- Synthesis and Properties of High Molecular Weight Polypeptides Containing Proline
-
High-purity N-carboxy-L-proline anhydride (N-carboxy-2-pyrrolidinecarboxylic acid anhydride) was synthesized.We used triethylamine instead of expensive Ag2O to remove HCl during the synthesis.Copolypeptides with a random sequence of L-proline (Pro) with glycine, L-alanine (Ala), L-α-aminobutyric acid (Abu), L-Norvaline (Nva) or L-leucine (Leu) were synthesized by copolymerization of the corresponding N-carboxy-α-amino acid anhydrides in solution.Copolypeptides of Pro with Ala or Abu were partially soluble in water.However, the copolypeptides of proline with Nva or Leu with longer side chains were insoluble in water.The conformation of water-soluble copolymer at various pH was analyzed by circular dichroism (CD).The structures of the polypeptides in aqueous solution were almost independent of the pH, and were in a collagen-like conformation.
- Iizuka, Yasuko,Uchida, Chieko,Wakamatsu, Kaori,Oya, Masanao
-
-
Read Online
- Well-defined homopolypeptides, copolypeptides, and hybrids of poly(l-proline)
-
l-Proline is the only, out of 20 essential, amino acid that contains a cyclized substituted α-amino group (is formally an imino acid), which restricts its conformational shape. The synthesis of well-defined homo- and copolymers of l-proline has been plagued either by the low purity of the monomer or the inability of most initiating species to polymerize the corresponding N-carboxy anhydride (NCA) because they require a hydrogen on the 3-N position of the five-member ring of the NCA, which is missing. Herein, highly pure l-proline NCA was synthesized by using the Boc-protected, rather than the free amino acid. The protection of the amine group as well as the efficient purification method utilized resulted in the synthesis of highly pure l-proline NCA. The high purity of the monomer and the use of an amino initiator, which does not require the presence of the 3-N hydrogen, led for the first time to well-defined poly(l-proline) (PLP) homopolymers, poly(ethylene oxide)-b-poly(l-proline), and poly(l-proline)-b-poly(ethylene oxide)-b-poly(l-proline) hybrids, along with poly(γ-benzyl-l-glutamate)-b- poly(l-proline) and poly(Boc-l-lysine)-b-poly(l-proline) copolypeptides. The combined characterization (NMR, FTIR, and MS) that results for the l-proline NCA revealed its high purity. In addition, all synthesized polymers exhibit high molecular and compositional homogeneity.
- Gkikas, Manos,Iatrou, Hermis,Thomaidis, Nikolaos S.,Alexandridis, Paschalis,Hadjichristidis, Nikos
-
-
Read Online
- Thermoresponsive and Mechanical Properties of Poly(l -proline) Gels
-
Gelation of the left helical N-substituted homopolypeptide poly(l-proline) (PLP) in water was explored, employing rheological and small-angle scattering studies at different temperatures and concentrations in order to investigate the network structure and its mechanical properties. Stiff gels were obtained at 10 wt % or higher at 5 °C, the first time gelation has been observed for homopolypeptides. The secondary structure and helical rigidity of PLP has large structural similarities to gelatin but as gels the two materials show contrasting trends with temperature. With increasing temperature in D2O, the network stiffens, with broad scattering features of similar correlation length for all concentrations and molar masses of PLP. A thermoresponsive transition was also achieved between 5 and 35 °C, with moduli at 35 °C higher than gelatin at 5 °C. The brittle gels could tolerate strains of 1% before yielding with a frequency-independent modulus over the observed range, similar to natural proline-rich proteins, suggesting the potential for thermoresponsive or biomaterial-based applications.
- Gkikas, Manos,Avery, Reginald K.,Olsen, Bradley D.
-
-
Read Online
- Rethinking Transition Metal Catalyzed N-Carboxyanhydride Polymerization: Polymerization of Pro and AcOPro N-Carboxyanhydrides
-
Polyproline (PP) based polypeptides have broad applications as protein mimics, ordered materials, hydrogels, and surface coatings. However, a lack of rapid and efficient preparatory methods has challenged synthesis of well-defined high molecular weight materials. Here, we report facile and high-yielding methods for preparation and polymerization of Pro and trans-4-acetoxy-Pro N-carboxyanhdrides (NCAs). For decades, transition metal initiators of NCA polymerization were assumed to be nonstarters with Pro due to the lack of an amide NH proton. We carefully considered the known steps in the initiation mechanism and applied a Ni initiator that intercepts an intermediate and does not require an NH group. This initiator efficiently catalyzes controlled, living polymerization of Pro NCAs, revealing that routes alternate to the previously proposed mechanism must be at play. We also found Co species can catalyze Pro NCA polymerization, and we improved the synthetic methods to prepare the NCA monomers. Our methods are high-yielding and rapid and give tunable, end-functional PP-based homo, statistical, and block polypeptides. We characterized the conformation of PP and trans-4-hydroxy-PP by CD and confirmed the time scale for quantitative conversion from PPI to PPII helices. Overall, our data shed light on the general propagation mechanism of transition metal catalyzed NCA polymerization and have opened the door for efficient preparation of a desirable class of biomaterials.
- Detwiler, Rachel E.,Schlirf, Austin E.,Kramer, Jessica R.
-
-
Read Online
- METHOD FOR PRODUCING AMINO ACID-N-CARBOXYLIC ACID ANHYDRIDE
-
PROBLEM TO BE SOLVED: To provide: a method for safely and efficiently producing amino acid-N-carboxylic acid anhydride; and a method for producing peptide by using the obtained amino acid-N-carboxylic acid anhydride. SOLUTION: The method for producing an amino acid-N-carboxylic acid anhydride according to the present invention is characterized in that the amino acid-N-carboxylic acid anhydride is represented by the following formula (II), and a step of irradiating a composition containing a halogenated methane and an amino acid compound represented by the following formula (I) with high energy light in the presence of oxygen is included. [In the formula, R1 represents an amino acid side chain group in which the reactive group is protected, and R2 represents H or the like.]. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
- -
-
Paragraph 0085
(2020/08/07)
-
- Oxazolidinone compound as well as preparation method, application and pharmaceutical composition thereof
-
The invention relates to an oxazolidinone compound used as an Lp-PLA2 covalent inhibitor and a pharmaceutical composition of the oxazolidinone compound, the structure of the oxazolidinone compound isshown as a general formula I, and R1, R2 and R3 are defined as the specification and claims. The compound shown in the general formula I or the stereoisomer or the pharmaceutically acceptable salt thereof can be used as the Lp-PLA2 covalent inhibitor to prevent and/or treat and/or improve diseases related to Lp-PLA2 enzyme activity. Meanwhile, the stereoisomer or the pharmaceutically acceptable salt of the compound shown in the general formula I can be used as an Lp-PLA2 specific molecular probe.
- -
-
Paragraph 0093-0094; 0096
(2020/11/05)
-
- METHOD OF SYNTHESIZING N-CARBOXYANHYDRIDE USING FLOW REACTOR
-
PROBLEM TO BE SOLVED: To provide a synthesis method that allows high-yield continuous production of a compound of interest in synthesis and production of N-carboxyanhydride (NCA) and the like using a flow reactor. SOLUTION: In a synthesis method using a flow reactor 100, a basic solution adjusted in advance to a pH of 7-14 becomes acidic with a pH of 0-7, or an acidic solution adjusted in advance to a pH of 0-7 becomes basic with a pH of 7-14, within 60 seconds after the start of mixture of at least two ingredient solutions. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2020,JPOandINPIT
- -
-
Paragraph 0092-0096; 0115-0116
(2020/03/26)
-
- Rapid and Mild Synthesis of Amino Acid N-Carboxy Anhydrides: Basic-to-Acidic Flash Switching in a Microflow Reactor
-
Polymerization of N-carboxy anhydrides (NCAs) is the primary process used to prepare polypeptides. The synthesis of various pure NCAs is key to the efficient synthesis of polypeptides. The only practical method that can be used to synthesize NCAs requires harsh acidic conditions that make acid-labile substrates unusable and results in an undesired ring opening of NCAs. Basic-to-acidic flash switching and subsequent flash dilution technology in a microflow reactor was used to demonstrate the synthesis of NCAs. It is both rapid (0.1 s) and mild (20 °C) and includes substrates containing acid-labile functional groups. The basic-to-acidic flash switching enabled both an acceleration of the desired NCA formation and avoided the undesired ring opening of NCAs. The flash dilution precluded the undesired decomposition of acid-labile functional groups. The developed process allowed the synthesis of various NCAs which cannot be readily synthesized using conventional batch methods.
- Otake, Yuma,Nakamura, Hiroyuki,Fuse, Shinichiro
-
supporting information
p. 11389 - 11393
(2018/08/28)
-
- Nonenzymatic acylative kinetic resolution of Baylis-Hillman adducts
-
(Chemical Equation Presented) The first efficient nonenzymatic acylative kinetic resolution of Baylis-Hillman adducts is reported. Chiral pyridine catalyst 1a and an optimized analogue 1e are capable of promoting the synthetically useful enantioselective
- O Dalaigh, Ciaran,Connon, Stephen J.
-
p. 7066 - 7069
(2008/02/11)
-
- Structure reassignment and synthesis of jenamidines A1/A 2, synthesis of (+)-NP25302, and formal synthesis of SB-311009 analogues
-
The proposed structures of jenamidines A, B, and C (1-3) were revised to jenamidines A1/A2, B1/B2, and C (8-10). Jenamidines A1/A2 (8) were synthesized from activated proline derivative 43 by conversion to 26 in two steps and 50% overall yield. Acylation of 26 with acid chloride 38d gave 39d, which was deprotected with TFA and then mild base to give 8 in 45% yield from 26. (-)-trans-2,5- Dimethylproline ethyl ester (49) was prepared by the enantioselective Michael reaction of ethyl 2-nitropropionate (51) and methyl vinyl ketone (50) using modified dihydroquinine 60 as the catalyst. Further elaboration converted 49 to natural (+)-NP25302 (12). A Wittig reaction of proline NCA (76) with ylide 79 gave 72 as a 9/1 E/Z mixture in 27% yield, completing a one-step formal synthesis of SB-311009 analogues.
- Duvall, Jeremy R.,Wu, Fanghui,Snider, Barry B.
-
p. 8579 - 8590
(2007/10/03)
-
- Diastereoselective alkylation of a proline-derived bicyclic lactim ether
-
N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis- and trans-9. The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis-9, sterically more-demanding alkyl halides resulted in cisltrans mixtures. Electrophiles bearing a π-system favored the trans-products 9. Some isolated cis- and tranx-lactim ethers 9 were converted to the corresponding diketopiperazines cis- and trans-10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystallography (Figs. 1-4).
- Hendea, Daniela,Laschat, Sabine,Baro, Angelika,Frey, Wolfgang
-
p. 1894 - 1909
(2007/10/03)
-
- Towards more chemically robust polymer-supported chiral catalysts: α,α-diphenyl-L-prolinol based catalysts for the reduction of prochiral ketones with borane
-
α,α-Diphenyl-L-prolinol derivatives with para-bromo substituants in either one or both of the phenyl rings are easily bound to crosslinked polystyrene beads containing phenylboronic acid residues by Suzuki couplings. By using extended reaction periods boronic acid residues that do not take part in the couplings are simply lost by hydrolysis. The polymer-supported (PS) α,α-diphenyl-L-prolinols were used to catalyse reductions of several prochiral ketones with borane in tetrahydrofuran at 22 °C. The expected secondary alcohols were obtained in high chemical yields and ees were generally in the range 79-97 %. One PS catalyst was recycled 14 times without loss of stereochemical performance.
- Kell, Roger J.,Hodge, Philip,Snedden, Peter,Watson, David
-
p. 3238 - 3243
(2007/10/03)
-
- Esterification of amino acids and mono acids using triphosgene
-
Alkyl esters of several amino acids and acids were prepared using triphosgene [trichloromethyl carbonate, TPA (2)].
- Rivero,Heredia,Ochoa
-
p. 2169 - 2175
(2007/10/03)
-
- Friedel-Crafts α-aminoacylation of aromatic compounds with a chiral N- carboxy-α-amino acid anhydride (NCA); Part 2
-
The N-carboxy-α-amino acid anhydrides (NCA) derived from L-Asp(OEt), L- Glu(OMe), L-Met, and L-Pro reacted with aromatic compounds (toluene or benzene) in the presence of AlCl3 to afford the corresponding α-aminoalkyl aryl ketones as hydrochloride salts in moderate yields. The β- and γ-amino acid esters, which were obtained from the reaction of the aromatic compounds with L-Asp(OEt)- and L-Glu(OMe)-NCA, were hydrolyzed by hydrochloric acid to the corresponding β- and γ-amino acids as hydrochloride salts. L-Phe-NCA did not react with benzene in the presence of AlCl3, instead an intramolecular acylation occurred to afford (S)-2-aminoin-danone hydrochloride. The chiralities of the original L-α-amino acids were most retained during these α-aminoacylation.
- Itoh, Osamu,Amano, Akira
-
p. 423 - 428
(2007/10/03)
-
- New routes to 1,4-benzodiazepin-2,5-diones
-
1,4-benzodiazepin-2,5-diones have been synthesized in good overall yields by two routes, the first one by cyclisation of dipeptides prepared from Boc anthranilic acid and α-amino acid methyl esters, the second one by reaction of N-carboxy α-amino acid anhydrides with Boc anthranilic acid.
- Akssira,Boumzebra,Kasmi,Dahdouh,Roumestant,Viallefont
-
p. 9051 - 9060
(2007/10/02)
-
- A Practical Enantioselective Synthesis of α,α-Diaryl-2-pyrrolidinemethanol. Preparation and Chemistry of the Corresponding Oxazaborolidines
-
A practical two-step enantioselective synthesis of α,α-diaryl-2-pyrrolidinemethanols (1) from proline, based on the addition of aryl Grignard reagents to proline-N-carboxanhydride (3), is reported.An investigation into the chemistry of the corresponding B-alkyl- and B-aryloxazaborolidines (2) led to the development of a reliable procedure for their preparation.
- Mathre, David J.,Jones, Todd K.,Xavier, Lyndon C.,Blacklock, Thomas J.,Reamer, Robert A.,et al.
-
p. 751 - 762
(2007/10/02)
-