Hafnium(IV) triflate as a highly efficient catalyst for Ferrier rearrangement of O- and S-nucleophiles with glycals

Article abstract of DOI:10.1016/j.tetlet.2016.05.026

A highly efficient method to afford 2,3-unsaturated glycosides was described. In the presence of Hafnium(IV) triflate, a variety of 2,3-unsaturated-O- and S-glycosides have been obtained by stereoselective glycosylation of 3,4,6-tri-O-acetyl-d-glucal and hexa-O-acetyl-d-lactal with various acceptors in good isolated yields.

Full text of DOI:10.1016/j.tetlet.2016.05.026

Tetrahedron Letters 57 (2016) 2758–2762
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Tetrahedron Letters
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Hafnium(IV) triflate as a highly efficient catalyst for Ferrier
rearrangement of O- and S-nucleophiles with glycals
⇑
Yonghui Liu, Tianbang Song, Weijia Meng, Yun Xu, Peng George Wang, Wei Zhao
The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park,
38 Tongyan Road, Tianjin 300353, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient method to afford 2,3-unsaturated glycosides was described. In the presence of Hafnium
Received 17 March 2016
Revised 5 May 2016
Accepted 9 May 2016
Available online 9 May 2016
(IV) triflate, a variety of 2,3-unsaturated-O- and S-glycosides have been obtained by stereoselective gly-
cosylation of 3,4,6-tri-O-acetyl-
D-glucal and hexa-O-acetyl-
D
-lactal with various acceptors in good iso-
lated yields.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Hafnium(IV) triflate
3,4,6-Tri-O-acetyl-D-glucal
Hexa-O-acetyl- -lactal
D
Ferrier rearrangement
2,3-Unsaturated glycosides
Carbohydrates are a kind of biomolecules which participate in
almost all biological processes in life, including cell recognition,1
cell adhesion,2 cell communication,3 inflammation,4 and immune
response.5 Most carbohydrates found on cell surface or in extracel-
lular matrix exist as polysaccharide and glycoconjugates (i.e. gly-
colipid, glycopeptide, glycoprotein, sugar nucleotide),6 in which
sugar units are connected with aglycones through glycosidic
bonds. Therefore, the stereoselective construction of glycosidic
bonds is the critical processes for glycoconjugate syntheses.
To date, a number of strategies have been demonstrated for the
stereoselective formation of glycosidic bonds.7 Ferrier rearrange-
ment is one of the methods for stereoselective synthesis of
2,3-unsaturated glycosides,8 which can be further diversified into
bioactive compounds, such as oligosaccharides9 and natural prod-
ucts.10 The reaction mechanism is proposed in Scheme 1. Firstly,
the leaving group at the C-3 position of the glycal is removed in
the presence of promotor; subsequently, the cyclic allyloxycarbe-
nium ion intermediate is attacked by the nucleophile to form a
new glycosidic bond.
OR
O
OR
O
OR
O
Nu-
Promotor
RO
RO
RO
LG
Nu
allyloxycarbenium ion
LG = leaving group
Scheme 1. Mechanism of type I Ferrier rearrangement.
Table 1
Optimization of solventa
OAc
OAc
O
Hf(OTf)4, (10mol%)
Solvent, 40°C
O
AcO
AcO
AcO
+
EtOH
OEt
Entry
Nucleophile
Reaction time
Conversionb (%)
a
:bc
1
2
3
4
5
6
7
CH3CN
CH2Cl2
THF
Et2O
Dioxane
DCE
6 h
Trace
40
96
90
80
/
30 min
10 min
10 min
10 min
15 min
10 min
5:1
6:1
6:1
5.5:1
5:1
6:1
Various catalysts have been introduced in the Ferrier reaction,
including some Lewis acid catalysts11 such as ZnCl2, Sc(OTf)3, Yb
(OTf)3, Dy(OTf)3, Cu(OTf)2, RuCl3Á3H2O, Sm(OTf)3, Cu(OTf)2, Tm
(OTf)3, TiCl3(OTf), and Gd(OTf)3, Bronsted acid catalysts12 such as
p-TsOH, trichloroacetic acid (TCA), trifluoroacetic acid (TFA),
60
65
Toluene
a
Reaction conditions: tri-O-acetyl-D-glucal (200 mg, 0.73 mmol), EtOH
(1.2 equiv), Hf(OTf)4 (10 mol%), solvent (5 mL), 40 °C.
b
Determined by analysis of the 1H NMR spectra of the crude reaction mixture.
The anomeric ratio was determined by integration of the anomeric hydrogen in
c
⇑
Corresponding author. Tel./fax: +86 022 2350 7760.
E-mail address: wzhao@nankai.edu.cn (W. Zhao).
the 1H NMR spectra.
http://dx.doi.org/10.1016/j.tetlet.2016.05.026
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

Y. Liu et al. / Tetrahedron Letters 57 (2016) 2758–2762
2759
Table 2
Glycosidation of 3,4,6-tri-O-acetyl-D-glucal 1 catalyzed by Hf(OTf)4
a
OAc
O
OAc
O
Hf(OTf)4, (10 mol%)
THF, 40°C
AcO
AcO
AcO
+
ROH
OR
3
1
2
Entry
1
Nucleophile
Reaction time
10 min
Product
Yieldb (%)
96
a
:bc
OAc
O
2a
OH
AcO
86:14
89:11
O
3a
OAc
O
2b
OH
AcO
AcO
2
3
10 min
40 min
94
95
O
3b
OAc
O
OH
2c
2d
Cl
87:13
O
Cl
3c
OAc
O
OH
AcO
AcO
AcO
AcO
AcO
4
5
6
7
10 min
30 min
10 min
40 min
62
85
92
90
90:10
90:10
93:7
O
3d
OAc
O
F
F
F
2e
2f
OH
F
F
F
O
3e
OAc
O
OH
O
3f
OAc
O
OH
2g
2h
92:8
O
3g
OAc
O
OH
O
8
30 min
74
91:9
O
3h
O
2i
2j
N
9
24 h
No reaction
—
—
OH
OH
OAc
O
AcO
10
30 min
88
89:11
O
3j
OAc
O
Cl
2k
2l
AcO
AcO
AcO
OH
Cl
11
12
35 min
30 min
80
72
90:10
92:8
O
3k
OAc
O
OH
O
3l
OAc
O
HO
2m
OBn
FmocH2HN
O
O
13
25 min
79
>99:1
OBn
FmocH2HN
3m
O
(continued on next page)

2760
Y. Liu et al. / Tetrahedron Letters 57 (2016) 2758–2762
Table 2 (continued)
Entry
Nucleophile
Reaction time
30 min
Product
Yieldb (%)
a
:bc
HO
OAc
O
AcO
2n
OBn
FmocHN
O
O
14
15
75
>99:1
94:6
OBn
FmocH2HN
3n
OAc
O
O
OH
AcO
2o
O
3o
20 min
68
SH
OAc
O
2p
AcO
AcO
16
17
20 min
30 min
80
78
83:17
95:5
S
3p
SH
OAc
O
2q
S
3q
OH
OAc
O
O
O
AcO
O
2r
O
O
O
O
18
50 min
78
76
94:6
93:7
O
O
O
O
3r
O
OAc
O
HO
O
2s
AcO
O
O
O
19
30 min
O
O
O
O
O
3s
O
a
Reaction conditions: tri-O-acetyl-
D-glucal (200 mg, 0.73 mmol), EtOH (1.2 equiv), Hf(OTf)4 (10 mol %), solvent (5 mL), 40 °C.
b
c
Isolated yield by flash column chromatography on silica gel.
The anomeric ratio was determined by integration of the anomeric hydrogen in the 1H NMR spectra.
camphorsulfonic acid (CSA), TfOH-SiO2, 3,5-dinitro benzoic acid
(DNBA), and other catalysts13 such as iodonium dicollidinium per-
chlorate (IDCP), NIS, ceric(IV) ammonium nitrate (CAN), H2O2, Pd
(OAc)2, Zn, and pyridinium bromide salts. However, some of these
methods suffered from the drawbacks in terms of harsh reaction
conditions, excess amount of sensitive catalysts, and low yields.
Therefore, exploration of efficient promoters for this reaction is
still a challenge. Previous studies show that Hafnium(IV) triflate
was an efficient promoter in many reactions such as the
Friedel–Crafts acylation, Fries rearrangement, hydroamination,
thioacetalization, transthioacetalization, N-aminomethylation,
and Prins-type cyclization.14 Herein, we report a more practical
Ferrier rearrangement using Hafnium(IV) triflate as an efficient
Lewis acid catalyst.
To test the feasibility of this approach, various alcohols (2a–s)
were further applied under the optimized condition to the synthe-
sis of corresponding 2,3-unsaturated glycosides. The Ferrier rear-
rangement was performed between tri-O-acetyl
D-glucal(1)
(1 equiv) and various nucleophiles (1.2 equiv) at 40 °C, with
Hafnium(IV) triflate (10 mol %) as the catalyst and THF as the
solvent. As presented in Table 2, the substrate scope of various
linear alkyl alcohols (Table 2, entries 1–3) gave the products with
higher yields, while the branched alkyl alcohols (Table 2, entries
4, 5 and 8) with lower yields but higher stereoselectivity.
Functionalized alkyl alcohols (Table 2, entries 6 and 7) gave the
products with higher yield and better stereoselectivity, while
aromatic alcohols (Table 2, entries 10, 11 and 15) and adaman-
tanemethanol (Table 2, entry 12) with a higher steric hindrance
gave the products with higher stereoselectivity but lower yields.
The reactions of glucal with amino acids (Table 2, entries 13 and
14) were investigated. Interestingly, the glycosylated serine and
threonine building blocks were synthesized with almost a single
Our Initial studies started with tri-O-acetyl-D-glucal (1) as the
donor and EtOH as the nucleophile in a model system catalyzed
by Hf(OTf)4. As reaction medium has influence on the reaction,
we then paid efforts to screen the best reaction solvents among
CH3CN, CH2Cl2, THF, Et2O, dioxane, 1,2-dichloro ethane (DCE),
and toluene. As shown in Table 1, the ratio and the yield of desired
target compound varied. After stirring at 40 °C in THF and Et2O for
10 min, the corresponding 2,3-unsaturated glycoside was obtained
in an isolated yield of 96% and 90%, respectively.
a
configuration. Thio-phenol (Table 2, entry 16) and thiol (Table 2,
entry 17) were used as nucleophile to provide the corresponding
thioglycosides with satisfactory anomeric selectivity. For entry 9,
it was hypothesized that the catalyst was quenched by the
substrate, leading to the reactivity loss of Hf(OTf)4.

Y. Liu et al. / Tetrahedron Letters 57 (2016) 2758–2762
2761
Table 3
a
Glycosidation of hexa-O-acetyl-D-lactal 4 catalyzed by Hf(OTf)4
OAc
AcO
OAc
O
OAc
O
AcO
AcO
OAc
O
Hf(OTf)4, (10 mol%)
THF, 40°C
O
O
+
O
ROH
AcO
AcO
OAc
OAc
OR
4
5
6
Entry
1
Nucleophile
Reaction time
30 min
Product
Yieldb (%)
85
a
:bc
OH
OAc
AcO
OAc
O
5a
O
O
O
AcO
82:18
88:12
OAc
6a
O
OH
OH
OAc
O
AcO
AcO
OAc
O
5b
2
2 h
78
OAc
6b
O
OAc
OAc
O
AcO
AcO
5c
5d
O
O
O
3
4
30 min
35 min
86
85
86:14
89:11
OAc
O
6c
Cl
OAc
AcO
AcO
OAc
O
O
OH
Cl
OAc
O
6d
OH
OAc
O
AcO
AcO
OAc
O
O
5e
5f
OAc
O
5
6
30 min
25 min
68
73
>99:1
63:37
6e
OAc
O
OAc
O
AcO
AcO
O
SH
OAc
6f
S
a
b
c
Reaction conditions: hexa-O-acetyl-D-lactal (405 mg, 0.73 mmol), nucleophile (1.2 equiv), Hf(OTf)4 (10 mol %), solvent (5 mL), 40 °C.
Isolated yield by flash column chromatography on silica gel.
The anomeric ratio was determined by integration of the anomeric hydrogen or separable proton in the 1H NMR spectra.
Synthesis of 2,3-unsaturated glycosides from hexa-O-acetyl-
-lactal (4) with various alcohols was further investigated, as
summarized in Table 3. Six O-, S-nucleophiles coupling with the
protected lactal gave corresponding 2,3-unsaturated glycosides
with satisfactory yield and stereoselectivity. In all these cases,
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Supplementary data
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