ADVERTORIAL
ADVERTORIAL
Fig. A
O O
O NH2
HO
CI
CI
O Cyclization
NH
HO - HCI
R
O
O
CI
R
- HCI
R
NCA
Chloroformamide
by Takeshi Endo, Molecular Engineering Institute, Kinki University Polypeptides have been widely employed to prepare a wide variety of the functional biomaterials for the use of drug delivery system (DDS) and tissue engineering, because of their excellent biocompatibility and biodegradability. One of the most effcient routes for the synthesis of polypeptides is the ring-opening polymerization of -amino acid N-carboxyanhydrides (NCAs). The NCA polymerization gives polypeptides with well-defned structures involving molecular weights and terminal structures and thus widely used as a highly reliable method for the precision synthesis of polypeptide-containing materials. However, the syntheses of NCAs have usually required highly toxic phosgene and its derivatives (Fig. A Fuchs-Farthing Method). In addition, sensitive nature of NCAs to moisture and heat has prevented the production and the utilization of NCAs in an industrial scale. To solve these problems, we have developed a phosgenefree synthesis of NCA using diphenyl carbonate (DPC) as an alternative of phosgene. The synthesis has been achieved by the selective intramolecular cyclization of “N-phenoxycarbonyl” -amino acids that can be easily synthesized by N-carbamylation of onium salts of -amino acid with DPC (Fig. B). These urethane
Fuchs-Farthing Method - Lethal Toxicity of Phosgene - Evolution of HCI
derivatives can be used not only as precursors of NCAs but also as useful monomers for a more straightforward synthesis of polypeptides, where heating these urethane derivatives in the presence of amines gives the corresponding polypeptides through the in situ formation (Fig. C) of NCAs and the polycondensation along with the elimination of phenol and CO2. During the investigation of the polycondensation, we have found that this synthetic approach has some following advantages: (1) the successful incorporation of amine residue in the chain end, 2) the control of molecular weight by varying feed ratio between the urethane derivative and amine, and 3) the easy handling and simple procedure without the use and formation of any toxic compounds. Now a series of polypeptides have been synthesized the from the corresponding N-phenoxycarbonyl derivatives including L-alanine, L-phenylalanine, N- ε -carbobezoxy-L-lysine and tert-butyl-L-glutamate. These N-phenoxycarbonyl derivatives are commercially available from Watanabe Chemical Industries, Ltd. (Japan). We have expected these compounds to be used as good monomer for designing the functional polypeptide-based biomaterials.
NH
O
NOVEL PHOSGENE FREE ROUTE No Phosgene Anymore! O CI
O CI
O
O
Diphenyl Carbonate “Alternative of Phosgene”
Fig. B Synthesis of Urethane Derivative from DPC and
-Amino Acid O
1) O
+ -(n-Bu)4N OH
NH2
HO
MeOH) / H2O
R
O
O
O + -(n-Bu)4N O
O
2) 1N HCI aq.
NH2
H N
HO MeCN - Ph0H
R
O O
R
Fig. C in situ Formation of NCA and Polypeptide O R AcOH
Our published paper relative to this work: (1) Y. Fujita, K. Koga, H. K. Kim, X. S. Wang, A. Sudo, H. Nishida, T. Endo, J. Polym. Sci. Part A: Polym. Chem. 2007, 45, 5365–5369. (2) Y. Kamie, A. Sudo, T. Endo, Macromolecules 2008, 41, 7913–7919. (3) K. Koga, A. Sudo, T. Endo, J. Polym. Sci. Part A: Polym. Chem. 2010, 48, 4351–4355. (4) S. Yamada, K. Koga, T. Endo, J. Polym. Sci. Part A: Polym. Chem. 2012, 50, 2527-2532. (5) S. Yamada, K. Koga, A. Sudo, M. Goto, T. Endo, J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 3726-3731. (6) S. Yamada, A. Sudo, M. Goto, T. Endo, J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 4565-4571.
O
+ Ph0H
HN
O
in THF, MEK
H N
HO R
O
NCA
O O
O
O R’-NH2
R O
in DMAc - Ph0H
H N
R’ HN
- C02
O
N H
R
n
Polypeptide
For more information, please contact Research and Development Dept. of JSR Corporation.
H
