698
Published on the web May 29, 2010
Racemization-free Monomer: ¡-Hydroxyisobutyric Acid from Bio-based Lactic Acid
Kohtaro Watanabe,1 Yoshito Andou,2 Yosihito Shirai,1,2 and Haruo Nishida*2
1Department of Biological Functions and Engineering, Kyushu Institute of Technology,
2-4 Hibikino, Wakamatsu-ku, Kitakyushu 808-0196
2Eco-Town Collaborative R&D Center for the Environment and Recycling, Kyushu Institute of Technology,
2-4 Hibikino, Wakamatsu-ku, Kitakyushu 808-0196
(Received March 17, 2010; CL-100258; E-mail: nishida@lsse.kyutech.ac.jp)
In order to solve the important problem of the racemization of
poly(L-lactic acid), synthesis11 of the racemization-free mono-
mer HIBA was achieved using D,L-lactic acid as a starting
material to prepare the biomass-based PTMG.
poly(L-lactic acid), a high yield of racemization-free monomer:
a-hydroxyisobutyric acid (HIBA) was synthesized from bio-
based lactic acid by methylation using specific bases with bulky
side groups. Obtained HIBA can be converted into poly(tetra-
methylglycolide), which is racemization-free and has higher
melting and glass transition points than poly(L-lactic acid).
Before the substitution of a methine proton by a methyl
group, more reactive groups hydroxy and carboxyl groups were
protected with methoxymethyloxy12 and ethyl ester groups,
resulting in the preparation of an ethyl lactate derivative 2 in
high yield (Scheme 1).13 The methoxymethyloxy group was
chosen as a specific protection group because of its stability
under basic conditions of methylation. Protected derivative 2
was reacted with various kinds of basic reagents and methyl
iodide (CH3I) to substitute the methine proton by a methyl
group. General basic reagents, such as K2CO3, NaOH, NaH, and
DBU gave no methylated product, because of preferential
reactions of the reagents with ester groups and CH3I. In order
to control the nucleophilicity of the counter anions of basic
reagents, bulky side groups, such as isopropyl and trimethylsilyl
groups, were introduced plurally in the anions. These bulky side
groups may allow a center anion to abstract a proton from the
methine group, but prevent attacks on the carbonyl carbon.
Typical bases with bulky side groups are lithium diisopropyl-
amide (LDA),14 hexamethyldisilazane lithium (LHMDS) and
sodium (NHMDS) salts.15 These are strong bases as demon-
strated by the pKa’s values for the conjugate acids of LDA and
LHMDS are 35.7 and 25.8, respectively.16
When LDA and CH3I were reacted with the protected
derivative 2 at ¹84 °C, the methylation proceeded smoothly
to give an ethyl ¡-hydroxyisobutyrate derivative 3 in 83%
conversion. The derivative 3 was isolated in 74% yield. In
Figure 1, 1H NMR spectra of the derivatives 2 and 3 clearly
show a doublet peak at 1.43 ppm and a singlet peak at 1.47 ppm,
respectively.17 In the same manner, LHMDS and NHMDS also
gave the derivative 3 with moderate conversions of 45 and 23%
as listed in Table 1, respectively. When another lithium amide
having compact side groups, for example LiNH2, was used, no
methylation proceeded, indicating the steric hindrance effect of
bulky side groups.
Poly(L-lactic acid) (PLLA), a biomass-based biodegradable
polyester capable of synthesis from renewable resources, is
already well known for its excellent attributes of thermoplas-
ticity, transparency, crystallinity, and high melting point
(Tm = 170 °C).1 Recently, however, PLLA has been attracting
much interest from researchers as a superior recyclable polymer
capable of conversion into the cyclic monomer L,L-lactide under
heating.2 This reversible conversion results from the equilibrium
between PLLA and lactide.3 However, one important issue
affecting monomer recovery is racemization,4 thereby resulting
in the recovery of diastereoisomers, meso and D,D-lactide
causing decrease in the crystallinity and melting point of the
reproduced PLLA.5
This racemization of PLLA, reported as resulting from
ester-semiacetal tautomerization,6 suggests the reactivity of ¡-
hydrogen on a chiral carbon. However, by substituting the active
¡-hydrogen with a methyl group, lactic acid can be changed into
the racemization-free ¡-hydroxyisobutyric acid (HIBA), which
has been synthesized from petroleum via many processes using
HCN.7 Poly(¡-hydroxyisobutyric acid) [poly(tetramethylglyco-
lide): PTMG], which has been prepared by the ring-opening
polymerization of a cyclic diester of HIBA: tetramethylglycolide
(TMG),8 is known as an optically nonactive polymer and has a
higher Tm value (>190 °C) than PLLA.9
Previously, the methylation of lactic acid was also attempted
by using hindered lithium dialkylamides, but a very low
conversion of less than 10% was reported.10 In the present
study, in order to solve the important issue of the racemization of
H2SO4, EtOH
reflux, 4h
NaH, CMME
r.t., 1h
O
OH
O
O
O
HO
HO
O
O
O
lactic acid
ethyl lactate 1 (yield 83%)
ethyl lactate derivative 2 (71%)
KOH, H2O/MeO
O
r.t., over night
O
p-TSA/EtOH
LDA, CH3I
OH
O
HO
HO
O
O
r.t., 1h
-84°C, 4h
O
O
ethyl α-hydroxyisobutyrate
derivative 3 (74%)
ethyl α-hydroxyisobutyrate
4 (83%)
α-hydroxyisobutyric acid (89%)
Scheme 1. Synthesis of ¡-hydroxyisobutyric acid from lactic acid.
© 2010 The Chemical Society of Japan
Chem. Lett. 2010, 39, 698-699
Watanabe, Kohtaro
