More Magic Methyls, Please

Medicinal chemists have long been familiar with the "magic methyl" effect. That's the dramatic change in affinity that can be seen (sometimes) with the addition of a single methyl group in just the right place. (Alliteration makes that the phrase of choice, but there are magic fluoros, magic nitrogens, and others as well). The methyl group is also particularly startling to a chemist, because it's seen as electronically neutral and devoid of polarity - it's just a bump on the side of the molecule, right?

Some bump. There's a very useful new paper in Angewandte Chemie that looks at this effect, and I have to salute the authors. They have a number of examples from the recent literature, and it couldn't have been easy to round them up. The methyl groups involved tend to change rotational barriers around particular bonds, alter the conformation of saturated rings, and/or add what is apparently just the right note of nonpolar interaction in some part of a binding site. It's important to remember just how small the energy changes need to be for things like this to happen.

The latter part of the paper summarizes the techniques for directly introducing methyl groups (as opposed to going back to the beginning of the sequence with a methylated starting material). And the authors call for more research into such reactions: wouldn't it be useful to be able to just staple a methyl group in next to the nitrogen of a piperidine, for example, rather than having to redo the whole synthesis? ...

Source: In the Pipeline - October 30, 2013 Category: Chemists Tags: Chemical News Source Type: blogs