- Isostearyl Mixed Anhydrides for the Preparation of N-Methylated Peptides Using C-Terminally Unprotected N-Methylamino Acids
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Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.
- Cary, Douglas R.,Handa, Michiharu,Kobayashi, Yutaka,Kurasaki, Haruaki,Masuya, Keiichi,Matsuda, Ayumu,Matsumoto, Masatoshi,Morimoto, Koki,Nagaya, Akihiro,Nishizawa, Naoki,Taguri, Tomonori,Takeuchi, Hisayuki
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p. 8039 - 8043
(2020/11/02)
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- Iridium-Catalyzed Asymmetric Hydrogenation of N-Alkyl α-Aryl Furan-Containing Imines: an Efficient Route to Unnatural N-Alkyl Arylalanines and Related Derivatives
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High throughput experimentation (HTE) has enabled the rapid identification of ligand/precatalyst combinations that facilitate highly enantioselective hydrogenations of prochiral N-alkyl α-aryl ketimines containing a furyl moiety. The chiral amines obtained have proven to be modular precursors in the synthesis of unnatural mono N-alkylated arylalanines and related derivatives. (Figure presented.).
- Mazuela, Javier,Antonsson, Thomas,Knerr, Laurent,Marsden, Stephen P.,Munday, Rachel H.,Johansson, Magnus J.
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supporting information
p. 578 - 584
(2018/12/11)
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- Investigation for the cyclization efficiency of linear tetrapeptides: Synthesis of tentoxin B and dihydrotentoxin
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Investigation of the cyclization efficiency of N-methyl linear tetrapeptides using a molecular modeling study and chemical synthesis is described. The linear peptide with two N-methyl groups, MeAla-Leu-MePhe-Gly, forms γ-turn like conformation with the am
- Sato, Ryota,Oyama, Kie,Konno, Hiroyuki
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p. 6173 - 6181
(2018/09/17)
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- A new GLP-1 analogue with prolonged glucose-lowering activity in vivo via backbone-based modification at the N-terminus
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Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N-methylated analogues 2-6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7-13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs.
- Bai, Xiaohui,Niu, Youhong,Zhu, Jingjing,Yang, An-Qi,Wu, Yan-Fen,Ye, Xin-Shan
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p. 1163 - 1170
(2016/03/01)
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- A total synthesis of a highly N-methylated cyclodepsipeptide [2S,3S-Hmp]-aureobasidin L using solid-phase methods
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[2S,3S-Hmp]-Aureobasidin L 2 has been successfully synthesised through a combination of solution- and solid-phase peptide synthesis. All of the Fmoc-protected residues including a depsidipeptide, Fmoc-MeVal-Hmp-OH, were prepared in solution phase. Chain e
- Maharani, Rani,Brownlee, Robert T.C.,Hughes, Andrew B.,Abbott, Belinda M.
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p. 2351 - 2358
(2014/04/03)
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- Fluorenylmethoxycarbonyl-N-methylamino acids synthesized in a flow tube-in-tube reactor with a liquid-liquid semipermeable membrane
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Both steps of the N-methylation of 9-fluorenylmethoxycarbonyl (Fmoc) amino acids were carried out in a microstructured tube-in-tube reactor equipped with a semipermeable Teflon AF 2400 membrane as the inner tubing. In the first step, gaseous formaldehyde
- Buba, Annette E.,Koch, Stefan,Kunz, Horst,Loewe, Holger
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p. 4509 - 4513
(2013/07/26)
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- Enantioselective total synthesis of eudistomidins G, H, and I
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Asymmetric first total synthesis of eudistomidins G, H, and I, tetrahydro-β-carboline alkaloids from the Okinawan marine tunicate Eudistoma glaucus, has been accomplished with the Bischler-Napieralski reaction and the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configurations of eudistomidins G, H, and I were confirmed from comparison of the 1H and 13C NMR, and CD spectral data of synthetic and natural eudistomidins G, H, and I, respectively.
- Ishiyama, Haruaki,Yoshizawa, Kazuaki,Kobayashi, Jun'ichi
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p. 6186 - 6192
(2012/08/27)
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- An efficient preparation of N-Methyl-α-amino acids from N-Nosyl-α-amino acid phenacyl esters
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Chemical Equation Presented In this paper we describe a simple and efficient solution-phase synthesis of N-methyl-TV-nosyl-α-amino acids and N-Fmoc-N-methyl-α-amino acids. This represents a very important application in peptide synthesis to obtain N-methylated peptides in both solution and solid phase. The developed methodology involves the use of N-nosyl-α-amino acids with the carboxyl function protected as a phenacyl ester and the methylating reagent diazomethane. An important aspect of this synthetic strategy is the possibility to selectively deprotect the carboxyl function or alternatively both amino and carboxyl moieties by using the same reagent with a different molar excess and under mild conditions. Furthermore, the adopted procedure keeps unchanged the acid-sensitive side chain protecting groups used in Fmoc-based synthetic strategies.
- Leggio, Antonella,Belsito, Emilia Lucia,De Marco, Rosaria,Liguori, Angelo,Perri, Francesca,Viscomi, Maria Caterina
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supporting information; experimental part
p. 1386 - 1392
(2010/06/11)
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- Chemical models of peptide formation in translation
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Ribosomal incorporations of N-alkyl amino acids including proline are slower than incorporations of non-N-alkyl L-amino acids. The chemical reactivity hypothesis proposes that these results and the exclusion of nonproline N-alkyl amino acids from the gene
- Watts, R.Edward,Forster, Anthony C.
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experimental part
p. 2177 - 2185
(2011/02/25)
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- Improving oral bioavailability of peptides by multiple N-methylation: Somatostatin analogues
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Full methyl jacket? A complete library of the N-methylated somatostatin cyclopeptidic analogue Veber-Hirschmann peptide cyclo(-PFwKTF-) has been prepared with the aim of improving its bioavailability. Several analogues from the library were found to bind
- Biron, Eric,Chatterjee, Jayanta,Ovadia, Oded,Langenegger, Daniel,Brueggen, Joseph,Hoyer, Daniel,Schmid, Herbert A.,Jelinek, Raz,Gilon, Chaim,Hoffman, Amnon,Kessler, Horst
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p. 2595 - 2599
(2008/12/23)
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- Multiple N-methylation by a designed approach enhances receptor selectivity
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An unselective cyclic peptide integrin ligand was sequentially N-methylated by a designed approach, where only the externally oriented (solvent exposed) amide bonds were N-methylated. The N-methylation resulted in tremendous enhancement in selectivity amo
- Chatterjee, Jayanta,Ovadia, Oded,Zahn, Grit,Marinelli, Luciana,Hoffman, Amnon,Gilon, Chaim,Kessler, Horst
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p. 5878 - 5881
(2008/04/12)
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- Facile synthesis of Fmoc-N-methylated α- and β-amino acids
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A highly efficient and environmentally friendly synthesis of Fmoc-N-methyl α- and β-amino acids from the corresponding Fmoc-amino acid, via intermediate oxazolidinones/oxazinanones, has been developed. Microwave heating for 3 min was required for the synt
- Govender, Thavendran,Arvidsson, Per I.
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p. 1691 - 1694
(2007/10/03)
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- An improved synthesis of Fmoc-N-methyl-α-amino acids
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A highly efficient and environmentally more benign synthesis of Fmoc-N-methyl-α-amino acids from the corresponding Fmoc-amino acid, via intermediate 5-oxazolidinones, has been developed by using Lewis acid catalysis for the reductive opening of the oxazol
- Zhang, Suode,Govender, Thavendran,Norstroem, Thomas,Arvidsson, Per I.
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p. 6918 - 6920
(2007/10/03)
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- Solid phase synthesis of Fmoc N-methyl amino acids: Application of the Fukuyama amine synthesis
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N-Methyl amino acids and their Fmoc derivatives are synthesized in high yield and purity on solid support using the Fukuyama amine synthesis protocol.
- Yang, Lihu,Chiu, Kuenley
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p. 7307 - 7310
(2007/10/03)
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- Preparation of Chemically Misacylated Semisynthetic Nonsense Suppressor tRNAs Employed in Biosynthetic Incorporation of Non-Natural Residues into Proteins
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Both run-off transcription and direct chemical synthesis were employed to prepare semisynthetic, nonhypermodified tRNAGly nonsense suppressors acylated with non-natural residues.L-3-Iodotyrosyl-tRNAGlyCUA-dCA (3) was prepa
- Bain, J. D.,Wacker, Dean A.,Kuo, Eric E.,Lyttle, Matthew H.,Chamberlin, A. Richard
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p. 4615 - 4625
(2007/10/02)
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- Synthesis of 9-Fluorenylmethyloxycarbonyl-Protected N-Alkyl Amino Acids by Reduction of Oxazolidinones
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A new two-step synthesis of Fmoc-protected N-alkyl amino acids has been developed.The first step involves acid-catalyzed condensation of an Fmoc-protected amino acid with an aldehyde to form an oxazolidinone.This intermediate is then reduced with triethyl
- Freidinger, Roger M.,Hinkle, Jeffery S.,Perlow, Debra S.,Arison, Byron H.
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