Useful synthetic method of polypeptides with well-defined structure by polymerization of activated urethane derivatives of α-amino acids

Article abstract of DOI:10.1002/pola.26052

A facile polymerization strategy for synthesis of polypeptides with well-defined structure using urethane derivatives of α-amino acids in the presence of amine is reported. N-(phenoxycarbonyl) α-amino acid was polymerized at 60°C in N,N-dimethyl acetamide

Full text of DOI:10.1002/pola.26052

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Useful Synthetic Method of Polypeptides with Well-Defined Structure by
Polymerization of Activated Urethane Derivatives of a-Amino Acids
Shuhei Yamada, Koichi Koga, Takeshi Endo
Molecular Engineering Institute, Kinki University, 11-6 Kayanomori, Iizuka, Fukuoka 820-8555, Japan
Correspondence to: T. Endo (E-mail: tendo@moleng.fuk.kindai.ac.jp)
Received 8 December 2011; accepted 13 March 2012; published online
DOI: 10.1002/pola.26052
KEYWORDS: amino acid; N-carboxyanhydride; block copolymers; monomers; polypeptides; ring-opening polymerization
INTRODUCTION Polypeptides have received great attention
structure, using N-(phenyloxycarbonyl) amino acid as precur-
sor of NCA in the presence of amine, and approaching for the
synthesis of block copolypeptides. In this synthetic method,
these urethane derivatives were easily synthesized with N-car-
bamoylation of a-amino acid with diphenyl carbonate (DPC)
and stable for moisture or heating. Therefore, polypeptides
synthesis using urethane derivatives is more convenient than
conventional ring opening polymerization of highly reactive
NCAs, for application to various functional materials.
as promising components for new design of various macro-
1
–5
molecular architectures,
because of its intriguing feature
such as a-helix and b-sheet. For polypeptide synthesis, various
synthetic strategies have been developed. Small peptide
sequences were generally synthesized by stepwise solid-phase
synthesis, whereas, for synthesis of high molecular weight
polypeptides, living ring-opening polymerizations of N-carbox-
yanhydride (NCA) of a-amino acid are widely used. The poly-
merization of NCA was usually initiated by nucleophiles such
as primary or secondly amines, which lead to the production
of polypeptides with well-defined chain length and terminal
structure. Therefore, its polymerization system could allow to
construct various kinds of polypeptides-based functional
RESULTS AND DISCUSSION
The general synthetic routes toward urethane derivatives of a-
amino acids are outlined in Scheme 1. According to previous
our report, we synthesized N-(phenyloxycarbonyl) amino acids
by two step reactions: (1) transformation of a-amino acids into
the corresponding ammonium salts and (2) N-carbamoylation
of the salts with DPC. After carefully purification by column
chromatography and recrystallization, urethane derivatives of
a-amino acid were successfully obtained in moderate yield
6
–8
9
materials, including drug delivery,
face modification,
tissue engineering, sur-
1
0–12
13,14
and organic electronics.
Although living polymerization of NCA affords an important
advantage in synthesis of well-defined polypeptide, the suscep-
tive nature of NCA for moisture and heating is major draw-
backs for its production toward practical use. Thus, develop-
ment of alternative procedure for polypeptide synthesis is a
great challenge in this research area. To date, some useful
monomers for polypeptides synthesis have been reported. For
example, Hurd and Buess developed a-carboxy hydroxamic
(
68%). These urethane derivatives of a-amino acid could be
stored stably for several months at room temperature.
To investigate polymerization behavior of their urethane
derivatives in details, as illustrated in Scheme 2, polymeriza-
tion of 1a was first examined in N,N-dimethylacetamide
1
5
acid for synthesis of polypeptides, and Ehler and Orgel used
ꢀ
1
6
(
DMAc) at 60 C for 48 h without any additives. The time-
N-imidazolylcarboxyl amino acid as precursor of NCA. Also,
1
conversion relationship of 1a was tracked with H NMR
analysis, by which completely consumption of 1a within 48
h (Fig. 1) and production of the corresponding poly-Z-L-ly-
we previously reported selective synthesis of NCA and polypep-
1
7–22
tides through N-(4-nitrophenyloxycarbonyl) amino acid.
1
Recently, we have developed newly synthetic route for produc-
tion of NCA through intramolecular cyclization of N-(phenylox-
ycarbonyl) amino acids under heating in moderately polar sol-
vents, such as 2-butanone, tetrahydrofuran (THF), and
acetonitrile to give the corresponding NCA, without the use
sine (PZLL). During polymerization process, H NMR spectra
clearly detected a small amount of Z-L-lysine-N-carboxyanhy-
dride (ZLL-NCA). The obtained polypeptides (2a) were col-
lected as ether-insoluble parts in moderate yield (65%). The
size exclusion chromatography (SEC) analysis revealed that
isolated polypeptides had number-average molecular weight
2
3
and production of any toxic compounds. In this study, we
report the polypeptides synthesis with well-defined terminal
(M ) of 56,000 and wide polydispersity index (M /M
n
¼
n
w
V
C
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SCHEME 1 Synthetic routes for urethane derivatives of a-
amino acids (1a).
2.83). These results might indicate that the polypeptides
were synthesized through various reaction pathways. Second,
polymerizations in the presence of n-butylamine (n-BuNH2)
(
feed ratio [1]
0
/[n-BuNH
2
]
0
¼ 50) were investigated in
ꢀ
1
DMAc at 60 C (entry 2, in Table 1). From H NMR analysis
of 1a in reaction mixture, it was observed that consumption
of 1a was dramatically accelerated in the presence of n-
BuNH2 (Fig. 1). The corresponding polypeptides were
obtained as ether-insoluble parts in excellent yield (89%). In
the SEC analysis, the obtained polypeptides possessed M
n
of
1
5,600 and narrow M /M of 1.28. Furthermore, the poly-
w
n
FIGURE 1 Time-conversion relationship of 1a in DMAc, at
merization of 1a was carried out with various feed ratio of
n-BuNH , and their results were summarized in Table 1.
ꢀ
6
0 C in the absence or presence of n-BuNH
2
.
2
Intriguingly, the Mn of obtained polypeptides could be con-
trolled well as varying the initial ratio of 1a to n-BuNH , in
the range of 8000–28,000, and each polypeptides showed
of the PZLL (entry 3, in Table 1) and the authentic sample
2
2
2
(M
and [a]
: 12,500, M
/M
¼ 1.18) was [a]
: 3.8 (c ¼ 0.1, CHCl
)
3
n
w
n
D
2
2
narrow molecular weight distribution (M
Also, the acceleration effects could be highly observed as the
w
/M
n
¼ 1.28–1.34).
D
: 4.2 (c ¼ 0.1, CHCl
3
), respectively. The lysine side
chains were deprotected by stirring under acidic condition
to determine optical rotation, and second, structure of poly-
L-lysine (PLL) in aqueous solution. Each deprotected sample
amount of n-BuNH increased for 1a (Fig. 1).
2
To determine terminal-structure of polypeptides, MALDI-TOF-
mass spectroscopy analysis was carried out, using 2,5-dihy-
droxybenzoic acid and sodium trifluoroacetate, as a matrix ma-
terial and a cationization agent, respectively. In the spectrum
(
PLL prepared from urethane derivatives or ring opening
2
2
polymerization of ZLL-NCA) also showed close values, [a] D:
2
2
ꢁ
65.0 (c ¼ 0.1, H
2
O) and [a]
D
: ꢁ66.8 (c ¼ 0.1, H
2
O),
respectively. The CD spectra of PZLL and PLL were obtained
in CH Cl and aqueous solution (Fig. 3). In CH Cl solutions,
of polypeptides synthesized with n-BuNH , significant signals
2
2
2
2
2
were observed at m/z value of 1145, 1408, 1670, 1932, 2194,
þ
CD spectra of each sample showed a negative cotton effect
with similar intensity, suggesting the formation of a-helical
polypeptides, while positive band at around 220 nm and
negative one at 196 nm, which is attributed to random coil
conformation, were observed in aqueous solution of polypep-
tides. From the results of optical rotation and CD spectra of
polypeptides, it was confirmed that the present polymeriza-
tion system affords well-defined polypeptides without any
racemization of chiral centers.
2
456, and 2718, as Na adducts (Fig. 2). These signals were
regularly located with an interval of 262, which corresponds to
the formula weight of ZLL. From these results of MALDI-TOF-
mass spectra, we could presumed that the resulting polypep-
tides possessed n-BuNH -incorporated initiating end and
2
2
ANH group at propagating end without any side reactions
terminating chain growth. These results suggested that steri-
cally unhindered n-BuNH2 was successfully reacted with
formed NCA in the initiating stage, resulting in production of
polypeptides with well-defined terminal structure.
TABLE 1 Polymerization of 1a in DMAc, at 60 8C in the
In addition, property [optical rotation and circular dichroism
a
Presence of n-BuNH
2
(
CD) spectra] of synthesized PZLL was compared with
authentic sample, which was synthesized by ring opening po-
lymerization of ZLL-NCA, to make it clear that no racemiza-
tion is taking place under reaction condition. Optical rotation
Feed Ratio
Conv.
Yield
b
c
d
d
Entry
[1a]
0
/[amine]
0
(%)
(%)
M
n
w n
M /M
1
2
3
4
a
None
25
>99
>99
>99
>99
65
89
87
84
56,000
8,700
2.83
1.30
1.28
1.34
50
15,600
28,000
100
Polymerization condition: [1a]
0
¼ 1.0M.
b
c
1
Calculated by H NMR spectra.
Ether-insoluble parts.
SCHEME 2 Polypeptides synthesis using urethane derivatives
of a-amino acids (1a) in the presence of amines.
d
Estimated by SEC [eluent: DMF solution of LiBr (10 mM), calibrated by
polystyrene standards].
2
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n-BuNH2 in DMAc at 60 C. After complete consumption of
a, other urethane derivatives such as c-benzyl-L-glutamate
BLG) 1b were added into the reaction mixture to obtain the
1
(
corresponding block copolypeptides (3). As expected,
obvious chain growth from terminal group of PZLL was
observed in SEC analysis (Fig. 4), whereas molecular weight
distribution remained relatively narrow values (M /M
¼
w
n
1
1.40–1.55) (Table 2). H HMR spectra of the block copolype-
pitdes exhibited newly significant peaks, which is attributed
to BLG moieties. The composition ratio of block copolypepti-
des was easily adjusted by varying additional amount of ure-
thane derivatives. Block copolymerization with BLG moieties
gave soluble polypeptides in the common organic solvents
such as, N,N-dimethylformamide (DMF), THF, acetone, and
chloroform. This present polymerization system can be
extended to more facile synthesis of various polypeptides
with well-defined structures, compared with conventional
ring opening polymerization of NCA.
FIGURE 2 MALDI-TOF-mass spectrum of PZLL obtained by poly-
merization of 1a in the presence of n-BuNH
2
([1a]
0
/[amine]
0
¼ 50).
SUMMARY
We reported facile polymerization strategy for synthesis of
polypeptides with well-defined structure using urethane
derivatives of a-amino acids in the presence of n-BuNH . The
2
molecular weight of polypeptides was adjusted by varying
the initial ratio of 1a to n-BuNH , and molecular weight dis-
2
tribution remained narrow values (below 1.35). The MALDI-
TOF-mass spectroscopy revealed that the obtained polypep-
2 2
tides had n-BuNH -incorporated initiating end and ANH
SCHEME 3 Synthesis of block copolypeptides using urethane
derivatives of a-amino acids in the presence of n-BuNH
group at propagating end without any side reactions termi-
nating chain growth. The synthetic procedure for block copo-
lypeptides (3) was established by polymerization of 1a in
2
.
Furthermore, synthesis of block copolymer with a-amino
acid components, using the present polymerization system,
was carried out (Scheme 3). The polypeptide of ZLL was first
synthesized from urethane derivatives 1a in the presence of
the presence of n-BuNH , followed by subsequent addition of
2
other urethane derivatives 1b. This polymerization system
newly provides more facile synthesis of polypeptides with
well-defined structure for application to important
FIGURE 3 CD spectra of PZLL (a) in CH
prepared by ring-opening polymerization of ZLL-NCA, and PLL (b) in H
and subsequent deprotection, (ii) PLL derived from ring-opening polymerization of ZLL-NCA and subsequent deprotection.
2
Cl
2
(0.5 mg/mL): (i) PZLL prepared from urethane derivatives (entry 3, in Table 1), (ii) PZLL
2
O (0.25 mg/mL): (i) PLL derived from urethane derivatives
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and refractive index and ultraviolet detectors at 40 C. The
system was operated using 10 mM LiBr in DMF as the elu-
ent, at a flow rate of 0.5 mL/min. Polystyrene standards
were used for calibration. Matrix-assisted laser desorption/
ionization time-of-flight mass spectrometry (MALDI-TOF MS)
analysis was carried out on a PerSeptive Biosystems Voyager
DE Pro Bio Spectrometry workstation. The samples were
prepared using 2,5-dihydroxybenzoic acid and sodium tri-
fluoroacetate, as a matrix material and a cationization agent,
respectively. The resulting samples were irradiated with 337
nm of nitrogen laser, and detected on positive mode at 20
kV. CD spectroscopy was used to determine the secondary
structure of synthesized polypeptides on a JASCO J-720WI
spectropolarimeter. Melting point was measured on Bibby
Stuart scientific melting point apparatus SMP3.
FIGURE 4 SEC results of PZLL (a) and PZLL-b-PBLG (b),
obtained by urethane derivatives of 1a and 1b (entry 1, in
Table 2).
Synthesis of Urethane Derivatives of N -Carbobenzoxy-
L-lysine (1a)
e
To a stirred solution of N -carbobenzoxy-L-lysine (ZLL) (3.5
e
g, 12.5 mmol) in methanol (35 mL) and distilled water (5
mL), tetrabutylammonium hydroxide (37% in methanol)
(8.77 g, 12.5 mmol) was slowly added at room temperature.
After stirring for 1 h, the reaction mixture was concentrated
under reduced pressure. The resulting residues were dis-
solved in acetonitrile (25 mL). The solution was added drop-
wise over 10 min to a stirred solution of DPC (2.68 g, 12.5
mmol) in acetonitrile (25 mL) at ambient condition, and
then the reaction mixture was stirred overnight. To the reac-
tion mixture, 1N of HCl aqueous solution (20 mL) was
added. The mixture was transferred into a separatory funnel
containing distilled water (30 mL) and ethyl acetate (30
mL). The aqueous layer was extracted with ethyl acetate
(3 ꢂ 30 mL) and the organic fractions were combined, dried
over Na SO , filtrated, and concentrated under reduced pres-
biomaterials, compared with conventional ring opening poly-
merization of NCA.
EXPERIMENTAL
Generals
All reagents used were purchased from Aldrich and Tokyo
Chemical Industry and used as received without further puri-
fication. Butylamine (n-BuNH ) and DMAc were purified by
2
ꢀ
heating at 60 C for 1 h under calcium hydride (CaH ), fol-
2
lowed by fractional distillation before use. N-(phenoxycar-
bonyl)-BLG (1b) was synthesized by the reaction of BLG
with phenyl chloroformate, according to the procedures pre-
2
0 1
13
viously reported.
H and C NMR spectra were recorded
2
4
with a JEOL ECS-400 (400 MHz) spectrometer, and chemical
shifts were recorded in ppm units using tetremethylsilane as
an internal standard. IR spectra were taken with KBr disks
on a Nicolet iS10 FT-IR, Thermo Scientific, Japan. Elemental
analysis was performed with a LECO CHNS-932 analyzer. Op-
tical rotation was measured with a JASCO DIP-1000 digital
polarimeter. For the determination of number-average molec-
ular weight (M ) and polydispersity index (M /M ) for syn-
sure. The crude products were purified by flash column
chromatography (chloroform:acetone:acetic acid ¼ 7:3:0.1,
as eluent), and then recrystallization with ethyl acetate/
n-hexane to yield 3.4 g (68%) of 1a, as white solids, mp:
ꢀ
22
1
19.8–120.2 C. [a] D: 25.8 (c ¼ 0.1, CHCl3).
1
H NMR (400 MHz, CDCl , d, ppm): 1.34–1.58 (m, 4H), 1.67–
3
1.83 (m, 1H), 1.84–1.96 (m, 1H), 3.15 (m, 2H), 4.39 (m, 1H),
4.86(s, 1H), 5.08 (s, 2H), 5.84 (d, 1H, J ¼ 8.1 Hz),, 7.09 (d,
2H, J ¼ 7.8 Hz), 7.15 (t, 1H, J ¼ 7.4 Hz), 7.28–7.37 (m, 7H).
n
w
n
thesized polypeptides, SEC was performed on a TOSOH HLC-
220 system equipped with three consecutive polystyrene
8
1
3
gel columns [TSK-gels (bead size, exclusion limited molecular
C NMR (100 MHz, CDCl , d, ppm): 22.17, 29.33, 31.57,
3
5
weight); super-AW4000 (6 lm, > 4 ꢂ 10 ), super-AW3000
40.41, 53.78, 66.87, 121.53, 125.42, 128.07, 128.09, 128.48,
129.23, 136.30, 150.72, 154.67, 156.87, 175.82. IR (KBr, thin
4
3
(
4 lm, >6 ꢂ 10 ), and super-AW2500 (4 lm, >2 ꢂ 10 )]
TABLE 2 Synthesis of Block Copolypeptides Using Urethane Derivatives 1a and 1b
Feed Ratio Homopolypeptide Feed Ratio Block Copolypeptide
Conv.
Yield
a
a
b
c
Entry
[1a]
0
/[amine]
0
M
n
(Mw/
M
n
)
[1b]
0
/[amine]
M
n
(Mw/
M
n
)
(%)
(%)
1
2
3
a
50
100
25
16,000 (1.29)
26,000 (1.32)
8,000 (1.30)
25
40
25
23,000 (1.40)
31,000 (1.48)
13,500 (1.55)
1
>>9/>99
>99/>99
>99/>99
86
78
84
b
Estimated by SEC [eluent: DMF solution of LiBr (10 mM), calibrated by
polystyrene standards].
Calculated by H NMR spectra.
Ether-insoluble parts.
c
4
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ꢁ
1
film, cm ): 3385, 3332, 3063, 2942, 1726, 1689, 1534,
492, 1407, 1266, 1218, 1183, 1145. Anal. Calcd. for
C H N O : C, 62.99; H, 6.04; N, 7.00. Found: C, 62.65; H,
mmol/mL) was added. The polymerization was performed
by stirring at room temperature for 24 h under argon atmos-
phere and precipitated in diethyl ether. The products were
dried under vacuum to yield 242 mg (93%) of PZLL, as
white powder, M : 12,500, M /M ¼ 1.18.
1
2
1 24 2 6
5
.82; N, 7.00.
n
w
n
Synthesis of Polypeptides by Polymerization of Urethane
Derivatives in the Presence of Amines (2a)
1
H NMR (400 MHz, CDCl
, d, ppm): 1.25–2.10 (br, 6H), 3.15
3
Typical procedure is as follows: Urethane derivatives of ZLL
(s, 2H), 3.83 (s, 1H), 5.00 (s, 2H), 5.49 (s, 1H), 7.14–7.36 (br,
5H).
(1a) (0.4 g, 1.0 mmol) were dissolved in DMAc (1 mL), and
then added into flame-dried Schlenk tube, followed by addi-
ꢁ
3
tion of n-BuNH /DMAc solution (20 lL, 1.0 ꢂ 10 mmol/
Deprotection of the Lysine Side Chain
2
ꢀ
lL). The polymerization was performed at 60 C for 48 h
The each PZLL from urethane derivatives or ZLL-NCA was
deprotected by same procedure, to measure optical rotation
and CD spectra in aqueous solution. To a solution of PZLL
(70 mg) in trifluoroacetic acid (2 mL), 33% HBr solution in
acetic acid (0.2 mL) was added. The reaction mixture was
stirred for 2 h, at room temperature, and then poured into
diethyl ether. After the precipitated polymers were collected
by filtration, the polymer was washed with fresh diethyl
ether twice and then dried under vacuum to yield 50 mg
under argon atmosphere. After the reaction mixture was
cooled to room temperature, it was poured into diethyl ether.
The resulting precipitates were collected by filtration, and
then dried under vacuum to yield 228 mg (87%) of PZLL
(2a), as white solids.
1
H NMR (400 MHz, CDCl
s, 2H), 3.85 (s, 1H), 4.98 (s, 2H), 5.49 (s, 1H), 7.16–7.35 (br,
H).
3
, d, ppm): 1.29–2.09 (br, 6H), 3.15
(
5
(
89%) of PLL, as white powder.
Synthesis of Block Copolypeptides by Polymerization of
Urethane Derivatives (3)
The general polymerization procedures were followed as
described above. Urethane derivatives of ZLL (1a) (0.4 g,
1
H NMR (400 MHz, D O, d, ppm): 1.23–1.48 (br, 2H), 1.53–
2
1
.78 (br, 4H), 2.92 (s, 2H), 4.24 (s, 1H).
The authors thank Dr. Tomohiro Shiraki and Prof. Seiji Shinkai
Institute of Systems, Information Technologies and Nanotech-
(
1
.0 mmol) were polymerized in DMAc (1 mL) with
ꢀ
nologies) for assistance of circular dichroism measurement.
This work was financially supported by JSR Corporation.
n-BuNH (0.02 mmol) at 60 C for 48 h under argon atmos-
2
phere. An aliquot of reaction mixtures were withdrawn for
SEC analysis. After complete consumption of urethane
derivatives, DMAc solution of 1b (1 mL, 0.5 mol/L, 0.5
mmol) was added to the reaction mixture containing PZLL
REFERENCES AND NOTES
(
2a) for second block. The resulting block copolypeptides
1
Kricheldorf, H. R. Angew. Chem. Int. Ed. Engl. 2006, 45,
were reprecipitated by diethyl ether, followed by dried
under vacuum to yield 414 mg (86%) of PZLL-b-PBLG (3)
as white solids.
5
752–5784.
2
Brzezinska, K. R.; Deming, T. J. Macromolecules 2001, 34,
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348–4354.
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8,23
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(
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Kataoka, K.; Kwon, G. S.; Yokoyama, M.; Okano, T.; Sakurai,
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8.2–99.4 C.
9
McMillan, R. A.; Conticello, V. P. Macromolecules 2000, 33,
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H NMR (400 MHz, CDCl , d, ppm): 1.35–1.61 (m, 4H), 1.77–
.89 (m, 1H), 1.93–2.05 (m, 1H), 3.14–3.29 (m, 2H), 4.28 (m,
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0 Wang, Y.; Chang, Y. C. Langmuir 2002, 18, 9859–9866.
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5
4
1
H), 4.90 (s, 1H), 5.10 (s, 2H), 6.76 (s, 1H), 7.29–7.40 (m,
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3
H). C NMR (100 MHz, CDCl , d, ppm): 21.56, 29.21, 30.98,
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0.33, 57.58, 66.98, 128.10, 128.35, 128.69, 136.41, 152.84,
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Ring-Opening Polymerization of Z-L-Lysine-N-
Carboxyanhydride (ZLL-NCA)
To a solution of ZLL-NCA (306 mg, 1.0 mmol) in dry DMF
1
1
ꢁ
2
(
2.4 mL), n-BuNH /DMF solution (1.0 mL, 2.0 ꢂ 10
2409–2412.
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