856
Published on the web July 3, 2010
An Efficient and Practical Method for the Preparation of a Branched Oligoglycerol
with Acetonide Protection Groups
Hisao Nemoto,* Masaki Kamiya, Aki Nakamoto, Ayato Katagiri,
Kohsuke Yoshitomi, Tomoyuki Kawamura, and Hatsuhiko Hattori
Department of Pharmaceutical Chemistry, Division of Health Biosciences,
The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505
(Received May 28, 2010; CL-100507; E-mail: nem@ph.tokushima-u.ac.jp)
A novel method for the preparation of 1,3-bis(2,2-dimethyl-
O R2
1,3-dioxan-5-yloxy)propan-2-ol,
a
branched oligoglycerols
O
O
Cl
(BGL), was developed from 1,3-diallylated glycerol in excellent
yield.
O
O R1
O R2
HO
1
Preparation of 5-hydroxy-1,3-dioxanes 1 was previously
carried out by acetalization or ketalization of glycerol, which
generally produced a mixture of 1 and the isomer(s) 2
(Scheme 1).1
We recently reported that protected branched glycerol
trimers 3 (BGL003) and heptamers 4 (BGL007),2 which convert
very lipophilic molecules into water-soluble derivatives, were
synthesized starting from 1a1 and 1b3 (Scheme 2).
The protecting groups of 3a and 3b are deprotectable under
mild acidic conditions and under hydrogen atmosphere in the
presence of palladium catalysts to produce the volatile depro-
tected residues, acetone and toluene, respectively. Thus, it is
important to develop a facile and efficient method for the large-
scale preparation of small units of glycerol such as 1a, 1b, 3a,
and 3b for various projects concerning the synthesis of linear,
branched, and dendron oligo- and polyglycerols,4 including our
BGL-related projects.
O R1
3
a: R1 = R2 = Me
BGL003
O R2
R1
b: R1 = Ph, R2 = H
O
O
O
Cl
O R2
O R1
O R2
O R1
O R2
O R1
O
O
O
O
HO
O
4
BGL007
First, we report the successful large-scale preparation of 1b3
(1.2 kg) from glycerol (1.0 kg) and benzaldehyde (1.0 kg). The
dioxane 1b was isolated from a mixture of 1b, its trans-
diastereomer and a diastereomeric mixture of 2b by recrystal-
lization. All the reagents for this reaction and the subsequent
isolation (toluene as a reaction solvent, hexane and ethyl acetate
for recrystallization, and sulfonic acid for acetalization catalyst)
were reasonably priced and/or easily recoverable.
When the benzaldehyde dimethyl acetal was used instead of
benzaldehyde in the presence of various acids, 1H NMR analysis
of the crude product indicated that the molar ratio of the
undesired 2b was increased. Furthermore, isolation of 1b via
recrystallization was unsuccessful probably because of the high
Scheme 2.
molar ratio of 2b and contamination of the remaining benzal-
dehyde dimethyl acetal. Accordingly, use of benzaldehyde was
more suitable to prepare pure 1b than use of the dimethyl acetal.
In contrast, ketalization of glycerol with acetone (or 2,2-
dimethoxypropane) exclusively afforded undesired 2a, and not
even a trace amount of 1a was detected.1,5 Therefore, we initially
prepared 1a with the aid of Forbes’ contrivable method via three
steps,1 which involved acetonization of 2-amino-2-(hydroxy-
methyl)propane-1,3-diol, oxidative cleavage of the C-C bond,
and reduction of the resulting ketone. However, the method was
time-consuming and laborious on a kilogram-scale, due to the
presence of uneconomical processes such as reduction immedi-
ately after oxidation, loss of 25% of the carbon atoms,
requirement for 3.5-4.0 kg of NaIO4 and more than 100-150 g
of dangerous LiAlH4 in order to yield 1.0 kg of 1a.
To avoid this wasteful oxidation-reduction combination and
the use of expensive or dangerous reagents, we considered a new
synthetic route detouring around 1a. We herein report an
alternative and efficient method for the preparation of 3a
(Scheme 3).
The starting material 5 is commercially available, or was
prepared from epichlorohydrin and allyl alcohol in one step
according to a method for the preparation of 1,3-dibenzylgly-
cerol.6 Tetraallylated BGL003 67 was also prepared from four
O
OH
OH
OH
R1 R2
O
O
O
R1
or
O
OH OH
R2
R1 R2
R'O
OR'
R1 R2
2
1
Acid Catalyst
a: R1 = R2 = Me, b: R1 = Ph, R2 = H
Scheme 1.
Chem. Lett. 2010, 39, 856-857
© 2010 The Chemical Society of Japan
Nemoto, Hisao
