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Minimizing HCN in DIC/Oxyma Mediated Amide Bond Forming Reactions

preprint
submitted on 01.06.2020 and posted on 02.06.2020 by Marion Erny, Marika Lundqvist, Jon H. Rasmussen, Olivier Ludemann-Hombouger, Frédéric Bihel, Jan Pawlas

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 2 from cyclizing to oxadiazole 3 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 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 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-d7 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)‑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.

History

Email Address of Submitting Author

jan.pawlas@polypeptide.com

Institution

PolyPeptide Group

Country

Sweden

ORCID For Submitting Author

0000-0002-8151-4112

Declaration of Conflict of Interest

no conflict of interest

Version Notes

first version v1

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in Organic Process Research & Development

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