Minimizing HCN in DIC/Oxyma mediated amide bond forming reactions
| Autor: | Olivier Ludemann-Hombourger, Frédéric Bihel, Jon H. Rasmussen, Marika Lundqvist, Jan Pawlas, Marion Erny |
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| Přispěvatelé: | Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC) |
| Rok vydání: | 2020 |
| Předmět: |
Oxyma
010405 organic chemistry Chemistry Organic Chemistry Hydrogen cyanide macromolecular substances 010402 general chemistry HCN scavenging 01 natural sciences Combinatorial chemistry 0104 chemical sciences amide bond formation DIC chemistry.chemical_compound Amide Peptide synthesis Peptide bond minimizing HCN formation Physical and Theoretical Chemistry green solvents [CHIM.OTHE]Chemical Sciences/Other |
| Zdroj: | Organic Process Research and Development Organic Process Research and Development, American Chemical Society, 2020, 24 (7), pp.1341-1349. ⟨10.1021/acs.oprd.0c00227⟩ |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.0c00227 |
| Popis: | Aiming at advancing protocols for safer, environmentally sensible peptide synthesis we report our findings with regard to the occurrence of hydrogen cyanide (HCN, prussic acid) in amide bond-forming reactions mediated by diisopropylcarbodiimide (DIC) and ethyl (hydroxyimino)cyanoacetate (Oxyma). We determined that HCN is always formed in amide bond-forming reactions on solid support in N,N-dimethylformamide (DMF) when DIC/Oxyma is employed. In an attempt to minimize the formation of prussic acid by means of preventing the linear DIC/Oxyma adduct 2 from cyclizing to oxadiazole 3 and in turnreleasing 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 2 and 3 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 the order of DMF ≈ NBP < NBP/EtOAc (1:1) < NBP/EtOAc (1:4). Of thesolvents examined, the NBP/EtOAc (1:4) mixture gave the lowest rate of HCN formation and the highest rate of amide bond formation both in solution and on solid support. As altering the solvent for DIC/Oxyma-mediated amidations resulted in suppressing HCN rather than its full elimination we evaluated the concept of in situ scavenging of the HCN formed. We performed DIC/Oxyma-mediated amidation of Fmoc-Gly-OH + (S)-(−)-1-phenylethylamine in deuterated DMF with 0, 5, and 10 equiv of dimethyl trisulfide (DMTS) as HCN scavenger. The formation of HCN and rate of amidation was monitored by 1H NMR, revealing that DMTS scavenges HCN without inhibiting the rate of amidation. DIC/Oxyma-mediated amidations of Fmoc-Ser(t-Bu)−OHwith (S)-(−)-1-phenylethylamine in DMF and NBP/EtOAc (1:4) with and without 10 equiv of DMTS were performed and found to be comparable. |
| Databáze: | OpenAIRE |
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