Posts Tagged ‘Samuel Danishefsky’
Danishefsky + Rebek = ?
by Phil on Jun 18 2008 (3496 Views)I recently wrote about the reaction of isonitriles with carboxylic acids under microwave irradiation, as reported by Danishefsky. Rebek’s group took up this idea and tried the reaction inside capsules formed by two cavitands (DOI:10.1021/ja802288k).
In the presence of the capsule, acid 1 and isonitrile 2 react at room temperature to give the intermediate 3. However, the n-butyl intermediate 3a is not detected and immediately rearranges to the product 4a, still trapped inside the capsule. Release of the intermediate and reaction with 1 in the bulk solution gives a small amount of 5a (this side product gets trapped in a capsule again).
In the case of isopropyl substitution, intermediate 3b is actually seen by NMR. It cannot rearrange to product 4b, but is released from the capsule instead and reacts with 1 to give formamide 5b. The authors explain this with the steric bulk of the isopropyl group that prevents the rearrangement inside the capsule.
As far as I know, this is the first experimental evidence for intermediates of the type of 3, which take part in the reaction mechanism suggested by Danishefsky. In addition, it also shows that the carboxylic acid – isonitrile reaction can be “catalyzed” by cavitands without the need for microwave irradiation.
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by Phil on Apr 21 2008 (1860 Views)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?
