SPh
4a
5a
AcO
OAc
OAc
OAc
O
OAc
O
AcO
AcO
AcO
α/β =1.1/1
5
24
14 (0b)
AcO
AcO
AcO
OAc
OAc
α/β
>
99/1 5 '
SPh
OAc
O
OAc
O
AcO
AcO
AcO
AcO
SPh
NP1P2
6
74
0
NP1P2
P1 = P2 =C(O)C6H4C(O)
6
7
P1 = P2 =C(O)C 6H4C(O)
6
7
P1= H, P 2 = C(O)CH 3
P1= H, P2 = C(O)CH3
24
O
O
OAc
SPh
AcO
AcO
1
2
2
97
87
90
8
8a
AcO
OAc
AcO
OAc
Ac O
Ac O
OAc
O
OAc
O
OAc
O
OAc
AcO
O
AcO
O
OAc
9a
OAc
SPh
AcO
9
AcO
O
OAc
OAc
OAc
OAc
O
OAc
O
AcO
AcO
OAc
OAc
AcO
AcO
O
AcO
O
O
Ac
O
Ac
O
10a
SPh
O
10
OAc
AcO
O
O
Ac
Ac
a
b
c
All reactions were performed in CH2Cl2 at rt in the presence of 1.3 equiv benzenethiol and 3 mol % FeI3 as catalyst.
-Mannose penta-O-acetate was used.
Isolated yield after column chromatography.
a-D
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.077.
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0.03 mmol) in anhydrous CH2Cl2 solution (2 mL) was added I2 (12.2 mg,
0.048 mmol) at rt under nitrogen atmosphere. The resulting mixture was
stirred for 4 h until the iron powder was totally dissolved. A solution of
3 mmol peracetylated glycoside and 3.9 mmol thiol in 13 mL CH2Cl2 was
added by a cannula and the resulting dark brown mixture was stirred at
ambient temperature for indicated time. The reaction was monitored by
TLC analysis and quenched by adding 10 mL satd NaHCO3 (aq) solution.
The organic layer was separated, dried over MgSO4, and filtered. The crude
product was concentrated under reduced pressure and loaded directly on
top of an eluent-filled silica gel column and purified by flash column
chromatography.
17. See Supplementary data for details.
18. Typical experimental procedure for thioglycosylation of peracetylated
saccharide: To
a solution of iron metal powder (325 mesh, 1.67 mg,