Ortho-Alkynylphenyl thioglycosides as a new type of glycosylation donors under the catalysis of Au(I) complexes

Article abstract of DOI:10.1016/j.tetlet.2012.07.059

ortho-Alkynylphenyl thioglycosides, prepared readily via Sonagashira coupling of ortho-bromophenyl thioglycosides with alkynes, could undergo glycosidation effectively under the catalysis of a gold(I) complex.

Full text of DOI:10.1016/j.tetlet.2012.07.059

Tetrahedron Letters 53 (2012) 5231–5234
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ortho-Alkynylphenyl thioglycosides as a new type of glycosylation donors
under the catalysis of Au(I) complexes
⇑
Fei Yang, Qiaoling Wang, Biao Yu
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
ortho-Alkynylphenyl thioglycosides, prepared readily via Sonagashira coupling of ortho-bromophenyl
thioglycosides with alkynes, could undergo glycosidation effectively under the catalysis of a gold(I)
complex.
Received 8 June 2012
Revised 6 July 2012
Accepted 13 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Gold(I) catalyst
Glycosylation
Thioglycoside
ortho-Alkynylphenyl thioglycoside
Orthoester
New glycosylation methods are still in great demand to tackle
the synthesis of complex oligosaccharides and glycoconjugates in
efficient and economical manners.1 Recently, C–C triple bond, in-
stalled in the anomeric leaving group, has been employed as a trig-
ger for glycosylation.2–5 Especially, we disclosed that glycosyl
ortho-alkynylbenzoates were excellent glycosylation donors under
the catalysis of a gold(I) complex.4 This new protocol has shown
great advantages in the glycosylation of substrates susceptible to
acid and electrophiles.5 On the other hand, thioglycosides have
been used as one of the most versatile types of donors in glycosyl-
ation, because they are sufficiently stable to allow various protect-
ing group manipulations while they can be activated effectively to
undergo glycosidation in the presence of many thiophilic re-
agents.6 Nevertheless, the requirement of a stoichiometric amount
of the electrophilic reagents as promoters turns out to be a major
drawback. Thus, we envision ortho-alkynylphenyl thioglycosides
as privileged new donors, providing they could undergo glycosida-
tion under the mild gold(I)-catalyzed conditions while remain the
stability of thioglycosides. Herein we report the preliminary results
on the preparation and donor properties of ortho-alkynylphenyl
thioglycosides.
from the corresponding glycosyl acetates with ortho-bromo-thio-
phenol in the presence of BF3ÁEt2O, or from glycosyl bromides in
the presence of K2CO3 in acetone as reported.8
The glycosidic coupling reactions of perbenzyl ortho-hexynyl-
phenyl thioglycoside 2a with cholesterol 3a were firstly examined
in the presence of a variety of the gold(I) complexes. As shown
in Table 1, with PPh3AuOTf or [Btz-Au-PPh3]OTf as the catalyst
(0.1 equiv), the reaction of 2a (1.2 equiv) and 3a (1.0 equiv) in the
presence of 4 Å molecular sieves in dry CH2Cl2 proceeded smoothly,
providing the desired glycoside 4 in >90% yields within 30 min (en-
tries 3 and 4). However, similar reactions with PPh3AuNTf2 or
PPh3AuSbF6 as the catalyst led to the coupled glycoside 4 in only
moderate yields, in that C-glycoside 59 was isolated unexpectedly
in 30% and 46% yields, respectively (entries 1 and 2). The formation
of 5 could be explained by a [1,3]-sigmatropic rearrangement of a
benzothiophene sulfonium ion intermediate (Fig. 1).10
With [Btz-Au-PPh3]OTf as the catalyst, the coupling of ortho-
hexynylphenyl thioglycoside 2a with 1,2;3,4-di-O-isopropyli-
dene-
lar conditions provided the corresponding glycosides 6 and 7 in
excellent yields (Table 2 entries 1 and 2). Expectedly, no /b selec-
a-D-galactopyranoside (3b) and n-pentenol (3c) under simi-
a
ortho-Alkynylphenyl thioglycosides 2a–c were synthesized
conveniently via Sonagashira coupling of ortho-bromophenyl
thioglycosides 1a–c with 1-hexyne in high yields (Scheme 1).7
ortho-Bromophenyl thioglycosides 1a–c were readily prepared
tivity was attained in the absence of a neighboring participating
group (in donor 2a). With peracetyl ortho-hexynylphenyl thiog-
lucopyranoside 2b as the donor, the reactions with 3a–c under
similar conditions, however, led to a mixture of the corresponding
b-glycoside and orthoester in favor of the latter (entries 3–5). The
coupling of ortho-hexynylphenyl 3,4,6-tri-O-acetyl-2-deoxy-1-
⇑
Corresponding author. Fax: +86 21 64166128.
E-mail address: byu@mail.sioc.ac.cn (B. Yu).
thio-b-D-glucopyranoside 2c with cholesterol 3a led to the desired
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.059

5232
F. Yang et al. / Tetrahedron Letters 53 (2012) 5231–5234
nBu
Br
O
O
(PPh3)2PdCl2, CuI, PPh3,
S
S
S
+
nBu
RO
RO
i-Pr2NH, DMF, 60oC, 24 h
1a-c
2a-c
nBu
nBu
nBu
OAc
O
OBn
OAc
O
O
AcO
AcO
AcO
AcO
BnO
S
S
BnO
OBn
OAc
2a (83%)
2b (84%)
2c (99%)
Scheme 1. Preparation of ortho-hexynylphenyl thioglycosides 2a–c.
Table 1
Coupling of ortho-hexynylphenyl thioglycoside 2a with cholesterol 3a under the catalysis of Au(I) complexes
OBn
O
BnO
BnO
O
2a (1.2 equiv)
OBn
4
Au(I) (0.1 equiv),
4A MS, CH2Cl2, rt, 30 min.
HO
nBu
3a (1.0 equiv)
BnO
BnO
S
O
BnO
OBn
5
Entry
Au(I) complex
4 (Yield;
a
/b ratioa)
5 (Yield; a
/b ratioa)
1
2
3
4
PPh3AuNTf2
PPh3AuSbF6
PPh3AuOTf
66% (1:1)
48% (1:1)
95% (1:1)
90% (1:1)
30% (1:1)
46% (1:1)
Trace
[Btz-Au-PPh3]OTf
Trace
a
The
a
/b ratio was determined by isolated yields. Btz = benzotriazole.
nBu
O
OTf
S
O
PGO
PGO
ROH
V
II
O
OR
PGO
1,3-σ
or
nBu
nBu
AuL
O
S
O
PGO
AuL
S
PGO
O
O
HOTf
I
III
OR
nBu
LAu(I)
-OTf
nBu
O
S
S
PGO
H
IV
Figure 1. Mechanistic rational for the present glycosidic coupling of ortho-hexynylphenyl thioglycosides with alcohols under the catalysis of [Btz-Au-PPh3]OTf.
glycoside 14 nearly quantitatively, albeit in moderate
ity (entry 6).
A mechanistic rational for the present glycosylation reaction is
depicted in Figure 1. Thus, activation of the C–C triple bond
positioned in the ortho-alkynylphenyl thioglycoside with a gold(I)
a
/b selectiv-
complex leads to the formation of glycosyl benzothiophene sulfo-
nium ion I. Departure of benzothiophene-3-yl-gold(I) complex III
from I leaves behind the glycosyl oxocarbenium ion II, which can un-
dergo glycosidation or orthoester formation.11 Protonolysis of the
Au–C bond in III regenerates the Au(I) catalyst;12 the consumption

F. Yang et al. / Tetrahedron Letters 53 (2012) 5231–5234
5233
Table 2
Glycosidic coupling of ortho-hexynylphenyl thioglycosides (2a–c) with alcohols (3a–c) under the catalysis of [Btz-Au-PPh3]OTfa
nBu
O
OR
PGO
ROH (3a-c; 1.0 equiv)
O
or
S
PGO
[Btz-Au-PPh3]OTf (0.1eq),
4A MS, CH2Cl2, rt
O
O
PGO
2a-c (1.2 equiv)
O
6-14
OR
O
O
OBn
O
OBn
O
OAc
O
O
BnO
BnO
O
BnO
BnO
O
AcO
AcO
O
OBn
OBn
6
OAc
O
O
8
7
OAc
O
OAc
O
O
O
OAc
O
AcO
AcO
O
AcO
AcO
AcO
AcO
O
O
O
O
OAc
OAc
O
O
O
10
9
11
OAc
O
OAc
O
OAc
O
O
O
AcO
AcO
AcO
AcO
O
AcO
O
O
O
O
O
AcO
O
O
O
O
12
14
13
Product
Entry
Donor
Acceptor
Time
Yield (%)
Ratio (
a
/b)
1
2
3
4
5
6
2a
2a
2b
2b
2b
2c
3b
3c
3a
3b
3c
3a
6
7
30 min
30 min
30 min
30 min
30 min
2 h
96
96
99
99
99
99
1:1.5c
1:1.2c
0:1
8/11 = 7:92b
9/12 = 11:78c
10/13 = 9:90c
14
0:1
0:1
2.9:1c
a
For a typical procedure: To a stirred mixture of thioglucoside 2a (86 mg, 0.12 mmol), 1,2;3,4-di-O-isopropylidene-
a-D-galactopyranoside 3b (26 mg, 0.10 mmol), and 4Å
MS in CH2Cl2 (2 mL) at rt was added [Btz-Au-PPh3]OTf (7 mg, 0.01 mmol). After stirring at rt for 0.5 h (as monitored by TLC), the mixture was filtered through a Celite and
concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc 8:1) to provide glycoside 6 (75 mg, 96%,
a
/b 1:1.5).
b
The ratio was determined by isolated yields.
c
The ratio was determined by 1H NMR spectroscopic measurement of the crude products.
4. (a) Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604–3608; (b) Li, Y.; Yang,
X.; Liu, Y.; Zhu, C.; Yang, Y.; Yu, B. Chem. Eur. J. 2010, 16, 1871–1882; (c) Yang,
Y.; Li, Y.; Yu, B. Tetrahedron Lett. 2010, 51, 1504–1507; (d) Zhu, Y.; Yu, B. Angew.
Chem., Int. Ed. 2011, 50, 8329–8332; (e) Ma, Y.; Lian, G.; Li, Y.; Yu, B. Chem.
Commun. 2011, 47, 7515–7517.
5. (a) Yang, Y.; Li, Y.; Yu, B. J. Am. Chem. Soc. 2009, 131, 12076–12077; (b) Li, Y.; Yu,
B. Chem. Commun. 2010, 46, 6060–6062; (c) Yang, W.; Sun, J.; Lu, W.; Li, Y.;
Shan, L.; Han, W.; Zhang, W.-D.; Yu, B. J. Org. Chem. 2010, 75, 6879–6888; (d)
Zhang, Q.; Sun, J.; Zhu, Y.; Zhang, F.; Yu, B. Angew. Chem., Int. Ed. 2011, 50, 4933–
4936; (e) Li, Y.; Sun, J.; Yu, B. Org. Lett. 2011, 13, 5508–5511; (f) Liao, J.; Sun, J.;
Niu, Y.; Yu, B. Tetrahedron Lett. 2011, 52, 3075–3078.
of the proton (from alcohol ROH) ensures the inherent neutral
conditions for the reaction.4d Alternatively, [1,3]-sigmatropic rear-
rangement of the glycosyl benzothiophene sulfonium intermediate
I followed by protodeauration leads to the benzothiophene 3C-gly-
coside (e.g., 5).10
In summary, we have shown that ortho-alkynylphenyl thiogly-
cosides can be prepared easily and can be employed as glycosyl do-
nors for glycosidation under the catalysis of [Btz-Au-PPh3]OTf or
Ph3PAuOTf. The scope and applications of this new glycosylation
protocol is a subject of further studies.
6. Fügedi, P. In The Organic Chemistry of Sugars; Levy, D. E., Fügedi, P., Eds.; CRC
Press: Boca Raton, 2006; pp 89–179.
7. A general procedure for the preparation of ortho-hexynylphenyl thioglycosides.
A
mixture of 1a (356 mg, 0.5 mmol), (PPh3)2PdCl2 (70 mg, 0.1 mmol), CuI
Acknowledgments
(19 mg, 0.1 mmol), PPh3 (52 mg, 0.2 mmol), and i-Pr2NH (2 mL) in DMF (4 mL),
after carefully degassed, was stirred for 30 min under N2 at room temperature
before 1-hexyne (0.3 mL, 2.5 mmol) was introduced. After stirring at 60 °C for
24 h, the resulting mixture was diluted with CH2Cl2. The organic phase was
washed with saturated NH4Cl and saturated NaHCO3, respectively, and was
then dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (petroleum
ether/EtOAc 15:1) to afford 2a (295 mg, 83%) as a yellow solid: 1H NMR
(400 MHz, CDCl3) d 7.70–7.56 (m, 1H), 7.45–7.14 (m, 21H), 7.09 (dd, J = 5.6,
3.6 Hz, 2H), 4.94 (dd, J = 14.2, 10.4 Hz, 2H), 4.84 (dd, J = 10.4, 4.8 Hz, 3H), 4.70
(d, J = 10.0 Hz, 1H), 4.64–4.47 (m, 3H), 3.85–3.77 (m, 1H), 3.78–3.51 (m, 5H),
2.39 (t, J = 7.0 Hz, 2H), 1.59–1.39 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 138.6, 138.4, 138.2, 138.1, 137.7, 132.5, 128.8, 128.6, 128.6,
128.5, 128.3, 128.1, 127.9, 127.83, 127.80, 127.7, 126.0, 124.2, 97.3, 86.8, 86.0,
81.1, 79.2, 78.6, 77.9, 76.0, 75.6, 75.2, 73.6, 69.2, 30.8, 22.2, 19.5, 13.7; HR-
This work was financially supported by the Ministry of Science
and Technology of China (2012ZX09502-002) and the National
Natural Science Foundation of China (20932009 and 20921091).
References and notes
1. Yu, B.; Sun, J.; Yang, X. Acc. Chem. Res. 2012. http://dx.doi.org/10.1021/
ar200296m.
2. Imagawa, H.; Kinoshita, A.; Fukuyama, T.; Yamamoto, H.; Nishizawa, M.
Tetrahedron Lett. 2006, 47, 4729–4731.
3. (a) Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620–9621; (b)
Sureshkumar, G.; Hotha, S. Tetrahedron Lett. 2007, 48, 6564–6568; (c)
Kayastha, A. K.; Hotha, S. Chem. Commun. 2012. http://dx.doi.org/10.1039/
C2CC32649C.
ESIMS (m/z) calcd for
C
46H48O5S [M+Na]+ 735.3115, found 735.3124.
Compound 2b: 1H NMR (400 MHz, CDCl3) d 7.48 (d, J = 7.6 Hz, 1H), 7.39 (d,
J = 7.2 Hz, 1H), 7.25–7.13 (m, 2H), 5.26 (t, J = 9.2 Hz, 1H), 5.11 (t, J = 9.6 Hz, 2H),

5234
F. Yang et al. / Tetrahedron Letters 53 (2012) 5231–5234
4.93 (d, J = 10.2 Hz, 1H), 4.25 (dd, J = 12.2, 5.6 Hz, 1H), 4.14 (d, J = 12.2 Hz, 1H),
9. Compound 5–b: 1H NMR (400 MHz, CDCl3) d 8.10 (bs, 1H), 7.76 (d, J = 8.0 Hz,
1H), 7.44–6.98 (m, 20H), 6.94–6.85 (m, 2H), 5.02–4.87 (m, 3H), 4.76–4.57 (m,
3H), 4.51 (d, J = 12.0 Hz, 1H), 4.26 (d, J = 10.4 Hz, 1H), 4.15–3.75 (m, 5H), 3.65
(dd, J = 26.8, 10.0 Hz, 2H), 3.07–2.89 (m, 1H), 2.78 (bs, 1H), 1.74–1.60 (m, 2H),
1.45–1.32 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); HR-ESIMS (m/z) calcd for C46H48O5S
3.83–3.70 (m, 1H), 2.45 (t, J = 7.0 Hz, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H),
2.01 (s, 3H), 1.67–1.56 (m, 2H), 1.51 (dt, J = 14.7, 7.3 Hz, 2H), 0.96 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 170.7, 170.3, 169.5, 169.3, 135.6, 132.9,
130.1, 128.2, 127.1, 125.6, 97.4, 84.9, 78.4, 75.9, 74.1, 70.0, 68.5, 62.43, 30.8,
22.2, 20.83, 20.79, 20.73, 20.71, 19.5, 13.7; HR-ESIMS (m/z) calcd for C26H32O9S
[M+Na]+ 543.1659, found 543.1673. Compound 2c–b: 1H NMR (400 MHz,
CDCl3) d 7.49 (dd, J = 7.8, 1.2 Hz, 1H), 7.39 (dd, J = 7.4, 1.6 Hz, 1H), 7.24–7.14 (m,
2H), 5.07–4.98 (m, 3H), 4.25 (dd, J = 12.2, 5.8 Hz, 1H), 4.12 (dd, J = 12.1, 2.4 Hz,
1H), 3.71 (ddd, J = 9.6, 5.6, 2.4 Hz, 1H), 2.53 (ddd, J = 12.8, 5.2, 2.0 Hz, 1H), 2.47
(t, J = 7.0 Hz, 2H), 2.10–2.02 (m, 9H), 1.96 (dd, J = 18.3, 6.4 Hz, 1H), 1.61 (ddd,
J = 13.8, 9.2, 4.8 Hz, 3H), 1.57–1.45 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 170.8, 170.4, 169.9, 136.2, 132.8, 129.9, 128.1, 126.9, 125.2,
97.3, 80.9, 78.5, 76.1, 71.9, 69.1, 62.9, 36.3, 30.8, 22.1, 21.0, 20.89, 20.86, 19.4,
[M+Na]+ 735.3115, found 735.3110. Compound 5– 1H NMR (400 MHz, CDCl3)
a:
d 8.00–7.89 (m, 1H), 7.78–7.69 (m, 1H), 7.41-7.17 (m, 18H), 7.15–7.05 (m, 4H),
6.72 (d, J = 7.2 Hz, 2H), 5.50 (d, J = 2.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.63 (d,
J = 11.4 Hz, 1H), 4.60–4.50 (m, 3H), 4.44 (d, J = 12.0 Hz, 1H), 4.28–4.18 (m, 1H),
4.15–4.05 (m, 2H), 4.00–3.92 (m, 2H), 3.78 (d, J = 3.2 Hz, 2H), 3.70 (t, J = 2.6 Hz,
1H), 2.91 (dt, J = 15.4, 7.8 Hz, 1H), 2.78 (dt, J = 15.2, 7.8 Hz, 1H), 1.67–1.48 (m,
2H), 1.351.25 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
143.7, 140.0, 138.7, 138.6, 138.3, 138.2, 137.7, 128.6, 128.5, 128.4, 128.23,
128.17, 128.12, 128.03, 127.95, 127.8, 127.63, 127.57, 124.2, 123.7, 123.3,
121.7, 82.6, 80.8, 76.6, 74.3, 73.6, 72.9, 72.7, 71.3, 70.3, 34.1, 29.1, 22.8, 14.0;
HR-ESIMS (m/z) calcd for C46H48O5S [M+Na]+ 735.3115, found 735.3100.
10. (a) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 4473–
4475; (b) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett. 2008, 10,
2649–2651.
13.7. Compound 2c–a:
1H NMR (400 MHz, CDCl3) d 7.52 (dd, J = 7.8, 1.2 Hz, 1H),
7.40 (dd, J = 7.6, 1.6 Hz, 1H), 7.24–7.14 (m, 2H), 5.85 (d, J = 5.6 Hz, 1H), 5.38
(ddd, J = 11.6, 9.2, 5.4 Hz, 1H), 5.03 (t, J = 9.6 Hz, 1H), 4.53 (ddd, J = 10.1, 4.8,
2.1 Hz, 1H), 4.32 (dd, J = 12.4, 4.8 Hz, 1H), 3.96 (dd, J = 12.4, 2.0 Hz, 1H), 2.48
(dd, J = 13.6, 6.6 Hz, 3H), 2.27 (ddd, J = 13.6, 12.0, 6.0 Hz, 1H), 2.14–1.96 (m,
11H), 1.70–1.59 (m, 2H), 1.57–1.46 (m, 3H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 170.7, 170.1, 170.0, 136.1, 132.9, 130.5, 128.2, 126.9, 125.8,
96.8, 81.9, 78.7, 69.7, 69.5, 69.0, 62.3, 35.5, 30.8, 22.1, 21.0, 20.8, 19.4, 13.7.
8. Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett. 2003, 5, 455–458.
11. Crich, D. Acc. Chem. Res. 2010, 43, 1144–1153.
12. Benzothiophene IV: 1H NMR (400 MHz, CDCl3) d 7.76 (d, J = 8.0 Hz,1H),7.65(d,
J = 8.0 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 6.99 (s, 1H), 2.90
(t, J = 7.4 Hz, 1H), 1.73 (q, J = 14.8, 7.2 Hz, 2H), 1.40 (m, 2H), 0.95(t, J = 7.6 Hz,
3H).