Copper-Catalyzed Stereoselective Synthesis of 2-Deoxygalactosides

Article abstract of DOI:10.1055/s-0040-1707098

An efficient glycosylation method to synthesize 2-deoxy- O -galactosides based on a Cu(II)-catalyzed reaction without additional ligand has been developed. The glycosylation was amenable to different protected glycal donors and a wide range of acceptors including alcohols, amino acids, sugars, and phenol, and proceeds with excellent yield and high α-selectivity under mild conditions. The reaction proceeds readily on a gram scale, and its versatility is exemplified in the synthesis of oligosaccharides.

Full text of DOI:10.1055/s-0040-1707098

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–G
letter
A
en
Y. Dong et al.
Letter
Synlett
Copper-Catalyzed Stereoselective Synthesis of 2-Deoxygalactosides
Youxian Donga
Madina Yumaa
Yuling Meia
OP
OP
OP
PO
OP
PO
CuBr2 (5 mol%)
O
O
R-OH
+
DCM, rt
1–3 h
OR
Nan Jianga
P = protecting group
24 examples
up to 95%
α:β >30:1
Guofang Yanga
Zhongfu Wangb
Jianbo Zhang*a
First Cu-catalyzed synthesis of 2-deoxygalactosides
Mild reaction conditions
Affordable copper catalyst without additional ligand
0
0
0
0-0
0
0
3-3
7
2
6-
4
2
3
X
Broad substrate scope with high yields and excellent α-selectivity
Gram scale and synthesis of trisaccharide
a School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200241, P. R. of China
jbzhang@chem.ecnu.edu.cn
b School of Life Sciences, Northwestern University, Xian
710069, Shaanxi, P. R. of China
Received: 14.01.2020
Accepted after revision: 03.04.2020
Published online: 05.05.2020
HO
O
DOI: 10.1055/s-0040-1707098; Art ID: st-2020-b0025-l
N
O
O
O
O
Abstract An efficient glycosylation method to synthesize 2-deoxy-O-
galactosides based on a Cu(II)-catalyzed reaction without additional li-
gand has been developed. The glycosylation was amenable to different
protected glycal donors and a wide range of acceptors including alco-
hols, amino acids, sugars, and phenol, and proceeds with excellent yield
and high -selectivity under mild conditions. The reaction proceeds
readily on a gram scale, and its versatility is exemplified in the synthesis
of oligosaccharides.
OH
O
HO
HO
jadomycin
O
O
O
O
O
O
O
OH
HO
O
OH
Key words copper catalyst, 2-deoxygalactosides, glycosylation,
landomycin E
OH
glycals, stereoselectivity
HO
MeO
HO
O
OH
OMe
OAc
H
O
O
Deoxyglycosides are common components of a wide
range of bioactive natural products (Figure 1),1 and they of-
ten display antibiotic, anticancer, or cardiotonic activities.2
As a result, many methods have been developed for the syn-
thesis of 2-deoxyglycosides.3 However, unlike fully oxygen-
ated glycosides, the lack of substituents at C-2 to direct the
nucleophilic approach presents an additional synthetic
challenge that has piqued the interest of researchers for
many decades.4 To overcome these problems, many indirect
approaches have been developed for the synthesis of 2-de-
oxyglycosides, usually by installing a temporary directing
group at the C-2 position, which makes this methodology
inherently inefficient.4b,c,5 Thus, several direct approaches
have been formulated to achieve the stereoselective synthe-
sis of these compounds.6 Among them, it is still the most
atom-efficient route to synthesize 2-deoxyglycosides by
adding an alcohol to a glycal directly in a catalyzed pro-
cess.7–10
O
H
O
OH
O
OH OH
HO
O
O
O
HO
O
O
O
AcO
chromomycin A3
Figure 1 Representative deoxyglycoside-containing natural products
talysis8a,17 (Scheme 1). For instance, Galan et al.7 in 2012, re-
ported the selective synthesis of 2-deoxy-O-galactosides
using thiourea as an organocatalyst. Subsequently, in 2105,
Galan et al.12a used pyridinium cations as novel organocata-
lyst to synthesize 2-deoxyglycosides efficiently. Since 2017,
Galan’s group7–10 have developed several practical methods
by using Lewis acids, such as Au(I) in combination with Ag-
OTf, and Pd(II) in combination with a monodentate phos-
phine ligand and B(C6F5)3. Meanwhile, Wang11 reported the
selective synthesis of 2-deoxy-O-glycosides catalyzed by
photoacid. Despite the great efforts that have been made in
this area, noble metals or expensive ligands are still re-
Recently, many methodologies using glycal to synthesis
2-deoxyglycosides have been reported, including organoca-
talysis,11–13 Lewis acid catalysis,14–16 and Brønsted acid ca-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Dong et al.
Letter
Synlett
quired as catalysts in the reaction. Thus, there is a need to
find improved and more general catalysts to access these
high-value glycosides.
18). When the reaction was carried out at 0 or 40 °C, prod-
uct 3g was obtained in 71 and 75% yield, respectively (entry
22 and 23). Further optimization studies of catalyst load-
ings were conducted that revealed that 0.05 equivalent
CuBr2 provided the highest yield (82%; entry 25). Increasing
the number of equivalents of CuBr2 to 0.1 or decreasing it to
0.025, both led to decreased yields of 3g (entries 24 and 26).
Therefore, the optimized reaction conditions were: 1.0
Previous work
thiourea, pyridinium cations
Pd(II)/L; Au(I)/AgOTf
R
O
R
OP
PO
+
ROH
O
PO
B(C6F5)3; photoacid
OP
OR
P = protecting group
R = OP, H
α-selective
This work
Table 1 Optimization of the Reaction Conditionsa
O
R
PO
PO
OBn
BnO
OP
PO
CuBr2
OH
+
ROH
O
O
O
OBn
O
BnO
BnO
BnO
DCM, rt
conditions
O
OP
+
OR
α-selective
O
O
O
P = protecting group
O
O
O
O
O
Scheme 1 Representative strategies for the synthesis of deoxyglyco-
sides from glycals
O
1a
2g
3g
Entry Catalyst
Cat.
(equiv.)
Solvent
Time
(h)
Yield
(%)b
:
In recent years, copper catalysts have been widely em-
ployed in organic chemistry because of its abundance,
ready availability, and low toxicity.18 For example, Debaraj
et al. reported Cu(OTf)2 mediated stereoselective synthesis
of C-glycosides from unactivated alkynes.18b A recent reac-
tion was developed by Tang et al., in which glycosyl isoquin-
oline-1-carboxylate was used as glycosyl donor, promoted
by the Cu(OTf)2 salt under mild reaction conditions.18e More
recently, Messaoudi et al. reported Cu(OAc)2∙H2O catalyzed
anomeric O-arylation of carbohydrate derivatives at room
temperature.18f However, copper salts have not been ap-
plied to the stereoselective synthesis of 2-deoxyglycosides.
Based on our continuing interest in 2-deoxyglycosides,15 we
hoped to apply copper salts to the synthesis of 2-deoxygly-
cosides. Fortunately, we found that when CuBr2 was used as
the catalyst, 2-deoxy-O-glycosides could be successfully ob-
tained with -selectivity. Herein, we described an unprece-
dented Cu(II) direct activation of glycals to yield 2-deoxyga-
lactosides under mild conditions (Scheme 1).
We started our studies with galactal 1a and galactoside
acceptor 2g as model substrates. Initially, we examined a
series of iron(III) catalysts: FeCl3·6H2O/C, FeCl3/C,
Fe3O4@C@Fe(III), which have been widely used as efficient
catalysts in glycosylation reactions.19–21 As shown in Table
1, product 3g was gained with poor yield, with the forma-
tion of more 2,3-unsaturated Ferrier product (yield 42–60%;
entries 1–3). Next, a series of commercial Lewis catalysts
were screened (entries 4–9). To our delight, when CuBr2
was used as catalyst, the addition product 3g could be ob-
tained with 77% yield and : stereocontrol of >30:1 (entry
9).9 Subsequently, other copper salts were further tested as
catalysts (entries 10–15). The results indicated CuBr2 was
the best catalyst among copper salt catalysts. Solvent effect
was also evaluated. Reactions in DMF, 1,4-dioxane, or DMSO
did not proceed (entries 19–21), whereas reactions in DCE,
CH3CN and THF gave lower yields than in DCM (entries 16–
1
2
FeCl3·6H2O/C
FeCl3/C
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.05
0.025
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
4
22
–
–
–
–
–
–
–
–
3
2
30
3
Fe3O4@C@Fe(III)
PdCl2
45
4
6
48
5
CuCl2
12
12
12
N.R
N.R
N.R
5
6
CoCl2
7
CoBr2
8
ZnCl2
0.5
0.5
12
9
CuBr2
77
>30:1
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
24
25
26
CuNO3·3H2O
CuSO4
Cu(OTf)2
Cu(OAc)2
CuBr
N.R
N.R
71
–
12
12
12
12
12
–
–
N.R
5
–
–
CuI
N.R
68
–
CuBr2
1.5
–
CuBr2
CH3CN
THF
0.5
0.5
2
72
–
CuBr2
70
–
CuBr2
DMF
N.R
N.R
N.R
71
–
CuBr2
dioxane
DMSO
DCM
DCM
DCM
DCM
DCM
2
–
CuBr2
2
–
CuBr2
4
>30:1
>30:1
>30:1
>30:1
>30:1
CuBr2
0.5
1
75
CuBr2
80
CuBr2
1
82
CuBr2
3
79
a Reaction conditions: glycal donor 1a (0.1 mmol), acceptor 2g (0.12
mmol), catalyst (0.02 mmol), solvent (1.0 mL), 25 °C, N2.
b Isolated yield.
c The reaction was conducted at 0 °C.
d The reaction was conducted at 40 °C.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

C
Y. Dong et al.
Letter
Synlett
equiv donor, 1.2 equiv acceptor and 0.05 equiv CuBr2 as cat-
alyst in DCM at 25 °C.
(63–82%) and with high -selectivities. The results showed
that aliphatic acceptors including simple alcohols, amino
acids, and sugars could be used to obtain glycosides in ex-
cellent yields with high -selectivities.
Having established the optimum reaction conditions,
our attention then turned to expanding the substrate scope
of the glycosyl acceptors to other alcohols (Scheme 2; 2a–i).
Fortunately, in all cases, deoxy products 3a–i could be ob-
tained within three hours in good to excellent yields with
high stereoselectivities (: >30:1). When simple primary
alcohols such as benzyl alcohol 2a and ethanol 2b were
used as nucleophilic acceptors, products 3a and 3b were
obtained in yields of 86% and 95%, respectively. Additional-
ly, trichloroethanol 2c, an electron-deficient alcohol, react-
ed with glycal donor 1a smoothly in 82% yield, albeit with
longer time (3 h) due to the presence of a strong electron-
withdrawing group. Notably, when tert-butanol was used
as nucleophile, the expected product 3d was also obtained
in good yield (65%), despite its greater steric hindrance. 5-
Hydroxymethylfurfural (HMF) 2e, which is an important
biofuel, and its sugar derivatives, shows antitumor activity
in our previous research,22 was also applied in this catalytic
system with 89% yield.
Encouraged by these results, the substrate scope of this
reaction was further extended to phenol acceptors, which
are scarcely studied.15a,24 As illustrated in Scheme 3, reac-
tions involving phenol acceptors 2j–r were complete within
3 h in excellent yields (75−85%) and very high anomeric se-
lectivities (: >30:1). The glycosylation of phenols with
electron-donating substituents at the para-position such as
p-tert-butyl and p-methoxy groups proceeded smoothly,
giving the desired products 3k and 3l with excellent yields.
In addition, phenols with electron-withdrawing substitu-
ents at the para-position such as p-fluoro, p-chloro and p-
bromo were also employed to afford the desired products
3m–o in satisfactory yields. Moreover, coupling of glycal
donor 1a with the relatively hindered acceptors 2p–q also
proceeded successfully. In earlier reports,23,24 the synthesis
of naphthol 2-deoxygalactoside 3r usually involves 2-thio-
glycosides, which is a difficult donor to obtain; further-
more, the selectivity of the product was not very high. To
our delight, 2-naphthol could also be directly applied in the
catalytic system with excellent yield (77%) and pure -se-
lectivity.
The catalytic system was also suitable for use with ami-
no acid acceptors. For example, Fmoc-protected serine 2f
afforded the corresponding glycoside product 3f in 93%
yield within 1.5 h (Scheme 2). Moreover, sugar acceptors,
for instance, galactoside 2g, glucoside 2h, and rhamnoside
2i also afforded the desired 2-deoxy products in good yields
BnO
BnO
OBn
O
BnO
BnO
OBn
O
CuBr2
ArOH
+
DCM, 25 °C
OR
BnO
BnO
OBn
O
BnO
BnO
OBn
O
1a
2j–r
3j–r
CuBr2
+
ROH
DCM, 25 °C
OR
OBn
1a
2a–i
3a–i
OBn
BnO
BnO
OBn
O
BnO
BnO
BnO
BnO
O
O
OBn
O
BnO
BnO
O
BnO
BnO
OBn
BnO
BnO
OBn
O
O
O
O
OMe
Cl
Cl
O
OBn
3j, 1.5 h, 80%12
OEt
3l, 1.2 h, 85%14
3k, 1.5 h, 83%
Cl
3a, 1 h, 86%9
3b, 2.5 h, 95%14
3c, 3 h, 82%
OBn
OBn
O
OBn
OBn
BnO
BnO
BnO
BnO
O
O
OBn
OBn
BnO
BnO
BnO
BnO
BnO
BnO
BnO
CHO
O
O
O
O
O
O
BnO
COOMe
NHFmoc
O
O
O
O
Br
F
Cl
3m, 1.5 h, 79%
3n, 1.5 h, 75%
3o, 1.5 h, 75%
3d, 1.5 h, 65%14
3f, 1.5 h, 93%
3e, 1 h, 89%
OBn
O
OBn
BnO
OBn
OBn
BnO
BnO
OBn
BnO
OBn
BnO
BnO
BnO
BnO
BnO
O
O
O
O
O
BnO
BnO
BnO
O
O
OAc
O
O
O
O
O
O
OAc
O
BzO
BzO
O
SPh
O
O
O
OBz
3h,a 1 h, 73%9
OMp
3i, 1 h, 63%
3r, 1 h, 77%23
3g, 1 h, 82%9
3p, 3 h, 76%
3q, 1 h, 82%
Scheme 2 Alcoholic acceptor scope of glycosylation reactions with ga-
lactal 1a. Reagents and conditions: donor (0.1 mmol), acceptor (0.12
mmol), CuBr2 (5 mol%), stirred in DCM (1.0 mL), 25 °C, nitrogen atmo-
sphere. All yields are isolated yields; : ratio of all products was >30:1
and was determined based on the 1H NMR spectra. a CuBr2 (0.1 equiv)
was used.
Scheme 3 Phenolic acceptor scope of glycosylation reactions with ga-
lactal 1a. Reagents and conditions: donor (0.1 mmol), acceptor (0.12
mmol), CuBr2 (5 mol%), stirred in DCM (1.0 mL), 25 °C, nitrogen atmo-
sphere. All yields are isolated yields; : ratio of all products was >30:1
based on the 1H NMR spectra.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

D
Y. Dong et al.
Letter
Synlett
We then further investigated the donor scope of this
glycosylation. A series of differentially protected galactals
1b–g were prepared and reacted with 2g as a model nucleo-
phile under standard conditions (Scheme 4). Pleasingly, ex-
cellent yields (76–92%) and high selectivities (: >30:1) for
the -linked disaccharides were obtained in all cases except
when 1e was employed as glycal donor. The reason was
postulated as the low activity of the disarmed peracetylated
galactal.9 Encouragingly, the reaction was also applicable to
glycosylation with glycal donors 1f and 1g, which possess a
readily removable protecting group at the 6-position. In ad-
dition, galactal donor 1c could react with secondary alcohol
2s with 71% yield. These results demonstrate that our reac-
tion is tolerant of most protecting groups used in galactals,
including benzyl, ethyl, allyl, and silyl ethers. The reaction
was also amenable to glycosylation with perbenzylated glu-
cal 1h, affording the glycoside products in 77% yields with
It should be noted that this novel reaction could be
readily scaled up. A gram-scale reaction of 2 mmol of 1a
(0.83 g) and 2.4 mmol of 2g (0.63 g) was carried out with
2.5 mol% CuBr2 at room temperature (Scheme 5). To our de-
light, the reaction finished within 1 h and 1.73 g of 3g was
obtained with 78% isolated yield and pure stereocontrol
(: >30:1).
OBn
OBn
OH
O
O
O
OBn
O
BnO
OBn
BnO
CuBr2 (2.5 mol%)
DCM, rt
O
O
+
O
O
O
O
O
O
O
1a
2 mmol (0.83 g)
2g
2.4 mmol (0.63 g)
3g
1.73 g, 78%
α:β >30:1
Scheme 5 Gram scale-up reaction
1
similarly high -stereocontrol. However, H NMR analysis
showed that the product 4h was a mixture of addition
product and Ferrier rearrangement product with 8:1 ratio.
The structure and stereochemistry of all glycosidation
products were determined through spectroscopic analysis
and by comparison with the reported data.7
In addition, we extended the methodology to synthesize
oligosaccharides 5f (Scheme 6). Firstly, galactal 1f was re-
acted with 2g under the optimized condition, in which di-
saccharide 4f was obtained in a yield of 89%. Considering
that the silyl protecting group at the 6′-position of 4f could
be selectively removed using TBAF/THF solution, disaccha-
OMp
OBn
O
OAllyl
OR3
O
AllylO
AllylO
OBn
BnO
BnO
O
R2O
R1O
BnO
+
O
O
BnO
BnO
HO
2s
1h
OAc
OAc
OR2 OR3
O
CuBr2 (5 mol%)
DCM, 25 °C
O
O
O
O
OBn
O
OH
O
O
R1O
O
O
O
O
O
OMp
4s
1b–g
1b: R1 = R2 = R3 = Et
1c: R1 = R2 = R3 = Allyl
1d: R1 = R2 = R3 = TBS
1e: R1 = R2 = R3 = Ac
1f: R1 = R2 = Bn, R3 = TIPS
1g: R1 = R2 = Bn, R3 = Ac
O
O
O
O
4b–g
4h
O
O
O
2g
OAc
O
OTBS
O
OAllyl
OEt
EtO
AcO
AcO
TBSO
TBSO
AllylO
AllylO
O
O
EtO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4e, N/A
4d, 1.5 h, 85%
4b, 2 h, 76%
4c, 2 h, 92%
OTIPS
BnO
OAc
OBn
O
OAllyl
O
BnO
BnO
AllylO
AllylO
O
O
BnO
BnO
BnO
AcO
O
O
O
O
O
O
O
OBn
O
O
O
O
O
O
O
O
O
O
O
OMp
O
O
4g,a 5 h, 90%
4f, 2 h, 89%
4h,b 2 h, 77%
4s, 2 h, 71%
Scheme 4 Glycals scope of glycosylation reactions with acceptor 2g. Reagents and conditions: donor (0.1 mmol), acceptor (0.12 mmol) and CuBr2 (5
mol%), stirred DCM (1.0 mL) at 25 °C, nitrogen atmosphere. a CuBr2 (0.1 equiv) was used. b Product 4h was obtained as a mixture of addition product
and Ferrier rearrangement product with 8:1 ratio. All yields are isolated yields; / ratio of all products was >30:1 based on the 1H NMR spectra. N/A =
not applicable.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
Y. Dong et al.
Letter
Synlett
ride 4f could act as a new glycosyl acceptor for further gly-
cosylation. Thus, we tried to synthesize trisaccharide 5f by
using our strategy. To our delight, deoxygalactose-contain-
ing trisaccharide 5f was successfully obtained in two steps
with 51% yield and high -selectivity.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707098.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
OTIPS
BnO
(1) (a) McCranie, E. K.; Bachmann, B. O. Nat. Prod. Rep. 2014, 31,
1026. (b) Daniel, P. T.; Koert, U.; Schuppan, J. Angew. Chem. Int.
Ed. 2006, 45, 872. (c) He, X. M.; Liu, H. W. Curr. Opin. Chem. Biol.
2002, 6, 590. (d) Gao, J.; Guo, Z. Med. Res. Rev. 2018, 38, 556.
(e) Zhang, X. T.; Gu, Z. Y.; Liu, L.; Wang, S.; Xing, G. W. Chem.
Commun. 2015, 51, 8606.
(2) (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Satyanarayana, M.
Tetrahedron Lett. 2002, 43, 7009. (b) Elshahawi, S. I.; Shaaban, K.
A.; Kharel, M. K.; Thorson, J. S. Chem. Soc. Rev. 2015, 44, 7591.
(3) (a) Hou, D.; Lowary, T. L. Carbohydr. Res. 2009, 344, 1911.
(b) Zeng, J.; Xu, Y.; Meng, Q. Sci. China. Chem. 2017, 60, 1162.
(c) Bennett, C. S.; Galan, M. C. Chem. Rev. 2018, 118, 7931.
(4) (a) Thiem, J.; Gerken, M. J. Org. Chem. 1985, 50, 954. (b) Roush,
W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(c) Blanchard, N.; Roush, W. R. Org. Lett. 2003, 5, 81.
(5) (a) Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1,
891. (b) Hou, D.; Lowary, T. L. J. Org. Chem. 2009, 74, 2278.
(c) Bandi, R.; Chalapala, S.; Chandrasekaran, S. Org. Biomol.
Chem. 2018, 16, 2248.
OH
O
O
O
OTIPS
O
BnO
BnO
BnO
CuBr2 (0.05 equiv)
DCM, 25 °C
+
O
O
O
O
O
O
O
1f
2g
4f
O
O
89%
α:β >30:1
OTIPS
BnO
O
BnO
O
OBn
(1) TBAF/THF
O
BnO
(2) 1f, CuBr2 (0.05 equiv)
O
O
DCM, 25 °C
O
O
O
O
5f
51%
α:β >30:1
Scheme 6 Synthetic applications
(6) (a) Gillard, J. W.; Israel, M. Tetrahedron Lett. 1981, 22, 513.
(b) Verma, V. P.; Wang, C. C. Chem. Eur. J. 2013, 19, 846.
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2016, 35, 315. (d) Wever, W. J.; Cinelli, M. A.; Bowers, A. A. Org.
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2017, 28, 2024.
In conclusion, we have demonstrated a direct and stere-
oselective synthesis of 2-deoxygalactosides catalyzed by li-
gand-free Cu(II) catalyst. Moreover, the new method is
widely applicable to a range of differentially protected ga-
lactal donors and nucleophile acceptors. The reaction pro-
ceeds with excellent yields and high selectivities for the -
anomer in short time. In addition, its synthetic potential
was successfully demonstrated in gram-scale reaction and
by a simple synthesis of oligosaccharides. It should be
pointed out that the reaction may result from various pro-
cesses:25,26 Cu-alcohol-complexes that lower the pKa of the
alcohol components is the most likely, but ‘hidden acid ca-
talysis’ (i.e., hydrolysis/alcoholysis of the salt), acid impuri-
ties in the salt used, or bromine formation from CuBr2 may
also be operating.
(7) Balmond, E. I.; Coe, D. M.; Galan, M. C.; McGarrigle, E. M. Angew.
Chem. Int. Ed. 2012, 51, 9152.
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McGarrigle, E. M.; Galan, M. C. Angew. Chem. Int. Ed. 2014, 53,
8190. (b) Sau, A.; Williams, R.; Palo-Nieto, C.; Franconetti, A.;
Medina, S.; Galan, M. C. Angew. Chem. Int. Ed. 2017, 56, 3640.
(9) Palo-Nieto, C.; Sau, A.; Galan, M. C. J. Am. Chem. Soc. 2017, 139,
14041.
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Ed. 2015, 54, 12479. (b) Palo-Nieto, C.; Sau, A.; Williams, R.;
Galan, M. C. J. Org. Chem. 2017, 82, 407.
Funding Information
(13) Bradshaw, G. A.; Colgan, A. C.; Allen, N. P.; Pongener, I.; Boland,
M. B.; Ortin, Y.; McGarrigle, E. M. Chem. Sci. 2019, 10, 508.
(14) Cui, X. K.; Zhong, M.; Meng, X. B.; Li, Z. J. Carbohydr. Res. 2012,
358, 19.
The project was financially supported by Natural Science Foundation
of Shanghai (11ZR1410400) and by the Large Instruments Open
Foundation of East China Normal University (20162015).
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(15) (a) Yang, G. F.; Wang, Q. B.; Luo, X. S.; Zhang, J. B.; Tang, J. Glyco-
conj. J. 2012, 29, 453. (b) Yang, G. F.; Luo, X. S.; Guo, H.; Wang, Q.
B.; Zhou, J. F.; Huang, T. Y.; Tang, J.; Shan, J. J.; Zhang, J. B. J. Car-
bohydr. Chem. 2018, 37, 128. (c) Qiu, S. F.; Zhang, W.; Sun, G. S.;
Wang, Z. F.; Zhang, J. B. ChemistrySelect 2016, 1, 4840.
(16) (a) Sau, A. T.; Palo-Nieto, C.; Galan, M. C. J. Org. Chem. 2019, 84,
2415. (b) Singh, A. K.; Venkatesh, R.; Kandasamy, J. Synthesis
2019, 51, 4215. (c) Mishra, K. B.; Kandasamy, J. Asian J. Org.
Chem. 2019, 8, 549. (d) Singh, A. K.; Kandasamy, J. Org. Biomol.
Chem. 2018, 16, 5107.
Acknowledgment
We are thankful to the analytical centre of East China Normal Univer-
sity for data measurements. The authors express sincere gratitude for
helpful discussions with Mr Zekun Ding.
(17) Thomba, R. S.; Jadhav, V. H. RSC Adv. 2016, 6, 30846.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

F
Y. Dong et al.
Letter
Synlett
(18) (a) Tai, C.-A.; Kulkarni, S. S.; Hung, S.-C. J. Org. Chem. 2003, 68,
8719. (b) Kusunuru, A. K.; Tatina, M.; Yousuf, S. K.; Mukherjee,
D. Chem. Commun. 2013, 49, 10154. (c) Srinivas, B.; Reddy, T. R.;
Krishna, P. R.; Kashyap, S. Synlett 2014, 25, 1325. (d) Joseph, R.;
Dyer, F. B.; Garner, P. Org. Lett. 2013, 15, 732. (e) Wang, H. Y.;
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Tang, W. Angew. Chem. Int. Ed. 2017, 56, 15698. (f) Verdelet, T.;
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J. Synthesis 2019, 51, 2984.
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 = 177.84, 157.96, 152.84, 138.85, 138.51, 138.11, 128.49,
128.31, 127.88, 127.81, 127.63, 127.37, 111.63, 97.69, 74.60,
74.39, 73.58, 72.93, 70.58, 70.48, 69.59, 60.96, 30.93. HRMS
(ESI): m/z [M + Na]+ calcd for C33H34NaO7: 565.2197; found:
565.2196.
N-(9-fluorenylmethoxycarbonyl)-L-serine methyl ester-3,4,6-
tri-O-benzyl-2-deoxy--D-galactopyranoside (3f)
Yield: 70.4 mg (93%); yellow syrup; : >30:1. 1H NMR (500
MHz, CDCl3):  = 7.76 (d, J = 7.6 Hz, 2 H), 7.58 (d, J = 7.4 Hz, 2 H),
7.41–7.26 (m, 19 H), 5.91 (d, J = 8.7 Hz, 1 H), 4.94 (dd, J = 14.2,
7.0 Hz, 2 H), 4.64–4.56 (m, 3 H), 4.56–4.45 (m, 2 H), 4.43–4.32
(m, 3 H), 4.21 (t, J = 7.1 Hz, 1 H), 3.99 (dd, J = 10.8, 3.7 Hz, 1 H),
3.93–3.83 (m, 4 H), 3.75 (s, 3 H), 3.62–3.57 (m, 1 H), 3.56–3.51
(m, 1 H), 2.23 (td, J = 12.4, 3.4 Hz, 1 H), 1.96 (dd, J = 12.5, 3.9 Hz,
1 H). 13C NMR (125 MHz, CDCl3):  = 170.81, 156.09, 143.91,
141.36, 138.79, 138.40, 138.03, 128.60, 128.21, 128.05, 127.53,
127.46, 127.13, 125.19, 120.04, 99.22, 74.38, 73.49, 72.82,
70.55, 69.58, 68.77, 67.18, 54.56, 52.63, 47.19, 31.12. HRMS
(ESI): m/z [M + Na]+ calcd for C46H47NNaO9: 780.3143; found:
780.3127.
(23) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.; Raffaelli, B.
Chem. Eur. J. 1999, 5, 1748.
(24) Paul, S.; Jayaraman, N. Carbohydr. Res. 2007, 342, 1305.
(25) Tatina, M. B.; Moussa, Z.; Xia, M. X.; Judeh, Z. M. A. Chem.
Commun. 2019, 55, 12204.
4-t-Butyl-Phenyl-3,4,6-tri-O-benzyl-2-deoxy--D-galactopy-
ranoside (3k)
Yield: 47.0 mg (83%); yellow syrup; : >30:1. 1H NMR (500
MHz, CDCl3):  = 7.41–7.26 (m, 15 H), 7.24 (d, J = 7.2 Hz, 2 H),
7.00 (d, J = 8.7 Hz, 2 H), 5.69 (d, J = 2.9 Hz, 1 H), 4.98 (d, J =
11.5 Hz, 1 H), 4.70–4.64 (m, 3 H), 4.43 (d, J = 11.6 Hz, 1 H), 4.37
(d, J = 11.6 Hz, 1 H), 4.15 (dd, J = 11.1, 3.2 Hz, 1 H), 4.09 (t, J =
6.5 Hz, 1 H), 4.03 (s, 1 H), 3.70–3.64 (m, 1 H), 3.56 (dd, J = 9.3,
5.7 Hz, 1 H), 2.40 (td, J = 12.4, 3.6 Hz, 1 H), 2.21 (dd, J = 12.7,
4.4 Hz, 1 H), 1.30 (s, 9 H). 13C NMR (125 MHz, CDCl3):  =
154.83, 144.65, 138.92, 138.57, 138.15, 128.52, 128.39, 128.3,
127.85, 127.69, 127.66, 127.62, 127.43, 126.26, 116.15, 96.82,
74.73, 74.51, 73.42, 72.98, 70.65, 69.32, 34.21, 31.59, 31.43.
HRMS (ESI): m/z [M + Na]+ calcd for C37H42NaO5: 589.2924;
found: 589.2916.
(26) Sletten, E. T.; Tu, Y. J.; Schlegel, H. B.; Nguyen, H. M. ACS Catal.
2019, 9, 2110.
(27) 6-O-(3’,4’,6’-Tri-O-benzyl-2’-deoxy--D-galactopyranosyl)-
1,2:3,4-di-O-isopropylidene--D-galactopyranoside (3g)
Under a nitrogen atmosphere, glycal donor 1a (0.10 mmol, 41.6
mg) and nucleophile acceptor 2g (0.12 mmol, 31.2 mg) were
dissolved in anhydrous DCM (1.0 mL). Meanwhile CuBr2 (0.005
mmol, 1.3 mg) was added to the system quickly. The reaction
mixture was stirred at 25 °C until the reaction was determined
to be complete by TLC. The reaction was then quenched with
sat. aq. NaHCO3, and the mixture was extracted with DCM. The
combined organic phases were washed with sat. aq. NaHCO3
and brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography (PE/EtOAc = 6:1) to give a yellow
syrup. Yield: 55.4 mg (82%), : >30:1.
4-Fluoro-Phenyl-3,4,6-tri-O-benzyl-2-deoxy--D-galactopy-
ranoside (3m)
1
Yield: 41.7 mg (79%); colorless syrup; : >30:1. H NMR (500
MHz, CDCl3):  = 7.42–7.19 (m, 15 H), 7.01 (dd, J = 8.7, 4.4 Hz,
2 H), 6.93 (t, J = 8.5 Hz, 2 H), 5.62 (s, 1 H), 4.97 (d, J = 11.5 Hz,
1 H), 4.71–4.61 (m, 3 H), 4.43 (d, J = 11.6 Hz, 1 H), 4.37 (d, J =
11.6 Hz, 1 H), 4.12 (d, J = 11.6 Hz, 1 H), 4.04 (dd, J = 15.5, 9.2 Hz,
2 H), 3.67–3.60 (m, 1 H), 3.55 (dd, J = 9.2, 6.1 Hz, 1 H), 2.39 (dd,
J = 12.4, 3.1 Hz, 1 H), 2.20 (dd, J = 12.7, 4.1 Hz, 1 H). 13C NMR
(125 MHz, CDCl3):  = 159.05, 157.14, 153.08, 138.83, 138.48,
138.06, 128.55, 128.43, 128.36, 128.32, 127.79, 127.77, 127.72,
127.68, 127.44, 118.14, 118.08, 115.94, 115.76, 97.36, 74.56,
74.51, 73.45, 72.93, 70.80, 70.66, 69.40, 31.31. HRMS (ESI): m/z
[M + Na]+ calcd for C33H33FNaO5: 551.2204; found: 551.2194.
4-Chloro-Phenyl-3,4,6-tri-O-benzyl-2-deoxy--D-galactopy-
ranoside (3n)
Trichloroethyl-3,4,6-tri-O-benzyl-2-deoxy--D-galactopyrano-
side (3c)
1
Yield: 46.2 mg (82%); colorless syrup; : >30:1. H NMR (500
MHz, CDCl3):  = 7.39–7.26 (m, 15 H), 5.24 (d, J = 2.3 Hz, 1 H),
4.95 (d, J = 11.6 Hz, 1 H), 4.62 (d, J = 11.4 Hz, 3 H), 4.51 (d, J =
11.8 Hz, 1 H), 4.44 (d, J = 11.8 Hz, 1 H), 4.19 (d, J = 11.5 Hz, 1 H),
4.07 (d, J = 11.5 Hz, 1 H), 4.04–3.98 (m, 2 H), 3.96 (s, 1 H), 3.59
(d, J = 6.3 Hz, 2 H), 2.29 (td, J = 12.5, 3.4 Hz, 1 H), 2.16 (dd, J =
12.7, 4.2 Hz, 1 H). 13C NMR (125 MHz, CDCl3):  = 138.81,
138.39, 138.09, 128.52, 128.50, 128.34, 128.34, 127.82, 127.70,
127.68, 127.53, 98.87, 96.85, 79.15, 74.43, 73.55, 72.90, 71.03,
70.69, 69.46, 30.73. HRMS (ESI): m/z [M + Na]+ calcd for C29H31Cl3NaO5:
587.1129; found: 587.1110.
1
Yield: 45.8 mg (75%); colorless syrup; : >30:1. H NMR (500
MHz, CDCl3):  = 7.41–7.19 (m, 17 H), 6.99 (t, J = 6.1 Hz, 2 H),
5.66 (d, J = 3.0 Hz, 1 H), 4.97 (d, J = 11.5 Hz, 1 H), 4.70–4.62 (m,
3 H), 4.41 (d, J = 11.6 Hz, 1 H), 4.36 (d, J = 11.6 Hz, 1 H), 4.10
(ddd, J = 11.9, 4.3, 2.3 Hz, 1 H), 4.03–3.97 (m, 2 H), 3.63 (dd, J =
9.3, 7.2 Hz, 1 H), 3.52 (dd, J = 9.4, 5.8 Hz, 1 H), 2.40 (td, J = 12.5,
3.6 Hz, 1 H), 2.20 (dd, J = 12.8, 4.5 Hz, 1 H). 13C NMR (125 MHz,
CDCl3):  = 155.51, 138.81, 138.45, 138.01, 129.40, 128.56,
128.44, 128.36, 128.31, 127.81, 127.78, 127.74, 127.69, 127.44,
126.94, 118.05, 96.86, 74.53, 74.50, 73.44, 72.86, 70.87, 70.67,
Furfuraldehyde-5-methyl-3,4,6-tri-O-benzyl-2-deoxy--D-
galactopyranoside (3e)
Yield: 48.2 mg (89%); yellow syrup; : >30:1. 1H NMR (500
MHz, CDCl3):  = 9.61 (s, 1 H), 7.36–7.26 (m, 15 H), 7.17 (d, J =
3.5 Hz, 1 H), 6.48 (d, J = 3.5 Hz, 1 H), 5.08 (d, J = 3.1 Hz, 1 H), 4.94
(d, J = 11.6 Hz, 1 H), 4.66–4.58 (m, 4 H), 4.56–4.42 (m, 3 H),
3.96–3.90 (m, 3 H), 3.61–3.54 (m, 2 H), 2.26 (td, J = 12.6, 3.6 Hz,
1 H), 2.04 (dd, J = 12.8, 4.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3):
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
Y. Dong et al.
Letter
Synlett
69.29, 31.20, 29.79. HRMS (ESI): m/z[M + Na]+ calcd for C33H33ClNaO5:
567.1909; found: 567.1895.
1 H), 4.18–4.11 (m, 1 H), 4.03 (d, J = 7.6 Hz, 2 H), 3.67 (t, J =
8.4 Hz, 1 H), 3.53 (dd, J = 9.2, 5.5 Hz, 1 H), 2.42 (td, J = 12.5,
3.4 Hz, 1 H), 2.22–2.18 (m, 1 H), 2.17 (s, 3 H). 13C NMR
(125 MHz, CDCl3):  = 154.98, 138.92, 138.37, 138.05, 130.69,
128.53, 128.41, 128.33, 128.30, 127.89, 127.74, 127.73, 127.62,
127.15, 126.95, 121.58, 114.24, 96.28, 74.51, 74.28, 73.47,
72.96, 70.78, 70.53, 69.18, 31.50, 16.3. HRMS (ESI): m/z [M +
Na]+ calcd for C34H36NaO5: 547.2455; found: 547.2441.
2-Methyl-Phenyl-3,4,6-tri-O-benzyl-2-deoxy--D-galactopy-
ranoside (3p)
1
Yield: 39.8 mg (76%); colorless syrup; : >30:1. H NMR (500
MHz, CDCl3):  = 7.41–7.20 (m, 15 H), 7.15–7.08 (m, 3 H), 6.94–
6.86 (m, 1 H), 5.71 (d, J = 1.9 Hz, 1 H), 4.99 (d, J = 11.5 Hz, 1 H),
4.73–4.62 (m, 3 H), 4.42 (d, J = 11.6 Hz, 1 H), 4.36 (d, J = 11.6 Hz,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G