Minimizing HCN in DIC/Oxyma-Mediated Amide Bond-Forming
Reactions
Posted on 2020-06-22 - 21:29
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 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 the order of DMF ≈ NBP < NBP/EtOAc (1:1)
< NBP/EtOAc (1:4). Of the solvents 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)–OH with (S)-(−)-1-phenylethylamine
in DMF and NBP/EtOAc (1:4) with and without 10 equiv of DMTS were
performed and found to be comparable.
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Erny, Marion; Lundqvist, Marika; Rasmussen, Jon H.; Ludemann-Hombourger, Olivier; Bihel, Frédéric; Pawlas, Jan (2020). Minimizing HCN in DIC/Oxyma-Mediated Amide Bond-Forming
Reactions. ACS Publications. Collection. https://doi.org/10.1021/acs.oprd.0c00227
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AUTHORS (6)
ME
Marion Erny
ML
Marika Lundqvist
JR
Jon H. Rasmussen
OL
Olivier Ludemann-Hombourger
FB
Frédéric Bihel
JP
Jan Pawlas