Chemistry Blog

“Danishefsky 2-component reaction”

This JACS communication by Danishefsky’s group is inspired by the well-known Passerini 3-component (isonitrile + aldehyde + acid) and Ugi 4-component (isonitrile + aldehyde + amine + acid) reactions. They ask the question if isonitriles 1 react with carboxylic acids 2. At room temperature, they do not, but under microwave irradiation they furnish N-formyl amides 3 in good yields. The authors go on to propose the mechanism shown, which could probably be further supported by isotope labeling.

They wanted to apply this new kind of reaction to the synthesis of asparagine-linked glycopeptides. Therefore glycosylisonitrile 4 was reacted with aspartate 5. Instead of the expected product, ester 6 was formed. In the paper, the formation of a “β-GlcNAc donor” by participation of the NAc group is assumed. Its structure is not specified, but I suppose it could be something like 7.

To get around this problem, non-participating neighboring groups like OBn and N₃ were used (8). Now, reaction under the same conditions furnished the expected glycosyl amino acids 9. Even better, the reaction was anomerically specific; that is, β-isonitrile 8 gave exclusively the β-linked product 9, while α-isonitrile 10 yielded only 11.

The formyl group could also be converted into methyl or completely removed, which sets the stage for building up a peptide chain. What is really striking about this new type of reaction is its simplicity. To quote the paper: “[The results described herein]… might well have been discovered a century ago.” Why has nobody ever tried this before? Is it because of the bad smell of isonitriles?