Synthesis Nibble 5

A small piece of synthesis today, based on a paper in JMC ASAP (DOI) from Vertex, on their ubiquitous pyrazolyl-pyrrole motif, which they seem to use against every kinase going. This time it is ERK. In this program they identified pyrazolyl-pyrrole 1 as a micromolar inhibitor of ERK. Early in the program they fiddled with the phenyl ring of 1 and found a meta chloro to give the most potent compounds.

The prepared compounds of this type using the following route

It all started in fairly standard fashion with a Friedel-Crafts acylation of ethyl pyrrole-2-carboxylate. In the next step (formation of the enamine) they use Bredereck’s reagent [(tert-butoxy-bis(dimethylamino)methane)]. I would have thought you could perform this transformation with DMFDMA? Anyone have any ideas why you would use one and not the other? Maybe this Bredereck’s reagent is simply more reactive?

EDIT - It seems that DMFDMA will indeed methylate acidic heterocycles and phenols, so many thanks to DrSnowboard for pointing that out in the comments.

Subsequently they cyclised with hydrazine, hydrolysed the ester with NaOH, then did some EDC/HOBt couplings with a variety of amines to give the desired amides.

The enamine adducts prepared in such ways are pretty useful in general, especially for the preparation of carboxylate substituted heterocycles (as shown in scheme below). Reaction of an ester enolate with an acid chloride yields the beta keto ester, which can then be reacted to yield the enamine shown. Cyclisation with which ever hetero component you desire gives an ester substituted heterocycle.

One interesting point to note in this paper is the totally flipped binding mode of these compounds when bound to JNK3 (hence the title of the paper “Flipped Out: Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors”). Med chemists tend to believe that similar compounds tend to bind in highly similar ways, and identical compounds bind in similar ways to closely related targets. Seems that isn’t always true.