12 research outputs found
Minimizing HCN in DIC/Oxyma Mediated Amide Bond Forming Reactions
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.</p