Are Aminomethyl Thioesters Viable Intermediates in Native Chemical Ligation Type Amide Bond Forming Reactions?

2018 ◽  
Vol 71 (9) ◽  
pp. 697
Author(s):  
Carlie L. Charron ◽  
Jade M. Cottam Jones ◽  
Craig A. Hutton
Keyword(s):  
Amide Bond ◽  
Native Chemical Ligation ◽  
Direct Reaction ◽  
Chemical Ligation ◽  
Bond Forming ◽  
Type Process ◽  
Bond Forming Reactions ◽  
Subsequent Conversion ◽  
Three Component Coupling

The condensation of N-mercaptomethyl amines and thioesters is a potential route to amides, via aminomethyl thioester intermediates, in a native chemical ligation type process followed by self-cleavage of the ‘mercaptomethyl’ auxiliary. This paper describes investigations towards the preparation of aminomethyl thioesters, and subsequent conversion into amides, from a three-component coupling of formaldehyde, a thioacid, and an amine. Our studies suggest that while such intermediates may be formed en route to amides, no advantages are offered over the direct reaction of the amine and thioacid precursors.

scholarly journals Minimizing HCN in DIC/Oxyma-Mediated Amide Bond-Forming Reactions

2020 ◽  
Vol 24 (7) ◽  
pp. 1341-1349 ◽  
Author(s):  
Marion Erny ◽  
Marika Lundqvist ◽  
Jon H. Rasmussen ◽  
Olivier Ludemann-Hombourger ◽  
Frédéric Bihel ◽  
...  
Keyword(s):  
Amide Bond ◽  
Bond Forming ◽  
Bond Forming Reactions

scholarly journals SEA Ligation Is Accelerated at Mildly Acidic pH. Application to the Formation of Difficult Peptide Junctions

2019 ◽  
Author(s):  
Marine Cargoet ◽  
Vincent Diemer ◽  
Laurent Raibaut ◽  
Elizabeth Lissy ◽  
Benoît Snella ◽  
...  
Keyword(s):  
Total Synthesis ◽  
Peptide Bond ◽  
Native Chemical Ligation ◽  
Acidic Ph ◽  
Chemical Ligation ◽  
Bond Forming ◽  
Neutral Ph ◽  
Wide Range ◽  
Peptide Segments ◽  
Model Peptides

The bis(2-sulfanylethyl)amido (SEA)-mediated ligation has been introduced in 2010 as a novel chemoselective peptide bond forming reaction. SEA ligation is a useful reaction for protein total synthesis that is complementary to the native chemical ligation (NCL). In particular, SEA ligation proceeds efficiently in a wide range of pH, from neutral pH to pH 3-4. Thus, the pH can be chosen to optimize the solubility of the peptide segments or final product. It can be also chosen to facilitate the formation of difficult junctions, since the rate of SEA ligation increases significantly by decreasing the pH from 7.2 to 4.0. Here we describe a protocol for SEA ligation at pH 5.5 in the presence of 4-mercaptophenylacetic acid (MPAA) or at pH 4.0 in the presence of a newly developed diselenol catalyst. The protocols describe the formation of a valyl-cysteinyl peptide bond between two model peptides.<br>

scholarly journals Minimizing HCN in DIC/Oxyma Mediated Amide Bond Forming Reactions

2020 ◽  
Author(s):  
Marion Erny ◽  
Marika Lundqvist ◽  
Jon H. Rasmussen ◽  
Olivier Ludemann-Hombouger ◽  
Frédéric Bihel ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Peptide Synthesis ◽  
Hydrogen Cyanide ◽  
Reaction Rate ◽  
Solid Support ◽  
Amide Bond ◽  
Prussic Acid ◽  
Bond Forming ◽  
H Nmr ◽  
Bond Forming Reactions

<p>Aiming at advancing protocols for safer, environmentally sensible peptide synthesis we report our findings with regards to the occurrence of hydrogen cyanide (HCN, prussic acid) in amide bond forming reactions mediated by diisopropylcarbodiimide (DIC) and ethyl (hydroxyimino)cyanoacetate (Oxyma). We have determined that HCN is always formed in amide bond forming reactions on solid support in N,N-dimethylformamide (DMF) when employing DIC/Oxyma. In an attempt to minimize the formation of prussic acid by means of preventing the linear DIC/Oxyma adduct <b>2</b> from cyclizing to oxadiazole <b>3</b> and in turn releasing HCN, we evaluated a series of greener solvents such as N-butylpyrrolidinone (NBP), NBP/ethyl acetate (EtOAc, 1:1), methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (PolarClean, PC), and PC/EtOAc (1:1). We found that the ratio between <b>2</b> and <b>3</b> greatly depends on the solvent used and consequently, we further examined DMF, NBP, NBP/EtOAc (1:1) and NBP/EtOAc (1:4) as solvents for DIC/Oxyma mediated amidations on solid support and in solution. We found that using carboxylic acid/Oxyma/DIC in a 1:1:1 ratio the rate of HCN formation decreases in the following order DMF>NBP>NBP/EtOAc (1:1)>NBP/EtOAc (1:4) while the reaction rate increases in order of DMF~NBPin situ scavenging of the HCN formed. We carried out DIC/Oxyma mediated amidation of Fmoc-Gly-OH + (S)-(-)-1-phenylethylamine in DMF-d<sub>7</sub> with 0, 5 and 10 equiv of dimethyl trisulfide (DMTS) as HCN scavenger. The formation of HCN and rate of amidation was monitored by <sup>1</sup>H NMR, revealing that DMTS scavenges HCN without inhibiting the rate of amidation. DIC/Oxyma mediated amidations of Fmoc‑Ser(<i>t</i>‑Bu)‑OH with (S)-(‑)-1-phenylethylamine in DMF and NBP/EtOAc (1:4) with and without 10 equiv of DMTS were carried out and found to be comparable.</p>

Synthesis and reactivities of monofluoro acylboronates in chemoselective amide bond forming ligation with hydroxylamines

2016 ◽  
Vol 14 (1) ◽  
pp. 16-20 ◽  
Author(s):  
Hidetoshi Noda ◽  
Jeffrey W. Bode
Keyword(s):  
Bioorganic Chemistry ◽  
Amide Bond ◽  
Chemical Ligation ◽  
Bond Forming

Synthesis and reactivities of monofluoroacylboronates are described in the context of bioorganic chemistry and chemical ligation.

scholarly journals Peptide Bond Synthesis by a Mechanism Involving an Enzymatic Reaction and a Subsequent Chemical Reaction

2015 ◽  
Vol 291 (4) ◽  
pp. 1735-1750 ◽  
Author(s):  
Tomoko Abe ◽  
Yoshiteru Hashimoto ◽  
Ye Zhuang ◽  
Yin Ge ◽  
Takuto Kumano ◽  
...  
Keyword(s):  
Peptide Synthesis ◽  
Chemical Reaction ◽  
Enzymatic Reaction ◽  
Amide Bond ◽  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Specific Substrate ◽  
Chemical Ligation ◽  
Subsequent Chemical Reaction ◽  
Subsequent Chemical

We recently reported that an amide bond is unexpectedly formed by an acyl-CoA synthetase (which catalyzes the formation of a carbon-sulfur bond) when a suitable acid and l-cysteine are used as substrates. DltA, which is homologous to the adenylation domain of nonribosomal peptide synthetase, belongs to the same superfamily of adenylate-forming enzymes, which includes many kinds of enzymes, including the acyl-CoA synthetases. Here, we demonstrate that DltA synthesizes not only N-(d-alanyl)-l-cysteine (a dipeptide) but also various oligopeptides. We propose that this enzyme catalyzes peptide synthesis by the following unprecedented mechanism: (i) the formation of S-acyl-l-cysteine as an intermediate via its “enzymatic activity” and (ii) subsequent “chemical” S → N acyl transfer in the intermediate, resulting in peptide formation. Step ii is identical to the corresponding reaction in native chemical ligation, a method of chemical peptide synthesis, whereas step i is not. To the best of our knowledge, our discovery of this peptide synthesis mechanism involving an enzymatic reaction and a subsequent chemical reaction is the first such one to be reported. This new process yields peptides without the use of a thioesterified fragment, which is required in native chemical ligation. Together with these findings, the same mechanism-dependent formation of N-acyl compounds by other members of the above-mentioned superfamily demonstrated that all members most likely form peptide/amide compounds by using this novel mechanism. Each member enzyme acts on a specific substrate; thus, not only the corresponding peptides but also new types of amide compounds can be formed.

scholarly journals Minimizing HCN in DIC/Oxyma Mediated Amide Bond Forming Reactions

2020 ◽  
Author(s):  
Marion Erny ◽  
Marika Lundqvist ◽  
Jon H. Rasmussen ◽  
Olivier Ludemann-Hombouger ◽  
Frédéric Bihel ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Peptide Synthesis ◽  
Hydrogen Cyanide ◽  
Reaction Rate ◽  
Solid Support ◽  
Amide Bond ◽  
Prussic Acid ◽  
Bond Forming ◽  
H Nmr ◽  
Bond Forming Reactions

<p>Aiming at advancing protocols for safer, environmentally sensible peptide synthesis we report our findings with regards to the occurrence of hydrogen cyanide (HCN, prussic acid) in amide bond forming reactions mediated by diisopropylcarbodiimide (DIC) and ethyl (hydroxyimino)cyanoacetate (Oxyma). We have determined that HCN is always formed in amide bond forming reactions on solid support in N,N-dimethylformamide (DMF) when employing DIC/Oxyma. In an attempt to minimize the formation of prussic acid by means of preventing the linear DIC/Oxyma adduct <b>2</b> from cyclizing to oxadiazole <b>3</b> and in turn releasing HCN, we evaluated a series of greener solvents such as N-butylpyrrolidinone (NBP), NBP/ethyl acetate (EtOAc, 1:1), methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (PolarClean, PC), and PC/EtOAc (1:1). We found that the ratio between <b>2</b> and <b>3</b> greatly depends on the solvent used and consequently, we further examined DMF, NBP, NBP/EtOAc (1:1) and NBP/EtOAc (1:4) as solvents for DIC/Oxyma mediated amidations on solid support and in solution. We found that using carboxylic acid/Oxyma/DIC in a 1:1:1 ratio the rate of HCN formation decreases in the following order DMF>NBP>NBP/EtOAc (1:1)>NBP/EtOAc (1:4) while the reaction rate increases in order of DMF~NBPin situ scavenging of the HCN formed. We carried out DIC/Oxyma mediated amidation of Fmoc-Gly-OH + (S)-(-)-1-phenylethylamine in DMF-d<sub>7</sub> with 0, 5 and 10 equiv of dimethyl trisulfide (DMTS) as HCN scavenger. The formation of HCN and rate of amidation was monitored by <sup>1</sup>H NMR, revealing that DMTS scavenges HCN without inhibiting the rate of amidation. DIC/Oxyma mediated amidations of Fmoc‑Ser(<i>t</i>‑Bu)‑OH with (S)-(‑)-1-phenylethylamine in DMF and NBP/EtOAc (1:4) with and without 10 equiv of DMTS were carried out and found to be comparable.</p>

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