Highly stereoselective synthesis of 2,3-unsaturated thioglycopyranosides employing molecular iodine

Article abstract of DOI:10.1055/s-0029-1218722

Molecular iodine has been utilized for the first time for the thioglycosidation of d-glycals with various thiols to afford the corresponding 2,3-unsaturated thioglycosides in high yields. In the case of tri-O-acetyl-d-glucal, the -anomer was obtained exclusively. The use of readily available iodine makes this method quite simple, more convenient, and practical. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218722

PAPER
1617
Highly Stereoselective Synthesis of 2,3-Unsaturated Thioglycopyranosides
Employing Molecular Iodine
Stereoselective
Sy
nthesis of
s
2,3-Unsat
i
urate
d
Thiogl
V
ycopyranoside
s
. Subba Reddy,*a Ch. Divyavani,a,b Jhillu S. Yadava
a
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: basireddy@iict.res.in
b
IICT – An Associate Institution of the University of Hyderabad, Hyderabad 500007, India
Received 29 January 2010; revised 4 February 2010
mild Lewis acidity associated with iodine enhanced its us-
age in organic synthesis to perform several organic trans-
formations using stoichiometric levels to catalytic
amounts. Owing to advantages associated with this eco-
Abstract: Molecular iodine has been utilized for the first time for
the thioglycosidation of D-glycals with various thiols to afford the
corresponding 2,3-unsaturated thioglycosides in high yields. In the
case of tri-O-acetyl-D-glucal, the a-anomer was obtained exclusive-
ly. The use of readily available iodine makes this method quite sim- friendly catalyst, molecular iodine has been explored as a
powerful reagent in organic synthesis.9
ple, more convenient, and practical.
Key words: glycals, iodine, thioglycosides, thia-Ferrier rearrange-
ment
In continuation of our interest on the use of molecular io-
dine for various organic transformations,10 we herein re-
port an efficient and practical method for the
thiaglycosidation of glycals with thiols in dichlo-
Thioglycosides are important chiral building blocks for
the synthesis of various biologically active natural prod-
ucts.1 Thioglycosides are used as glycosyl donors as they
are stable under mild acidic or basic conditions and can be
selectively activated by thiophilic reagents.2 They are usu-
ally prepared by the reaction of glycals with thiols in the
presence of acid catalysts. The acid-catalyzed allylic rear-
rangement of glycals in the presence of alcohols or thiols
is known as Ferrier rearrangement, which is widely used
to prepare 2,3-unsaturated glycosides.3 The reaction, as
originally reported by Ferrier, involves intermediacy of a
cyclic allylic oxocarbenium ion to which the nucleophile
adds preferentially in quasi-axial orientation. Conse-
quently, there have been some reports on the preparation
of thioglycosides using Lewis acids such as SnCl4,4
BF3·OEt2,5 LiBF4,6 and Sc(OTf)3.7 However, many of
these reagents are corrosive, moisture sensitive, and are
required in stoichiometric amounts. Use of these reagents
also lead to poor regioselectivity4,5 and hence low yields
due to the formation of mixture of products containing 3-
thioglycals4 and 1,3-dithioadducts.5
romethane using a catalytic amount of molecular iodine
under mild conditions. Accordingly, treatment of tri-O-
acetyl-D-glucal 1 with thiophenol (2) in the presence of 5
mol% of molecular iodine gave the 1-phenylthio-2,3-un-
saturated glycoside 3a in 85% yield (Scheme 1).
Similarly, various aryl and alkyl thiols reacted well with
tri-O-acetyl-D-glucal to furnish the aryl and alkyl 2,3-un-
saturated thioglycosides in high yields. It is of interest to
note that a-anomer was exclusively obtained in this reac-
tion (Table 1, entries b–g). In the case of propane-1,3-
dithiol, monothioglycoside was obtained instead of
dithioglycoside (Table 1, entry g). The reaction is highly
stereoselective affording a-anomer exclusively with tri-
acetyl glucal (Table 1, entries a–g). However, thiogly-
cosidation of 3,4,6-tri-O-methyl-, 3,4,6-tri-O-benzyl-,
and 3,4,6-tri-O-allyl-D-glucal with thiols gave the prod-
ucts in good yields, but with low selectivity when com-
pared to acylated analogues. The predominant formation
of a-anomer in the thiaglycosidation must arise from the
thermodynamic anomeric effect.11 The amount of the a-
anomer increased with long reaction time because the
configuration at the anomeric position isomerizes due to
the exposure of the product to the acidic conditions. The
ratio of a and b-anomers was determined on the basis of
Recently, molecular iodine has gained importance as a
low-cost, nontoxic, and readily available catalyst for var-
ious organic transformations affording the corresponding
products with high selectivity in excellent yields.8 The
1
integrated ratios of anomeric hydrogens in the H NMR
O
S
SH
O
I2 (5 mol%)
CH2Cl2, r.t.
AcO
AcO
AcO
+
AcO
OAc
1
2
3a
Scheme 1 Reaction between glucal 1 and thiophenol (2)
SYNTHESIS 2010, No. 10, pp 1617–1620
x
x.
x
x
.
2
0
1
0
Advanced online publication: 06.04.2010
DOI: 10.1055/s-0029-1218722; Art ID: Z01710SS
© Georg Thieme Verlag Stuttgart · New York

1618
B. V. S. Reddy et al.
PAPER
spectrum of the product and also by isolation of pure iso- literature. The results are summarized in Table 1. The
mers on column chromatography. The configuration of scope and generality of the reaction is illustrated with re-
the products was assigned by comparison of their spectral spect to various thiols and glycals. This method offers sig-
data with authentic compounds.4 The spectroscopic data nificant advantages such as high yields, short reaction
of the products was identical with the data reported in the times, high a-selectivity, and mild conditions over classi-
Table 1 Iodine-Catalyzed Thioglycosidation of Glycals
Entry Glycal
Thiol
Product
Time (min) Yield (%)a Ratio of a/b anomersb
O
S
AcO
O
SH
AcO
AcO
a
20
85
–
AcO
OAc
O
O
O
O
S
S
S
S
S
SH
AcO
AcO
b
20
15
15
15
20
20
80
90
85
89
80
71
–
–
–
–
–
–
SH
AcO
AcO
c
d
e
f
Cl
Cl
SH
AcO
AcO
AcO
AcO
SH
O
O
AcO
AcO
SH
SH
S
AcO
AcO
g
SH
HS
O
S
MeO
O
O
SH
MeO
MeO
h
25
25
30
30
80
83
70
75
9:1
9:1
4:1
4:1
MeO
OMe
S
SH
MeO
MeO
i
O
O
S
BnO
SH
BnO
BnO
j
BnO
OBn
SH
O
S
BnO
BnO
k
Cl
Cl
O
O
O
S
S
SH
O
O
O
l
25
25
80
82
5:1
5:1
O
O
O
SH
O
m
Cl
Cl
a Yield refers to pure products after chromatography.
b Ratio was determined on the basis of the integrated ratios of the anomeric hydrogens in the 1H NMR spectra and also by isolation of pure
isomers by column chromatography.
Synthesis 2010, No. 10, 1617–1620 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 2,3-Unsaturated Thioglycopyranosides
1619
13C NMR (50 MHz, CDCl3): d = 170.15, 169.78, 133.95, 133.40,
132.96, 129.10, 128.17, 128.13, 83.65, 67.47, 65.01, 62.90, 20.93,
20.73.
cal thia-Ferrier conditions. No 3-thioglycals and 1,3-
dithioadducts were formed under these reaction condi-
tions, which are normally observed with a stoichiometric
amount of either BF3·OEt2 or SnCl4.
ESI-MS: m/z = 356 (M+), 321, 245, 214, 154, 112, 83, 43.
In conclusion, iodine has proved to be an effective catalyst
for the synthesis of thioglycosides from glycals and thiols
by means of thia-Ferrier rearrangement. The method has
advantages of mild reaction conditions, high conversions,
short reaction times, remarkable selectivity, and simple
experimental/workup procedures, which makes it a useful
and alternative process for the synthesis of thioglycosides.
3d
Liquid.
IR (neat): 2928, 2190, 1749, 1646, 1565, 1499, 1451, 1370, 1239,
1052, 809, 780, 656 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59 (m, 1 H), 7.14 (m, 3 H), 6.09–
6.06 (m, 1 H), 5.88–5.82 (m, 1 H), 5.72–5.69 (m, 1 H), 4.42–4.35
(m, 1 H), 4.32–4.23 (m, 1 H), 4.16 (d, J = 2.0 Hz, 1 H), 2.42 (s, 3
H), 2.11 (s, 3 H), 2.03 (s, 3 H).
LC-MS: m/z = 336 (M + Na)+, 359.
Melting points were recorded on a Büchi R-535 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
240-c spectrophotometer using KBr optics. 1H NMR and 13C spec-
tra were recorded on Gemini-200 spectrometer (200 MHz) in
CDCl3 using TMS as internal standard. Mass spectra were recorded
on a Finnigan MAT 1020 mass spectrometer operating at 70 eV.
Column chromatography was performed using E. Merck 100–200
mesh silica gel.
3e
Liquid.
IR (neat): 2925, 2090, 1741, 1641, 1492, 1451, 1370, 1231, 1052,
809, 780 cm–1.
1H NMR (200 MHz, CDCl3 + DMSO-d6): d = 7.35 (d, J = 7.5 Hz,
2 H), 7.08 (d, J = 7.5 Hz, 2 H), 6.01–6.06 (m, 1 H), 5.80–5.84 (m,
1 H), 5.61–5.64 (m, 1 H), 5.30–5.35 (m, 1 H), 4.38– 4.44 (m, 1 H),
4.16–4.27 (m 2 H), 2.34 (s, 3 H), 2.11 (s, 3 H), 2.07 (s, 3 H).
Thioglycoside 3a; Typical Procedure
A mixture of 3,4,6-tri-O-acetyl-D-glucal (1; 272 mg, 1 mmol),
thiophenol (2; 108 mg, 1 mmol), and I2 (20 mg, 5 mol%) in CH2Cl2
(15 mL) was stirred at r.t. for 0.5 h. After complete conversion, as
indicated by TLC, the mixture was diluted with sat. aq Na2S2O3 (10
mL) and extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc–hex-
ane, 2:8) to afford the pure thioglycoside 3a as a solid; yield: 320
mg (85%); mp 58–60 °C.
ESI-MS: m/z = 336 (M + Na)+, 359.
3f
Liquid.
IR (neat): 2958, 2928, 2869, 1744, 1645, 1455, 1370, 1233, 1050,
975, 905, 792 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.96–5.87 (m, 1 H), 5.77–6.72 (m,
1 H), 5.48 (br s, 1 H), 5.33–5.28 (m, 1 H), 4.27–4.11 (m, 3 H), 2.76–
2.56 (m, 2 H), 2.08 (s, 6 H), 1.68–1.58 (m, 2 H), 1.49–1.37 (m, 2 H),
0.94 (t, J = 7.6 Hz, 3 H).
IR (KBr): 3458, 3059, 2926, 1742, 1581, 1475, 1440, 1372, 1232,
1124, 1046, 975, 899, 784, 745 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.52–7.47 (m, 2 H), 7.31–7.24 (m,
3 H), 6.05 (dt, J = 2.4, 10.3 Hz, 1 H), 5.85 (dt, J = 1.5, 10.3 Hz, 1
H), 5.74–5.70 (m, 1 H), 5.37–5.32 (m, 1 H), 4.43 (td, J = 2.4, 6.3
Hz, 1 H), 4.27 (dd, J = 6.3, 11.8 Hz, 2 H), 2.11 (s, 3 H), 2.05 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.6, 170.2, 134.8, 132.6, 129.8,
128.9, 128.7, 128.5, 127.6, 127.1, 83.6, 67.3, 65.4, 63.2, 63.0, 20.9.
ESI-MS: m/z = 345 (M + Na)+.
ESI-MS: m/z = 325 (M + Na)+.
HRMS: m/z calcd for C14H22O5S + Na: 325.1085; found: 325.1088.
3g
Liquid.
IR (neat):2926, 1743, 1649, 1372, 1222, 1103, 1042 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.90 (dt, J = 1.5, 10.1 Hz, 1 H),
5.76 (dt, J = 1.5, 10.1 Hz, 1 H), 5.51–5.47 (m, 1 H), 5.35–5.25 (m,
1 H), 4.25 (t, J = 4.6 Hz, 1 H), 4.19 (dd, J = 3.1, 9.3 Hz, 2 H), 1.95–
1.97 (m, 2 H), 2.88–2.58 (m, 4 H), 2.09 (s, 6 H), 1.27 (t, J = 7.8 Hz,
1 H).
HRMS: m/z calcd for C16H18O5S + Na: 345.0772; found: 345.0762.
3b
Solid.
IR (KBr): 2926, 1744, 1644, 1587, 1500, 1369, 1056, 947, 854, 784,
635 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.60–7.70 (m, 4 H), 7.3–7.40 (m,
3 H), 6.40 (d, J = 6.0 Hz, 1 H), 5.10 (dd, J = 4.5 Hz, 1 H), 4.90 (t,
J = 5.2 Hz, 1 H), 4.30–4.40 (m, 3 H), 4.25 (dt, J = 4.5, 2.2 Hz, 1 H),
2.04 (s, 3 H), 2.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 190.0, 189.7, 148.3, 146.4, 118.1,
100.0, 96.5, 93.5, 84.4, 53.0, 49.1, 40.3, 20.5.
ESI-MS: m/z = 343 (M + Na)+.
HRMS: m/z calcd for C13H20O5S2 + Na: 343.0649; found: 343.0648.
3h
Liquid.
ESI-MS: m/z = 372 (M + Na)+, 395.
IR (neat): 3054, 2962, 2822, 1581, 1472, 1384, 1313, 1193, 1106,
974, 848, 782 cm–1.
3c
Liquid.
1H NMR (200 MHz, CDCl3): d = 7.51–7.45 (m, 2 H), 7.27–7.16 (m,
3 H), 6.02–5.89 (m, 1 H), 5.69–5.65 (m, 1 H), 4.11 (dd, J = 2.2, 4.4
Hz, 1 H), 4.15–4.07 (m, 1 H), 3.90–3.86 (m, 1 H), 3.64–3.58 (m, 2
H), 3.38 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 135.7, 131.2, 128.7, 128.5, 128.2,
127.0, 96.1, 84.0, 81.7, 72.2, 71.5, 69.2, 56.2, 29.7.
IR (neat): 2925, 1743, 1477, 1437, 1231, 1086, 1055, 976, 905, 785,
649 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.40–7.49 (d, J = 8.7 Hz, 2 H),
7.20 (d, J = 8.7 Hz, 2 H), 5.90–6.00 (m, 1 H), 5.83–5.89 (m, 1 H),
5.29–5.37 (m, 1 H), 5.65–5.68 (m, 1 H), 4.39 (q, J = 4.3 Hz, 1 H),
4.22 (d, J = 4.3 Hz, 2 H), 2.11 (s, 3 H), 2.07 (s, 3 H).
ESI-MS: m/z = 289 (M + Na)+.
Synthesis 2010, No. 10, 1617–1620 © Thieme Stuttgart · New York

1620
B. V. S. Reddy et al.
PAPER
HRMS: m/z calcd for C14H18O3S + Na: 289.0874; found: 289.0871.
Acknowledgment
Ch.D. thanks CSIR New Delhi for the award of a fellowship.
3i
Liquid.
IR (neat): 2926, 2822, 1730, 1588, 1463, 1382, 1314, 1193, 1110,
1051, 975, 949, 849, 782, 749, 711, 527 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.51–7.60 (m, 1 H), 7.08–7.13 (m,
3 H), 5.94–6.05 (m, 2 H), 5.68–5.70 (m, 1 H), 4.07–4.13 (q, J = 2.6
Hz, 1 H), 3.93–3.97 (t, J = 1.5 Hz, 1 H), 3.54–3.60 (d, J = 3.7 Hz,
2 H), 3.42 (s, 3 H), 3.30 (s, 3 H), 2.30 (s, 3 H).
References
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ESI-MS: m/z = 280 (M + Na)+, 303.
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3j
Liquid.
IR (neat): 3030, 2919, 2862, 1725, 1645, 1493, 1452, 1371, 1306,
1206, 1179, 1080, 1023, 949, 849, 809, 780, 738, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39 (d, J = 8.3 Hz, 2 H), 6.99–
7.10 (d, J = 8.3 Hz, 2 H), 7.23–7.30 (m, 10 H), 5.95–5.97 (m, 1 H),
5.62–5.63 (m, 1 H), 4.50–4.58 (m, 2 H), 3.75–3.72 (m, 2 H), 2.31
(s, 3 H).
ESI-MS: m/z = 422 (M + H)+, 455.
(8) (a) Yadav, J. S.; Reddy, B. V. S.; Premalatha, K.; Swamy, T.
Tetrahedron Lett. 2005, 46, 2687. (b) Huang, G.; Isobe, M.
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33, 7911.
3k
Liquid.
IR (neat): 2920, 2865, 1763, 1678, 1532, 1521, 1470, 1078, 932,
742, 698, 535 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.48–7.45 (m, 1 H), 7.41 (d,
J = 7.9 Hz, 2 H), 7.3–7.20 (m, 10 H), 7.13 (d, J = 7.9 Hz, 2 H), 5.96
(dt, J = 10.1, 1.4 Hz, 2 H), 5.67–5.60 (m, 1 H), 4.60–4.40 (m, 5 H),
3.71 (d, J = 3.6 Hz, 2 H).
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LC-MS: m/z = 452.5 (M + Na)+, 475.5.
3l
Liquid.
IR (neat): 2924, 2855, 1743, 1646, 1544, 1549, 1458, 1089, 922,
741, 693, 585 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.50–7.30 (m, 2 H), 7.27–7.20 (m,
3 H), 5.91–5.70 (m, 3 H), 5.60 (d, J = 5.1 Hz, 1 H), 5.30–5.10 (m,
3 H), 4.00–3.90 (m, 6 H), 3.70–3.20 (m, 2 H).
LC-MS: m/z = 318 (M + Na)+, 341.
3m
Liquid.
IR (neat): 2958, 2924, 2854, 2362, 1736, 1646, 1459, 1375, 1270,
1081, 996, 922, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48 (d, J = 6.7 Hz, 2 H), 7.23 (d,
J = 6.7 Hz, 2 H), 5.76–6.02 (m, 6 H), 5.63–5.65 (m, 1 H), 5.16–5.30
(m, 4 H), 3.96–4.22 (m, 6 H), 3.60 (d, J = 3.0 Hz, 2 H).
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ESI-MS: m/z = 352 (M + Na)+, 375.
Synthesis 2010, No. 10, 1617–1620 © Thieme Stuttgart · New York