Reference: PD 12110

Background

In amide-forming reactions with R-amino acids, the use of a coupling additive such as benzotriazole derivatives (e.g., 1-hydroxy-7-azabenzotriazole (HOAt) and hydroxybenzotriazole (HOBt)) is essential to suppress racemization and improve the efficacy of peptide synthesis.

Oxyma, ethyl 2-cyano-2-(hydroxyimino)acetate, is considered as an excellent nonexplosive replacement for HOBt and HOAt. Effectiveness in suppressing racemization and increasing the reaction rate of peptide-forming reactions using Oxyma are believed to be similar to those of HOBt. To date, several attractive features of Oxyma in peptide chemistry have been reported using a conventional organic solvent such as DMF. Although peptide bond-forming reactions can often be performed in water containing organic solvents, no practical peptide coupling additive has been developed for the synthesis of oligopeptides in water.

The Technology

UTHSC researchers have developed  a new Oxyma derivative,(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate, which displays remarkable physicochemical properties as a peptide-coupling additive in water media. Short peptides to oligopeptides could be synthesized by using (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate, EDCI, and NaHCO₃ in water without measurable racemization products. Significantly, simple basic and acidic aqueous workup procedures can remove all reagents utilized in the reactions to afford coupling products in high yield with excellent purity.

Also, the Oxyma derivative displayed a remarkable effect on selective esterifications of primary alcohols.

·         Peptide coupling in water media

·         Can be used to synthesize short and oligopeptides

·         No measurable racemization

·         Simple aqueous work-up

·         Selective esterifications of primary alcohols

Recent publications: 

 Org Lett 2012, 14(13), 3372

 Org Lett 2012, 14(18), 4910

 Tet Lett 2013, 54, 2077