Gold(I)-catalyzed glycosidation of 1,2-anhydrosugars

Article abstract of DOI:10.1021/jo8003875

(Chemical Equation Presented) Being able to increase the yield by >20% compared to the conventional use of anhydrous zinc chloride (>1 equiv) as a promoter, Ph₃PAuOTf is disclosed to be a superior catalyst for the well-established glycosylation reaction with 1,2-anhydrosugars as donors.

Full text of DOI:10.1021/jo8003875

1,2-anhydrosugars with stannyl ethers better generated in situ
(under the promotion of Zn(OTf)2) proceeds.5a,b A number of
other acids (e.g., BF3 ·OEt2,6a,b,f AgOTf,6a,b,f TrClO4,6a ZnBr2,6c
TfOH,6d SiO2,6e and LiClO45c) have been occasionally used as
the promoters in the glycosidation with 1,2-anhydrosugars, but
no advantageous results are generalized. In principle, sugar 1,2-
epoxides are exceedingly sensitive to the opening of the alkoxy-
epoxide ring in the presence of acids; therefore, extremely mild
Lewis acids would be sufficient to activate the oxirane for a
nucleophilic attack of alcohols at the anomeric carbon. Stronger
acids would open the oxirane ring prior to glycoside bond
formation, thus leading to side reactions and the loss of the
stereoselectivity in glycoside formation.2,7 We envisioned that
a Lewis acid weaker than ZnCl2 and devoid of a nucleophilic
counteranion to be a better promoter for the glycosidation of
1,2-anhydrosugars. Here, we report that Ph3PAuOTf has turned
out to be the choice.
Gold(I)-Catalyzed Glycosidation of
1,2-Anhydrosugars
Yao Li, Pingping Tang, Youxi Chen, and Biao Yu*
State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China
byu@mail.sioc.ac.cn
ReceiVed February 20, 2008
Tremendous recent examples have shown that cationic gold
complexes are highly carbophilic Lewis acids that activate C-C
multiple bonds toward nucleophilic attack.8 Meanwhile, these
complexes, particularly Au(I) complexes, possess little oxophilic
character, thus displaying good functional oxo-group compat-
ibility and low air and moisture sensitivity.8,9 In fact, the
activation of epoxides with gold complexes has occasionally
been encountered.10 This prompted us to try Au(I) complexes
as catalysts for the activation of the exceedingly vulnerable sugar
1,2-epoxides for glycosidation.
Being able to increase the yield by >20% compared to the
conventional use of anhydrous zinc chloride (>1 equiv) as
a promoter, Ph3PAuOTf is disclosed to be a superior catalyst
for the well-established glycosylation reaction with 1,2-
anhydrosugars as donors.
Driven by the need for various carbohydrates of defined
composition to serve as molecular tools for significant bio-
chemical and biological studies, numerous glycosidic coupling
methods have been developed.1 Among these protocols, gly-
cosidation with 1,2-anhydrosugar as donors distinguishable in
one characteristic in that it provides the coupling products with
a free 2-hydroxyl group.2,3 This is extremely advantageous in
the synthesis of carbohydrates containing a 1 f 2 linkage, which
occurs characteristically in many natural glycoconjugates, such
as saponins.4 The glycosidation reaction of 1,2-anhydrosugars
and its application in the construction of complex carbohydrates
have been well elaborated by Danishefsky and co-workers.2
Multi equivalents of ZnCl2 is mostly employed as a promoter
in coupling with ordinary alcohol acceptors. However, com-
promised yields or even failure in obtaining the desired coupling
products are not uncommon.5 In some cases, coupling of the
Thus, the glycosidation of 1,2-anhydro-3,4,6-tri-O-benzyl-
R-D-glucopyranose (1)11 with cholesterol (2a) was first set up
as a model reaction for examining the action of Au(I) catalysts
(Table 1). Following the seminal procedure of Danishefsky and
Halcomb,11 coupling of the newly prepared glucose 1,2-epoxide
(1) with cholesterol under the promotion of three equivalents
of ZnCl2 in THF gave the ꢀ-glycoside (3a) stereoselectively in
47% yield, which is comparable to the yields reported in the
literature (52% and 42%).11,12 Gratifyingly, 0.1 equiv of
13
Ph3PAuNTf2 promoted the glycosidation to a similar extent
(entry 2). In a mixed solvent of CH2Cl2/THF (3: 2, v/v), the
reaction promoted by 0.1 equiv of Ph3PAuNTf2 was able to
provide the glycoside 3a in 78% (entry 4). Ph3PAuOTf14 in
CH2Cl2 gave similar results (entry 6), and the yield of the
product was increased to 88% upon increasing the catalyst load
to 0.2 equiv (entry 7).
(1) (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503–1531. (b) Fu¨gedi,
P. In The Organic Chemistry of Sugars; Levy, D. E., Fu¨gedi, P., Eds; CRC
Press: Boca Raton, FL, 2006; pp 89-179.
(2) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1380–1419.
(7) (a) Timmers, C. M.; van der Marel, G. A.; van Boom, J. H. Chem. Eur.
J. 1995, 1, 161–164. (b) Chiappe, C.; Lo Moro, G.; Munforte, P. Tetrahedron
1997, 53, 10471–10478.
(3) The recently reported C2-hydroxyglycosylation with glycal donors
involves the intermediacy of 1,2-anhydrosugars. Honda, E.; Gin, D. Y. J. Am.
Chem. Soc. 2002, 124, 7343–7352.
(8) For a recent review, see Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180–
3211.
(4) Yu, B.; Zhang, Y.; Tang, P. Eur. J. Org. Chem. 2007, 5145–5161.
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Soc. 1995, 117, 5693–5700. (b) Liu, K. K.-C.; Danishefsky, S. J. J. Am. Chem.
Soc. 1993, 115, 4933–4934. (c) Schmid, U.; Waldmann, H. Chem. Eur. J. 1998,
4, 494–501.
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Shi, Y.-L.; Liu, X.-G.; Shi, M. Org. Lett. 2007, 9, 3191–3194.
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6666.
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(b) Du, Y.; Kong, F. J. Carbohydr. Chem. 1995, 14, 341–352. (c) Danishefsky,
S. J.; Gervay, J.; Peterson, J. M.; McDonald, F. E.; Koseki, K.; Griffith, D. A.;
Oriyama, T.; Marsden, S. J. Am. Chem. Soc. 1995, 117, 1940–1953. (d) Lu,
P.-P.; Hindsgaul, O.; Li, H.; Palcic, M. M. Can. J. Chem. 1997, 75, 790–800.
(e) Matsushita, Y.-i.; Sugamoto, K.; Kita, Y.; Matsui, T. Tetrahedron Lett. 1997,
38, 8709–8712. (f) Ding, X.; Kong, F. J. Carbohydr. Chem. 1999, 18, 775–
787.
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10.1021/jo8003875 CCC: $40.75
Published on Web 04/24/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4323–4325 4323

TABLE 1. Au(I)-Catalyzed Glycosidation of 1,2-Anhydro-3,4,6-
TABLE 2. Au(I)-Catalyzed Glycosidation of 1,2-Anhydro-3,4,6-
tri-O-benzyl-r-D-glucopyranose (1) with Cholesterol (2a)a
tri-O-benzyl-r-D-glucopyranose (1)a
entry
catalyst (equiv)
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
ZnCl2 (3.0)
THF
THF
CH2Cl2
CH2Cl2/THF (3:2)
CH2Cl2/THF (3:2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
47; 52;11 42;12
50
47
78
66
78
88
trace
trace
Ph3PAuNTf2 (0.1)
Ph3PAuNTf2 (0.1)
Ph3PAuNTf2 (0.1)
Ph3PAuNTf2 (0.05)
Ph3PAuOTf (0.1)
Ph3PAuOTf (0.2)
Ph3PAuCl (0.1)
AgOTf (0.1)
a See the Experimental Section for a typical procedure. b Isolated
yield based on glucal; yields based on recovered cholesterol are >98%.
We then examined the glycosidation of 1,2-anhydrosugar (1)
with a set of alcohols (2b-e) under the influence of 0.1 equiv
of Ph3PAuNTf2 (in CH2Cl2/THF (3:2)) or Ph3PAuOTf (in
CH2Cl2) (Table 2). The reactions with the primary alcohols (2b
and 2c) in the presence of both Au(I) catalysts gave the desired
ꢀ-glycosides (3b and 3c) in excellent yields (82-89%, entries
1-4), which is remarkably higher than that with ZnCl2 as the
promoter (<63%).11,15 However, Ph3PAuNTf2 (and ZnCl2 as
well) hardly promoted the glycosidation with hindered sugar
alcohols (2d and 2e, entries 5 and 7). Nevertheless, the same
reactions in the presence of Ph3PAuOTf proceeded well,
providing the desired glycosides 3d and 3e in good yields (62%
and 59%, respectively). In the latter case (entry 8), the R-anomer
(3e-R) was also formed as a minor product, suggesting that a
portion of the sugar oxocarbenium was being formed prior to
the SN2-type opening of the oxirane ring.7
entry
Au(I)
HOR
2b
2b
2c
2c
2d
2d
2e(3b)
2e
product
yield (%)b
83; 6315
1
2
3
4
5
6
7
8
Ph3PAuNTf2
Ph3PAuOTf
Ph3PAuNTf2
Ph3PAuOTf
Ph3PAuNTf2
Ph3PAuOTf
Ph3PAuNTf2
Ph3PAuOTf
3b
3b
3c
3c
3d
3d
3e
3e
82
89; 5811
82
0
62
<10
59 (ꢀ:R )2.5)
a See the Experimental Section for a typical procedure. b Isolated
yield based on glucal; yields based on recovered acceptors are >98%.
co-workers by using galactal epoxides with cyclic carbonate
engaging the C3 and C4 oxygens.2,18
This point was validated by the glycosidation of 3,4-O-
carbonyl-6-O-tert-butyldimethylsilyl-1,2-anhydro-R-D-galacto-
pyranose (86c) with alcohols 2a and 2b (Table 4). Under the
action of Ph3PAuOTf (0.1 equiv.) in CH2Cl2, only the ꢀ-gly-
cosides 9a and 9b were obtained in excellent yields of 96%
and 94%, respectively.
To further confirm the superior properties of Ph3PAuOTf in
catalyzing the glycosidation of 1,2-anhydrosugars, glucosamine
derivative 2f5c was employed as an acceptor (Table 5). The
coupling of this hindered sugar alcohol (2f) with the glucose
1,2-epoxide 1 in the presence of LiClO4 provided the coupled
disaccharide 3f in only 13% yield with a ꢀ:R ratio of 2:1.5c
The use of Ph3PAuOTf (0.1 equiv) greatly increased the yield
of 3f (59%) and improved the ꢀ selectivity as well (ꢀ:R > 5:1,
entry 1). The coupling of 2f with the galactose 1,2-epoxide 6
in the presence of LiClO4, ZnCl2, or Zn(OTf)2 provided the
R-disaccharide 7f as the sole coupling product and in a low
5-11% yield;5c the use of Ph3PAuOTf (0.1 equiv) was again
able to increase the yield of 7f to 30% (entry 2).
3,4,6-Tri-O-acetyl- and 3,4,6-tri-O-benzyl-1,2-anhydro-R-D-
galactopyranose (416 and 65b,17) were readily prepared but rarely
used as glycosyl donors for the glycosylation of alcohols in the
literature. The glycosidation of these two 1,2-anhydrogalactoses
with alcohols (2a-2e) proceeded well under the influence of
0.1 equiv of Ph3PAuOTf, providing the corresponding coupling
products (5a-5e and 7a-7e) in satisfactory yields (38-96%,
Table 3). However, a significant amount of the R-anomer was
formed in each case (ꢀ:R < 7:1). Especially, the coupling of 4
with 2e, which gave the lowest yield of the product (38%, entry
5), formed equal amounts of the ꢀ:R anomers, while the coupling
of 6 with 2d led to the R-anomer only and in 41% yield (entry
9). These results reflect the ease of opening of the 1,2-oxiranes
in the 1,2-anhydrogalactoses 4 and 6, and this problem of a
lack of stereoselectivity has been addressed by Danishefsky and
(15) Gordon, D.; Danishefsky, S. J. Carbohydr. Res. 1990, 206, 361–366.
(16) Cavicchioli, M.; Mele, A.; Montanari, V.; Resnati, G. J. Chem. Soc.,
Chem. Commun. 1995, 901–902.
In summary, Ph3PAuOTf has been disclosed to be an effective
catalyst for the glycosidation of 1,2-anhydrosugars. In the
(17) (a) Bellucci, G.; Chiappe, C.; D’Andrea, F. Tetrahedron: Asymmetry
1995, 6, 221–230. (b) Tanaka, H.; Matoba, N.; Takahashi, T. Chem. Lett. 2005,
34, 400–401. (c) Bosse, F.; Marcaurelle, L. A.; Seeberger, P. H. J. Org. Chem.
2002, 67, 6659–6670.
(18) Gervay, J.; Peterson, J. M.; Oriyama, T.; Danishefsky, S. J. J. Org. Chem.
1993, 58, 5465–5468.
4324 J. Org. Chem. Vol. 73, No. 11, 2008

TABLE 3. Ph3PAuOTf-Catalyzed Glycosidation of 1,2-Anhydro-r-
TABLE 5. Glycosidation of 1,2-Anhydrosugars (1 and 6) with the
Glucosamine Derivative 2fa
D-galactopyranoses (4 and 6)a
entry
1
donor
HOR
product
yield (ꢀ:R)b
1
2f
3f
13% (2:1)5c
59% (>5:1)
5-11% (R)5c
30% (R)
2
6
2f
7f
a Reaction conditions as in Table 2 were applied. b Isolated yield
based on the glycal; yields based on recovered alcohols are >98%.
promotion of the conventional zinc chloride (∼3 equiv). Thus,
the Ph3PAuOTf catalyst shall find applications in the well-
established glycosidation protocol with 1,2-anhydrosugars as
donors.
entry
donors
HOR
product
yieldb
ꢀ:R
Experimental Section
1
2
3
4
5
6
7
8
9
4
4
4
4
4
6
6
6
6
6
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
5a
5b
5c
5d
5e
7a
7b
7c
7d
7e
83%
96%
78%
56%
38%
82%
80%
81%
41%
56%
3:1c
2.6:1c
4:1d
General Procedure for the Glycosidation of 1,2-Anhydro-
sugars (Table 1, entry 6). 3,4,6-Tri-O-benzyl-D-glucal (60 mg,
0.145 mmol) was dissolved in dry CH2Cl2 (1 mL), and the solution
was cooled to 0 °C under the protection of argon. A solution of
dimethyldioxirane (DMDO) in acetone (1.2 equiv, ca. 0.08 M),
prepared accordingly,19 was added. The resulting mixture was
stirred at 0 °C for 30 min. The 1,2-anhydroglucose 1 thus obtained
was concentrated to dryness by passing a stream of nitrogen over
the reaction mixture and placing it under vacuum for 30 min, and
the residue was then dissolved in cold dry CH2Cl2 (2 mL). To a
stirred mixture of cholesterol (2a, 84 mg, 0.217 mmol) and newly
activated 4 Å MS in dry CH2Cl2 (2 mL), was added a newly
prepared CH2Cl2 solution of PPh3AuOTf (0.0145 M, 1 mL, 0.0145
mmol).14c The mixture was stirred at RT for 30 min and was then
cooled to -78 °C; the previously prepared solution of 1,2-
anhydrosugar 1 was added slowly. The resulting mixture was
allowed to warm up naturally to RT and was left overnight. The
reaction mixture was then diluted with saturated brine and extracted
with CH2Cl2. The combined organic extracts were dried over
Na2SO4, then filtered, and concentrated. The residue was purified
with silica gel column chromatography (hexane/ethyl acetate
10:1) to provide 3a as a white solid (93 mg, 78% based on tri-O-
benzyl-glucal).
3:2c
1:1c
7:1d
4.5:1d
2:1d
R only
10
2:1c
a Reaction conditions as described in Table 2 were applied. b Isolated
yield based on glycal; yields based on recovered alcohols are >98%.
c Isolated ratio. Ratio determined by H NMR.
d
1
TABLE 4. Glycosidation of 3,4-O-Carbonyl-1,2-anhydro-r-D-
galactopyranose (8)a
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (20432020 and 20621062)
and the Committee of Science and Technology of Shanghai
(06XD14026).
entry
donor
HOR
product
yield (ꢀ only)b
Supporting Information Available: Full experimental de-
1
2
8
8
2a
2b
9a
9b
96%
94%
1
tails, characterization data, and H and 13C NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction conditions as described in Table 2 were applied. b Isolated
yield based on glycal.
JO8003875
comparable examples, the glycosidation catalyzed by Ph3-
PAuOTf (0.1 equiv) provided the coupling products in remark-
ably higher yields (>20%) than those obtained under the
(19) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847. (b)
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50–51.
J. Org. Chem. Vol. 73, No. 11, 2008 4325