LETTER
1627
Highly Efficient b-Glucosylation of the Acidic Hydroxyl Groups, Phenol and
Carboxylic Acid, with an Peracetylated Glucosyl Fluoride Using a
Combination of BF3·Et2O and DTBMP as a Promoter
Kin-ichi Oyama, Tadao Kondo
Chemical Instrument Center, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Fax +81-52-789-3062; E-mail: tkmail@cic.nagoya-u.ac.jp
Received 22 July 1999
side from 80% to 92% (Table 1). However, this reaction
Abstract: A combination of BF3·Et2O and DTBMP was established
is not applicable to the glucosylation of simple alcohols.8
to be an efficient promoter of b-glucosylation of both phenols and
carboxylic acids with a peracetylated glucosyl fluoride (2). This
new method achieved remarkably high yields and b-selectivity.
Key word: phenyl glucoside, 1-acylglucose, BF3·Et2O, 2,6-di-tert-
butyl-4-methylpyridine, peracetylated glucosyl fluoride
Aryl b-glucosides and acyl b-glucosides are widely found
in natural products such as anthocyanin, flavonoids,
polyphenols and antibiotics and play key roles in the ex-
pression of important biological functions.1,2,3 However,
in spite of a number of methods reported in the literature,4
glucosylation methods for hindered or low-nucleophilic
phenols, substituted with electron-withdrawing groups,
are not always satisfactory in terms of yield, stereoselec-
tivity or convenience.3,4a For example, in the case of low-
nucleophilic phenols, the Koenigs-Knorr reaction using a
glucosyl bromide or chloride predominantly gives an
orthoester or its transformed 1-hydroxy sugar, but only a
small amount of glucosides.4e Though peracetylglucosyl
fluoride (2) is very stable and effective for 1,2-trans-b-
glucosides,4b,c it is not suitable as a sugar donor because of
its low reactivity.5 Yamaguchi have approached the prob-
lem of glucosylation of phenols using BF3·Et2O / 1,1,3,3-
tetramethylguanidine (TMG) as a promoter.6 A Lewis
acid-and-base promotion system has been the subject of
our attention.
We have thereby developed a very efficient b-glucosyla-
tion methodology for phenols and carboxylic acids by per-
It was reported that phenols with electron-donating
groups showed high b-selectivity6 and electron-with-
drawing group retard the reaction.4a Thus, the high yield
and high b-selectivity might be realized by the increasing
the nucleophilicity of the phenols by formation of the na-
ked phenolic hydroxyl anion with the hindered base (DT-
BMP). Also, high b-selectivity might be realized by the
SN2-type process or the neighboring group participation
of the carbonyl oxygen at the C2. Less hindered pyridines
such as 2,6-lutidine may directly coordinate Lewis acid,
so that the reactivity is reduced.
acetylated glucosyl fluoride (2), using a combination of a
Lewis acid and highly hindered base, BF3·Et2O and 2,6-
di-tert-butyl-4-methylpyridine (DTBMP). Initially, meth-
yl p-coumarate (1), a low-nucleophilic phenol, was select-
ed as a glucosyl acceptor for the screening of the O-
glucosylation promoters (Table 1).7 BF3·Et2O specifically
enhanced its reaction to give the glycoside (in 37% yield,
3a predominated over 3b)6 in spite of being base-free,
whereas other Lewis acids, such as TiCl4, TMSOTf, and
SnCl4, afforded no glucosyl-products. Using CH3CN as
the solvent and BF3·Et2O as the Lewis acid in the presence
of DTBMP, the reaction gave 3 in 80% yield. However,
the glucosylation with TMG and 2,6-lutidine gave 3 in
68% and 32%, respectively. With the addition of the base,
b-glucosides predominated. The changing of the solvent
from CH3CN to CH2Cl2 improved the yield of the gluco-
The phenols substituted with electron-donating groups se-
lectively gave b-glycosides (Table 2). Furthermore, in
spite of hindered phenols, both 4 and 5 gave high yields
and complete b-selectivity. The phenols substituted with
Synlett 1999, No. 10, 1627–1629 ISSN 0936-5214 © Thieme Stuttgart · New York