Thread by @ChemistryWorld

What reaction would you put on your synthesis wish list? We’ve asked drug discovery chemists for their dream reactions. Here’s their top five.
chemistryworld.com/news/the-five-…

1. Fluorination.
A reaction that exchanges an H for an F in molecules with lots of other functional groups is one of med chem’s most wanted.

Even a single F atom can change a drug’s behaviour in the body. But adding one to a fully formed molecule isn’t easy. It often means having to start the synthesis over with fluorinated precursors – not ideal if you just want to test where in the molecule to best place the F.

A reaction that installs the slightly more unusual difluoromethyl group would be nice, too, medicinal chemists say. Even better would be one that doesn’t require explosive or corrosive reagents (nobody likes those).
blogs.sciencemag.org/pipeline/archi…

2. Selective alkylation.
It might sound mundane, but chemists really need a reaction to attach a methyl (or other alkyl) group to one specific nitrogen in complex ring systems.

Triazoles, pyridones and other multi-heteroatom rings show up a lot in drug-like molecules. But trying to only alkylate one heteroatom? Be prepared for endless column chromatography as you’ll most likely get a wild product mixture.

3. A perfect carbon coupling.
The dream cross coupling reaction works with lots of functional group (FG) precursors, tackles non-aromatic molecules and controls chirality.

Who doesn’t love cross couplings given how easy and robust they are. But they usually produce flat aromatics. With non-aromatic molecules, they fall short.

To escape ‘cross coupling flatland’ chemists might have to look further than palladium catalysts. Nickel, copper and iron are all good candidates (and cheaper, too). But their redox chemistry is complex and they’re not as easily tamed as Pd.

Some chemists want to go further and do away with pre-functionalising molecules prior to coupling. The goal is to convert C–H directly into C–C. But given how common C–H bonds are in organic molecules, these reactions might remain restricted to just a few types of compounds.

4. Ring editing.
It takes five steps to make this substituted piperazine, because the ring needs to be made from scratch. The same synthesis without the methoxymethyl is only three steps. Wouldn’t it be nice if there was a reaction to attach functional groups onto heterocycles?

60% of small molecule drugs contain heterocycles. The most common ones are piperidines, pyridines and pyrrolidines. But making substituted versions can become a major headache.

Reactions designed for all-carbon molecules don’t translate well to heterocycles, as they like to do side-reactions with catalysts and reagents. And then there’s the whole problem of regioselectivity.

And don’t even think about making new rings. Though if you need inspiration, look no further than a 2009 article entitled Heteroaromatic Rings of the Future, a list of 3000 heterocycles that, although they seem ‘synthetically viable’, have yet to be made.
pubs.acs.org/doi/abs/10.102…

Drumroll for our fifth and final wish list item: the atom swapping reaction.
A reaction that directly exchanges carbon for nitrogen or other heteroatoms. This molecular equivalent to gene editing has the potential to revolutionise chemistry. Sounds a bit like magic?

‘Some people don't like talking about this because they say it's just unrealistic,’ medicinal chemist David Rees told us. But then again, people once thought gene editing was sci-fi nonsense. Rees is sure that one day even atom swapping will be possible.

So there we have it, the five reactions that every medicinal chemist wishes existed. What do you think? And what would you add to your personal chemistry wish list?