Ethyl 2‐(tert‐Butoxycarbonyloxyimino)‐2‐cyanoacetate (Boc‐Oxyma) as Coupling Reagent for Racemization‐Free Esterification, Thioesterification, Amidation and Peptide Synthesis

Abstract

Here we report the synthesis and utility of ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma) as an efficient coupling reagent for racemization-free esterification, thioesterification, amidation reactions and peptide synthesis that uses equimolar amounts of acids and alcohols, thiols, amines or amino acids, respectively. Its application to solid phase as well as solution phase peptide synthesis is also demonstrated and a mechanistic investigation is discussed. Boc-Oxyma is similar to the well known coupling agent COMU {1-[1-cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylaminomorpholino]uronium hexafluorophosphate} in terms of its high reactivity and mechanism of action. However, it is not only much easier to prepare, but also to recover and reuse, thereby generating far less chemical waste.

K‐Oxyma: a Strong Acylation‐Promoting, 2‐CTC Resin‐Friendly Coupling Additive

“…Most of these reagents have reached the market at competitive prices, especially OxymaPure ( 4 ), which is easily and rapidly produced from ethyl cyanoacetate 5,12. The impact of Oxyma‐based coupling reagents has been so striking that in the following years analogues displaying greater suppression of epimerization have been designed by other research groups 13,14…”

Synthesis and Explosion Hazards of 4-Azido-l-phenylalanine

“…42 Oxyma-based acylation protocols have become a welcomed advancement in synthetic chemistry, owing to the reclassification of N -hydroxybenzotriazole (HOBt) as a UN0508, class 1.3C explosive in 2005. 43 Despite the claimed success of Boc-Oxyma in racemization-free coupling, it has not appeared in the literature again since its first report in 2013.…”

“…This observation may help to explain the high observed coupling efficiencies in the presence of mild bases, such as iPr 2 NEt (Hünig’s base). 42 …”

“…The image has been reproduced from ref. 42 and has been altered as follows: the spectrum has been reflected left-to-right.…”

Ethyl 2‐(tert‐Butoxycarbonyloxyimino)‐2‐cyanoacetate (Boc‐Oxyma): An Efficient Reagent for the Racemization Free Synthesis of Ureas, Carbamates and Thiocarbamates via Lossen Rearrangement

“…It readily activates the carboxylic acid group for the formation of amides, peptides, esters, thioesters [17] and hydroxamic acids. [18] Notable feature of Boc-Oxyma is in its excellent racemization suppression capability.…”