An efficient glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors under the catalysis of Ph3PAuOTf

Article abstract of DOI:10.1016/j.tetlet.2008.04.017

A new and powerful glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors and Ph₃PAuOTf as a promoter is disclosed. The donors are readily available and stable; the glycosidic coupling yields are generally excellent; the promotion system is catalytic, neutral, and orthogonal to the known glycosylation conditions.

Full text of DOI:10.1016/j.tetlet.2008.04.017

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3604–3608
An efficient glycosylation protocol with glycosyl
ortho-alkynylbenzoates as donors under the catalysis of Ph3PAuOTf
Yao Li a, You Yang b, Biao Yu a,*
a State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
b Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
Received 31 March 2008; revised 1 April 2008; accepted 1 April 2008
Available online 6 April 2008
Abstract
A new and powerful glycosylation protocol with glycosyl ortho-alkynylbenzoates as donors and Ph3PAuOTf as a promoter is dis-
closed. The donors are readily available and stable; the glycosidic coupling yields are generally excellent; the promotion system is cat-
alytic, neutral, and orthogonal to the known glycosylation conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Glycosylation; Gold; Catalyst; Glycosides; ortho-Alkynylbenzoates; Ph3PAuOTf
The continuous addition of various glycosylation meth-
ods, especially since 1980s, to the historical Koenigs–Knorr
protocol has enabled the synthesis of oligosaccharides and
glycoconjugates of increasing complexity in unprecedented
effectiveness.1,2 Not only the once formidable glycosylation
problems have been addressed satisfactorily, such as the b-
mannopyranoside synthesis,3 but also the assembly of oli-
gosaccharides and glycoconjugates could be achieved in
an efficient ‘programmable’ manner by employing a set of
the carefully designed glycosyl donors and acceptors,4 such
as the orthogonal glycosylation.5 However, those glycosyl-
ation methods are mostly variants (e.g., variation in pro-
tecting pattern or activating system) of the still limited
types of glycosyl donors with functional groups of dispa-
rate chemical nature at the anomeric position. The major
ones include (1) glycosyl halides, (2) thioglycosides, (3) imi-
dates, (4) phosphate/phosphite derivatives, (5) sulfoxides,
(6) glycals, (7) 1-acyl-, 1-carbonate, and variants, (8) 4-pen-
tenyl glycosides, (9) 1-hydroxyl sugars, (10) orthoesters,
(11) 1,2-anhydrosugars, and (12) glycosyl diazirines.2
Among them only glycosyl imidates and phosphate/phos-
phite derivatives are able to be activated for glycosidation
with a catalytic amount of the promoters.6 Development
of new anomeric leaving groups capable of being activated
(preferably catalytically) under new mechanisms (thus new
glycosylation conditions orthogonal to the present ones)
would raise the glycosidic coupling technique to a new
height, where automated synthesis of oligosaccharides as
efficient as the synthesis of nucleotides and peptides shall
be implemented.7
In fact, no advantageous properties have been disclosed
for glycosyl donors outside the above categories. A recent
trial was the activation of propargyl glycosides with AuCl3
for glycosidation.8a Unfortunately, acyl protected propar-
gyl glycosides failed to glycosidation, and the coupling of
the ‘armed’ propargyl per-benzylglucoside with a slightly
less active acceptor (i.e., cholesterol) led to a low yield
(39%) of the coupled product. Nevertheless, use of the C–
C triple bond as an activating element to trigger the glycos-
idation is novel and could find orthogonal conditions to the
conventional ones.8,9 In addition, recent studies have
shown that activation of C–C triple bonds could be highly
*
Corresponding author. Tel.: +86 21 5492 5131; fax: +86 21 6416 6128.
E-mail address: byu@mail.sioc.ac.cn (B. Yu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.017

Y. Li et al. / Tetrahedron Letters 49 (2008) 3604–3608
3605
O+
HOR
2
O
OR
OP
OP
O
H+
3
4
A
+
O
nBu
Au
O
nBu
O
OP
nBu
O
O
O
1
Au(I)
H
B
Au(I)
Scheme 1. Glycosylation with glycosyl ortho-hexynylbenzoates as donors under the catalysis of Au(I).
efficient with various cationic gold complexes, and those
complexes, particularly Au(I) complexes, possess little oxo-
philic character, thus displaying good functional group
compatibility and low air and moisture sensitivity.10 We
envisioned the position of the C–C triple bond installed
in the anomeric group as a key element to determine the
leaving property of the group and thus the efficiency of
the new glycosylation protocol. Here we report a new
and highly efficient glycosylation protocol with glycosyl
ortho-hexynylbenzoates as donors and Ph3PAuOTf as a
catalyst.
Our earlier studies showed that 4-pentynyl and 5-hexy-
nyl glycosides (in analogy to the 4-pentenyl glycosides
under the activation of iodonium species)11 were almost
inert under the action of gold complexes (e.g., AuCl3 and
Ph3PAuOTf). Therefore, an inherently more active alkynyl
group (toward the action of gold complexes) was desired to
serve as the leaving group in the new glycosylation proto-
col. o-Alkynylbenzoate perfectly fits this requirement; and
its leaving property (in the presence of Ph3PAuCl/AgOTf)
has just been demonstrated by Umetsu et al.12 Thus, acti-
vation of the benzylic triple bond with Au(I) in glycosyl
o-hexynylbenzoate 1 attracts nucleophilic attack of the
proximal carbonyl oxygen, resulting in subsequently the
cleavage of the glycosidic bond to give isocoumarin B
and the sugar oxocarbenium A, which is the common inter-
mediate for glycosidation (Scheme 1). Protonolysis of the
Au–C bond in B regenerates the Au(I) catalyst; an addi-
tional merit of this catalytic cycle is the consumption of
the proton (from alcohol 2), leading to inherent neutral
conditions for the reaction (to provide cleanly glycoside
3 and isocoumarin 4).
The representative glycosyl ortho-hexynylbenzoates (1a–
d) were readily prepared by condensation of the corre-
sponding lactols (5a–d) with o-hexynylbenzoic acid (6)13
in high yields (Table 1).14 Depending on the type of lactols
and the reaction conditions as well, a varied ratio of the a:b
anomers was attained. However, experiments showed little
difference (in accord with the glycosylation mechanism
shown in Scheme 1) between the pair of anomers in glyco-
sylation (e.g., Table 2, entry 4); thus the anomeric mixtures
were not separated but directly used in the glycosylation
reactions.
Exhilaratingly, the first trial in the coupling of per-ben-
zoyl-D-glucopyranosyl o-hexynylbenzoate (1a, 1.2 equiv)
with cholesterol (2b, 1 equiv) in the presence of Ph3PAu-
OTf (0.1 equiv)15 and 4 A MS in CH2Cl2 at rt has attained
˚
a very clean reaction within 2 h, leading to the desired
Table 1
Preparation of glycosyl ortho-hexynylbenzoates 1a –d
O
A) 6, SOCl2, reflux; then
Et3N, DMAP, CH2Cl2, rt
O
nBu
HO
O
O
nBu
nBu
O
OH
+
or
OP
1a d
OP
B) DCC, DMAP, CH2Cl2, rt
5a d
-
-
6
nBu
nBu
O
AcO
RO
O
O
O
RO
RO
AcO
AcO
O
O
O
AcO
OR
O
NPhth
O
AcO
OAc
1a R = Bz; 1b R = Bn
1c
Entry
Lactol
Ester
Conditions
Yield
b:a
1
2
3
4
5
6
7
5a
1a
A
B
A
B
A
B
A
80
95
81
98
69
94
83
1:2.2
1.4:1
1:2.5
1:1.4
b only
b only
1:12.4
5b
5c
5d
1b
1c
1d

3606
Y. Li et al. / Tetrahedron Letters 49 (2008) 3604–3608
glycoside 3ab and isocoumarin 4 in nearly quantitative
yields (Table 2, entry 2). Thus, we were eager to see a scope
of the present glycosylation protocol; the coupling results
of the glucose-type donors 1a–c with a panel of alcohols
(2a–e) were listed in Table 1. Worth noting is that (1) the
reactions were fast, those with the armed donor 1b com-
pleted at ꢀ0.5 h, and with the disarmed donors 1a and 1c
completed within 3 h; (2) the reactions were clean; even
in the cases of the glycosylation of the hindered 4-hydroxyl
sugar derivative 2e (entries 5, 10, and 15) where only good
yields (63–81%) of the coupling products were obtained,
the remaining acceptors could be largely recovered; (3)
thioglycosides and 4-pentenyl glycosides remained intact;
(4) a hindered phenol (2c)16 as well as the aliphatic and
sugar alcohols could be glycosylated in nearly quantitative
yields ( Scheme 2).
dered glucopyranoside 2,4-diol 9 with per-acetyl-L-rhamno-
pyranosyl donor 1d afforded the corresponding glycosides
(8 and 10, respectively) in nearly quantitative yields.
Exploiting the new activation conditions that are
orthogonal to the activation of the many known glycosyl
donors, new versions of the one-pot synthesis of glycocon-
jugates shall be realized easily. An example is shown in
Scheme 3, whereupon addition of the second acceptor (7)
and promoter NIS to the coupling system of 1a and thio-
glycoside 11 led to the steroidal disaccharide 12 in a good
70% yield. The combination of NIS and Ph3PAuOTf was
shown (for the first time) to be effective for the promotion
of the glycosidation of thioglycosides.
Summarizing, a glycosylation protocol with glycosyl
ortho-alkynylbenzoates as donors and Ph3PAuOTf as a
promoter is disclosed. This new method has significant
merits that chemists have been seeking after for a glycosyl-
ation reaction: (1) the glycosidic coupling yields are gener-
ally excellent; (2) the donors are readily available and
stable; (3) the promotion is catalytic; (4) the promotion
conditions are orthogonal to the others; (5) the reaction
The utility of the present protocol was further demon-
strated by the synthesis of a representative cytotoxic steroi-
dal saponin, dioscin (Scheme 3).17 Without modifying the
reaction conditions, both the glycosidic coupling between
1a and diosgenin (7) and the bis-glycosylation of the hin-
Table 2
Glycosidic coupling of glycosyl ortho-hexynylbenzoates (1) with alcohols (2) under the catalysis of Ph3PAuOTfa
O
OR
O
nBu
O
Ph3PAuOTf (0.1 eq)
CH2Cl2, 4 AMS, RT
O
+
HOR
+
4
OP
OP
2a e
-
(1 eq)
1 (1.2 eq)
3
HO
HO
2a
2c
2b
HO
OH
O
O
BnO
HO
BnO
O
O
O
OBn
O
OMe
2d
2e
Entry
Donor
Acceptor
Product
Yield
b:a
1
2
3
4b
5
6
7
8
9
1a
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
3aa
3ab
3ac
3ad
3ae
3ba
3bb
3bc
3bd
3be
3ca
3cb
3cc
3cd
3ce
98
98
97
99
81 (98)c
98
98
92
b only
b only
b only
b only
b only
1:1.2
1:1
1:1.2
1:1.4
1:2
b only
b only
b only
b only
b only
1b
1c
99
10
11
12
13
14
15
a
71 (95)c
99
99
91
99
63 (93)c
˚
For a typical procedure: To a stirred mixture of the glycosyl benzoate 1a (94 mg, 0.12 mmol), cholesterol 2b (39 mg, 0.1 mmol), and 4 A MS in CH2Cl2
(2.5 mL) at rt was added a newly prepared Ph3PAuOTf in CH2Cl2 (0.02 M, 0.5 mL). After stirring at rt for 0.5–3 h (as monitored by TLC), the mixture
was filtered throughCelite, and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc/CH2Cl2 12:1:1) to provide glycoside
3ab as a white solid (96 mg, 98%).
b
Using the pure a or b-anomer of 1a in the reaction led to similar results.
Yields based on the consumed acceptors.
c

Y. Li et al. / Tetrahedron Letters 49 (2008) 3604–3608
3607
O
2 steps
ref. 17
O
1a
(1.2 equiv)
BzO
O
O
BzO
Ph3PAuOTf, CH2Cl2,
4A MS, rt, 99%
BzO
7
8
OBz
HO
AcO
AcO
PivO
O
PivO
1d (2.5 equiv)
O
PivO
O
O
O
Ph3PAuOTf, CH2Cl2,
4A MS, rt, 99%
HO
O
O
PivO
OAc
10
9
O
OH
AcO
AcO
OAc
HO
HO
HO
O
HO
1 step
ref.17
O
O
O
O
O
O
OH
O
HO
Dioscin
HO
OH
Scheme 2. Synthesis of dioscin with glycosyl ortho-hexynylbenzoates as glycosylation donors.
Organic Chemistry of Sugars; Levy, D. E., Fugedi, P., Eds.; CRC
Press: Boca Raton, 2006; pp 89–179.
¨
HO
SEt
O
O
3. (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217–11223; (b)
Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435–436.
4. For recent reviews on the ‘one-pot’ glycoconjugate synthesis, see: (a)
Lee, J.-C.; Greenberg, W. A.; Wong, C.-H. Nature Protocols 2006, 1,
3143–3152; (b) Wang, Y.; Ye, X.-S.; Zhang, L.-H. Org. Biomol. Chem.
2007, 5, 2189–2200.
5. For early examples of orthogonal glycosylation, see: (a) Kanie, O.;
Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073–12074; (b) Ito,
Y.; Kanie, O.; Ogawa, T. Angew. Chem., Int. Ed. 1996, 35, 2510–2512.
6. Glycosylation with glycosyl sulfoxides could be catalyzed with the
strong acid TfOH in the presence of an acid scavanger. (a) Raghavan,
S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580–1581; (b) Alonso, I.;
Khiar, N.; Martin-Lomas, M. Tetrahedron Lett. 1996, 37, 1477–
1480.
O
11
Ph3PAuOTf, CH2Cl2,
4AMS, rt
1a (1.2 eq)
7 (1 eq)
NIS, rt
O
BzO
BzO
BzO
O
O
O
O
BzO
O
O
12
O
(70%; α:β = 2.2:1)
7. For a current state of the automated oligosaccharide synthesis, see:
(a) Castagner, B.; Seeberger, P. H. Top. Curr. Chem. 2007, 278, 289–
309; (b) Seeberger, P. H.; Werz, D. B. Nat. Rev. Drug Disc. 2005, 4,
751–763.
Scheme 3. A ‘one-pot’ orthogonal glycosylation with glycosyl ortho-
hexynylbenzoate and thioglycoside as donors.
8. (a) Hotha, S.; Kashyap, S. J. Am. Chem. Soc 2006, 128, 9620–9621;
(b) Sureshkumar, G.; Hotha, S. Tetrahedron Lett. 2007, 48, 6564–
6568.
9. A glycosylation method involving the intermediacy of a propynyl
cation has been reported, see: Mukai, C.; Itoh, T.; Hanaoka, M.
Tetrahedron Lett. 1997, 38, 4595–4598.
conditions are mild and neutral; thus (6) side reactions are
minimal. These excellent preliminary results shall warrant
further elaboration and application of this new glycosyla-
tion technique.
10. For a recent review on gold catalyzed reactions, see: Hashmi, A. S.
K. Chem. Rev. 2007, 107, 3180–3211.
Acknowledgments
11. Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.;
Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992,
927–942.
12. Asao, N.; Aikawa, H.; Tago, S.; Umetsu, K. Org. Lett. 2007, 9, 4299–
4302.
13. (a) Sashida, H.; Kawamukai, A. J. Heterocycl. Chem. 1998, 35, 165–
167; (b) Bytschkov, I.; Siebeneicher, H.; Doye, S. Eur. J. Org. Chem.
2003, 2888–2902.
14. Compound 1a-b: 1H NMR (300 MHz, CDCl3): d 8.06–7.22 (m, 24H),
6.35 (d, 1H, J = 7.8 Hz), 6.03 (t, 1H, J = 9.3 Hz), 5.84 (m, 2H), 4.69
(dd, 1H, J = 12.3, 2.1 Hz), 4.53 (dd, 1H, J = 12.0, 4.2 Hz), 4.44 (m,
1H), 2.46 (t, 2H, J = 6.6 Hz), 1.61 (m, 2H), 1.49 (m, 2H), 0.94 (t, 1H,
J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): d 166.00, 165.58, 165.04,
165.00, 163.29, 134.49, 133.43, 133.35, 133.24, 133.35, 133.00, 132.42,
Financial support from the National Natural Science
Foundation of China (20621062 and 20432020) and the
Committee of Science and Technology of Shanghai
(06XD14026) is acknowledged.
References and notes
1. For recent examples of glycoconjugate synthesis, see: (a) Galonic, D.
P.; Gin, D. Y. Nature 2007, 446, 1000–1007; (b) Seeberger, P. H.;
Werz, D. B. Nature 2007, 446, 1046–1051.
2. For selected reviews on the glycosylation methods, see: (a) Toshima,
K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531; (b) Fugedi, P. In The
¨

3608
Y. Li et al. / Tetrahedron Letters 49 (2008) 3604–3608
130.76, 129.72, 129.68, 129.39, 129.04, 128.59, 128.54, 128.34, 128.31,
2H), 1.41–1.51 (m, 2H), 0.94 (t, 3H, J = 6.9 Hz). 13C NMR (75 MHz,
CDCl3): d 170.6, 170.0, 169.5, 167.3, 162.9, 134.6, 134.3, 132.4, 131.1,
130.7, 129.0, 127.1, 125.8, 123.7, 97.4, 90.1, 78.8, 72.5, 70.4, 68.3, 61.5,
53.5, 30.5, 22.0, 20.7, 20.6, 20.4, 19.4, 13.6. MALDI-HRMS: m/z
128.23, 127.13, 125.76, 97.26, 92.39, 78.89, 73.01, 72.83, 70.79, 68.90,
62.56, 30.54, 21.95, 19.42, 13.60. MALDI-HRMS: m/z C47H40O11
[M+Na]+ calcd 803.2463, found 803.2479. Compound 1b-b: 1H NMR
(300 MHz, CDCl3): d 7.95–7.12 (m, 24H), 5.89 (d, 1H, J = 6.6 Hz),
4.91–4.76 (m, 5H), 4.60–4.44 (m, 3H), 3.84–3.62 (m, 6H), 2.47 (t,
2H, J = 6.0 Hz), 1.65–1.41 (m, 4H), 0.93 (t, 3H, J = 7.2 Hz). 13C
NMR (75 MHz, CDCl3): d 163.89, 138.36, 137.97, 137.88, 137.79,
134.59, 132.10, 130.59, 130.23, 128.38, 128.30, 128.01, 127.89, 127.88,
127.83, 127.76, 127.69, 127.65, 127.60, 127.00, 125.57, 97.02, 94.50,
84.85, 80.94, 79.15, 77.21, 75.69, 75.53, 75.00, 74.95, 73.42, 68.03,
30.65, 22.06, 19.55, 13.68. MALDI-HRMS: m/z C47H48O7 [M+Na]+
calcd 747.3292, found 747.3283. Compound 1c-b: 1H NMR
(300 MHz, CDCl3): d 7.80–7.85 (m, 3H),7.69–7.73 (m, 2H), 7.36–
7.46 (m, 2H), 7.22–7.27 (m, 1H), 6.72 (d, 1H, J = 9.0 Hz), 6.00 (dd,
1H, J = 9.3, 10.5 Hz), 5.27 (t, 1H, J = 9.3 Hz), 4.65 (dd, 1H, J = 8.7,
10.5Hz), 4.41 (dd, 1H, J = 3.6, 12.0 Hz), 4.09–4.18 (m, 2H), 2.45 (t,
2H, J = 6.9 Hz), 2.11 (s, 3H), 2.06 (s, 3H), 1.89 (s, 3H), 1.53–1.65 (m,
C
33H33NO11 [M+Na]+ calcd 642.1941, found 642.1946. Compound
1d-a: 1H NMR (300 MHz, CDCl3): d 7.96–7.33 (m, 4H), 6.28 (d, 1H,
J = 1.5 Hz), 5.47 (dd, 1H, J = 10.5, 3.6 Hz), 5.41 (m, 1H), 5.20 (t, 1H,
J = 9.9 Hz), 4.12 (m, 1H), 2.51 (t, 1H, J = 6.9 Hz), 2.20 (s, 3H), 2.07
(s, 3H), 2.01 (s, 3H), 1.62 (m, 2H), 1.50 (m, 2H), 1.64 (d, 1H,
J = 6.0 Hz), 0.95 (t, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCl3): d
169.65, 163.74, 134.83, 132.22, 130.62, 129.85, 127.20, 124.91, 96.82,
91.29, 79.40, 70.48, 68.84, 68.70, 68.61, 30.53, 21.96, 20.65, 20.53,
19.33, 17.33, 13.53. MALDI-HRMS: m/z C25H30O9 [M+Na]+ calcd
497.1782, found 497.1792.
15. Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966–6967.
16. Kahne, D.; Walker, S.; Cheng, Y.; van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881–6882.
17. Yu, B.; Tao, H. J. Org. Chem. 2002, 67, 9099–9102.