2332
Macromolecules 2004, 37, 2332-2334
Ta ble 1. Syn th esis of NCA w ith Di-ter t-bu tyltr ica r bon a tea
A F a cile Syn th esis of N-Ca r boxya n h yd r id es
a n d P oly(r-a m in o a cid ) Usin g
run
R-amino acid
yield (%)
Di-ter t-bu tyltr ica r bon a te
1
2
3
4
γ-benzyl-L-glutamate
L-alanine
L-leucine
84
41
33
25
Atsu sh i Na ga i,† Da isu k e Sa to,† J u n ich i Ish ik a w a ,†
Bu n go Och ia i,† Hir oto Ku d o,‡ a n d Ta k esh i En d o*,†
L-phenylalanine
a
Conditions: R-amino acid (1.0 mmol) and di-tert-butyltricar-
Department of Polymer Science and Engineering,
Faculty of Engineering, Yamagata University,
4-3-16 J onan, Yonezawa, Yamagata 992-8510, J apan, and
Department of Applied Chemistry, Faculty of Engineering,
Kanagawa University, Rokkakubashi,
bonate (1.0 mmol) in THF (20 mL) at 60 °C for 4 h.
the DBTC method.12 Herein, we describe (1) a facile
synthesis of NCAs from R-amino acids and DBTC and
(2) a one-pot synthesis of poly(amino acid) from an
amino acid and DBTC as a dehydrating agent.
Kanagawa-ku, Yokohama 221-8686, J apan
Received J anuary 22, 2004
We first tried to prepare γ-benzyl-L-glutamate-N-
carboxyanhydride (BLG-NCA) from BLG and DBTC
(Scheme 1; Table 1, run 1). BLG was added to a solution
of DBTC (1.1 equiv) in dry tetrahydrofuran (THF) (0.1
M) at 60 °C. Although the starting reaction mixture was
heterogeneous, the mixture changed to a homogeneous
solution after 2 h. Strong IR aborption assignable to the
isocyanate was observed at 2252.5 cm-1 in CHCl3
solution of the mixture after 2 h. After 4 h, this
absorption completely disappeared, and a new IR aborp-
tion assignable to the carbonyl moieties in N-carboxy-
anhydride was observed at 1851.3 and 1781.9 cm-1. The
resulting mixture was concentrated by a rotary evapo-
rator, and residual mass was washed with dry n-hexane,
followed by recrystallization from a mixed solvent (THF
and n-hexane) to obtain a colorless solid, BLG-NCA,
in high yield. In a similar fashion, NCAs could be
prepared from several R-amino acids such as L-alanine,
L-leucine, and L-phenylalanine (Table 1, runs 2-4).13
Although BLG gave the corresponding NCA effi-
ciently, other amino acids gave in lower yields. Because
the reaction remained heterogeneous after 4 h, the lower
yield may originate from the poor solubility of the amino
acids. The stoichiometry and the intermediates leading
to NCA formation are illustrated in Scheme 1 (path A).
Nucleophilic attack of an amine moiety in an amino acid
to a carbonyl moiety in DBTC forms an isocyanato acid
intermediate that is transformed to the corresponding
NCA via intramolecular cyclization. As a consequence,
this reaction affords NCAs in a simple procedure where
the byproducts are 2 equiv of CO2 and tert-butyl alcohol,
which are inert to NCAs and easily separated.
Revised Manuscript Received February 15, 2004
The chemistry of amino acids and peptides is impor-
tant in the structural elucidation and synthesis of oligo-
and polypeptides with useful biological function.1 We
can now obtain optically pure amino acids for low prices
due to recent remarkable improvements in the technol-
ogy in fermentation and organic synthesis. Conse-
quently, amino acids and some oligopeptides are now
widely used for drug, food, chiral sources in organic
synthesis, and polymers from chemical and biological
methods. Because synthetic polypeptides with high
molecular weight can be models for the general study
of physical, chemical, and biological properties of pro-
teins, a wide variety of methods for polypeptides syn-
thesis have been proposed.2-7 Chemical synthetic meth-
ods for polypeptides can be divided into two methods.
The first one is sequential condensation including solid-
phase synthesis that afford polypeptides with highly
regulated sequences.4 These polypeptides have been
widely applied in the field of biological and medicinal
areas, although this method requires demanding pro-
cesses and is not suitable for mass production. The
second one is polycondensation5 of activated amino acid
derivatives and ring-opening polymerization6,7 of R-ami-
no acid anhydrides (NCAs) that affords polypeptides
comprising linkage of one kind of amino acids, which
can easily produce high molecular weight polypeptides.
These polypeptides are regarded as important materials
in biological and industrial areas. Ring-opening poly-
merization of NCAs is advantageous over the polycon-
densation because ring-opening polymerization, which
is a chain polymerization, is capable of providing
polypeptides with precise topology (e.g., block and graft
polymers) and controlled architecture. The starting
materials NCAs have been generally prepared from
amino acids with phosgene or triphosgene, which are
highly toxic.8 The reaction generates hydrogen chloride
that makes preparation of pure NCAs without contami-
nation of amino acid hydrochloride salts as byproducts
difficult. To solve these troubles, we selected di-tert-
butyltricarbonate (DBTC)8,9 instead of phosgene (see
Supporting Information). DBTC has been already re-
ported to enable facile syntheses of multiisocyanate from
primary amines10 and R,ω-isocyanato alcohol from
amino alcohol.11 We have also reported a one-pot
synthesis of an L-tyrosine-based polyurethane by using
When this reaction was carried out under more
concentrated solutions of R-amino acids, some intermo-
lecular reactions should predominantly take place to
afford poly(amino acid)s (Scheme 1, path B). BLG as a
monomer was selected as a typical example. Polymer-
ization of BLG was carried out with DBTC as a
dehydrating agent in several solvents (1.0 M) for 24 h
to afford poly(BLG). The polymerization proceeded
heterogeneously, which is in contrast to the case of the
NCA synthesis. After 24 h, insoluble BLG was removed
by filtration, and the polymers were isolated by pre-
cipitation with methanol. Dichloromethane and 1,4-
dioxane were suitable solvents to obtain polymers with
high molecular weight (Mn > 104) in good yields (Table
1
2, runs 2-4). The H NMR,13C NMR, and IR spectra of
the obtained poly(BLG) were in identical to the authen-
tic spectra of poly(BLG) (see Supporting Information).14
In this polymerization system, the following two
mechanisms are possible: (1) intermolecular polycon-
† Yamagata University.
‡ Kanagawa University.
* To whom correspondence should be addressed: Tel +81-23-
26-3090; Fax +81-238-26-3090; e-mail tendo@yz.yamagata-u.ac.jp.
10.1021/ma0498464 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004
Nagai, Atsushi
