Tetrahedron Letters
KOtBu-mediated aromatic O-glycosylation of 1,2-anhydrosugar
and aryl boronic acid
Chen-Fu Liu a,y, De-Cai Xiong a,y, Xin-Shan Ye a,b,
⇑
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China
b National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach for the synthesis of phenolic glycosides via aromatic O-glycosylation of 1,2-anhydro-
sugar and aryl boronic acids was disclosed. This method is characterized by the use of aryl boronic acid
as the aryl source and produces phenolic glycosides in a stereoselective manner. This reaction provides an
alternative approach to the synthesis of phenolic glycosides. It also represents a new application of aryl
boronic acids as versatile reagents in organic synthesis.
Received 27 October 2015
Revised 4 February 2016
Accepted 16 February 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Anhydrosugar
Aryl boronic acid
Phenolic glycoside
Potassium tert-butoxide
O-glycosylation
Phenolic glycoside refers to the compounds containing a sugar
unit bound to a phenol aglycone and encompasses a vast number
of secondary metabolites such as vancomycin and chromomycin.1
The synthesis of phenolic glycosides has received considerable
attentions from both synthetic chemists and medicinal chemists
because of their diverse biological activities and pharmaceutical
potentials.2 During the past years, many efforts have been made
in the O-glycosylation of phenols by varying different glycosyl
donors and the corresponding activation conditions.3 However,
due to the electron-withdrawing properties of aromatic rings, phe-
nols are usually difficult to be glycosylated. The existing methods
suffer from some drawbacks such as anomerization,4 the formation
of C-glycoside by-products,5 or limited substrate scope. Thus, the
development of new approaches to the synthesis of phenolic glyco-
sides is still highly desired.
suitable surrogates of phenols for the synthesis of phenolic glyco-
sides.8 Herein we report the synthesis of phenolic glycosides by the
reaction of 1,2-anhydrosugars9 with aryl boronic acids.
To begin our study, the reaction of 1a with 2a was further
examined (Table 1). It was found that the catalyst Pd2(dba)3 was
not essential for the generation of phenolic glycoside 3a (entry
1). Base was crucial for this reaction and KOtBu was identified to
be the best base (entries 2–13, up to 73% yield). Although the reac-
tion was able to proceed in the solvents such as toluene, acetoni-
trile, and DME, THF was the most proper solvent (entries 13–19).
The yields of 3a decreased with the decrease of the reaction tem-
perature (entries 20 and 21). It seemed that the use of 2.0 equiv
of KOtBu afforded product 3a in the best yield (entries 22, 23 and
13). Under either argon atmosphere or air atmosphere, the reaction
gave no different results (entries 13 and 24). Therefore, the opti-
mized reaction conditions are as follows: 1,2-anhydrosugar
(1.0 equiv), aryl boronic acid (1.2 equiv), KOtBu (2.0 equiv) in THF
at 50 °C.10
With the optimized conditions in hand, the scope of aryl boro-
nic acids was examined, and the results are summarized in Table 2.
All aryl boronic acids with electron-donating, electron-withdraw-
ing, or sterically congested groups worked well. In the case of
ortho/meta/para-methyl substituted aryl boronic acids, the
expected coupling products 3b, 3c, and 3d were isolated in 71%,
74%, and 79% yields, respectively (entries 1–3). When the elec-
tron-rich aryl boronic acid 2e was used, the reaction occurred
and the desired product 3e was obtained in 69% yield (entry 4).
In our search for the development of new methods toward aryl-
C-glycoside synthesis, phenolic glycoside 3a was accidentally
obtained in 35% yield by the reaction of 1,2-anhydro-3,4,6-tri-O-
benzyl-a-
D
-glucopyranose (1a)6 with phenyl boronic acid (2a) cat-
alyzed by Pd2(dba)3, whereas C-glycoside 4a was not detected
(Scheme 1). In fact, aromatic boronic acids enjoy the high prestige
in organic synthesis due to their low toxicity, stability to air and
moisture, and good functional group tolerance.7 They might be
⇑
Corresponding author. Tel.: +86 10 8280 5736; fax: +86 10 8280 2724.
These authors contributed equally to this work.
y
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.