In 2019, ChemistryWorld published a “wish list” of reactions for organic chemistry, describing five hypothetical reactions which were particularly desirable for medicinal chemistry. A few recent papers brought this back to my mind, so I revisited the list with the aim of seeing what progress had been made. (Note that I am judging these based solely by memory, and accordingly I will certainly omit work that I ought to know about—sorry!)
1. Fluorination – Exchanging a specific hydrogen for a fluorine atom in molecules with many functional groups. A reaction that installs a difluoromethyl group would be nice too.
This is still hard! To my knowledge, no progress has really been made towards this goal in a general sense (although plenty of isolated fluorination reactions are still reported, many of which are useful).
C–H fluorination is particularly challenging because separating C–H and C–F compounds can be quite difficult. (Fluorine is often considered a hydrogen bioisostere, which is nice from a design perspective but annoying from a chromatography perspective.) For this reason, I’m more optimistic about methods that go through separable intermediates than the article’s author: “installing another reactive group… and exchanging it for fluorine” may not be particularly ideal in the Baran sense, but my guess is that this strategy will be more fruitful than direct C–H fluorination for a long while yet.
2. Heteroatom alkylation – A reaction that – selectively – attaches an alkyl group onto one heteroatom in rings that have several, such as pyrazoles, triazoles and pyridones.
This problem is still unsolved. Lloyd-Jones published some nice work on triazole alkylation a few weeks after the ChemistryWorld article came out, but otherwise it doesn’t seem like this is a problem that people in academia are thinking much about.
Unlike some of the others, this challenge seems ideally suited to organocatalysis, so maybe someone else in that subfield will start working on it. (Our work on site-selective glycosylation might be relevant?)
EDIT: I missed extremely relevant work from Stephan Hammer, which uses engineered enzymes to alkylate pyrazoles with haloalkanes (and cites the ChemistryWorld article directly). Sorry!
3. Carbon coupling – A reaction as robust and versatile as traditional cross coupling for stitching together aliphatic carbon atoms – ideally with control of chirality, too. Chemists also want more options for the kinds of molecules they can use as coupling precursors.
There’s been a ton of work on Csp3 cross coupling since this article came out: MacMillan (1, 2, 3, 4, 5, 6) and Baran (1, 2, 3) have published a lot of papers, and plenty of other labs are also working here (I can’t list everyone, but I’ll highlight this work from Sevov). I doubt this can be considered “solved” yet, but certainly things are much closer than they were in 2019.
(I haven’t seen much work on enantioselective variants, though: this 2016 paper and paper #2 from Baran above are the only ones that comes to mind, although I’m sure I’m missing something. Still—an opportunity!)
4. Making and modifying heterocycles – A reaction to install functional groups – from alkyl to halogen – anywhere on aromatic and aliphatic heterocycles, such as pyridine, piperidine or isoxazole. Reactions that can make completely new heterocycles from scratch would be a bonus.
I’m not a big fan of the way this goal is written—virtually every structure in medicinal chemistry has a heterocycle, so “making and modifying heterocycles” is just too vague. What would a general solution even look like?
Nevertheless, there are plenty of recent papers which address this sort of problem. Some of my favorites are:
(One of my friends in academia told me that they really disliked the Sather work because it was just classic reactivity used in a straightforward way, i.e. not daring enough. What a clear illustration of misaligned incentives!)
5. Atom swapping – A reaction that can exchange individual atoms selectively, like swapping a carbon for a nitrogen atom in a ring. This chemical version of gene editing could revolutionise drug discovery, but is probably furthest from realisation.
Ironically, this goal is probably the one that’s closest to realization today (or perhaps #3): Noah Burns and Mark Levin have both published papers converting benzene rings directly to pyridines recently. More broadly, lots of organic chemists are getting interested in “skeletal editing” (i.e. modifying the skeleton of a molecule, not the periphery), which seems like exactly what this goal is describing. To my knowledge, a comprehensive review has not yet been published, but this article gives a pretty good overview of the area.
Overall, it’s impressive how much progress has been made towards the goals enumerated in the original article, given that it’s only been four years (less than the average length of a PhD!). Organic methodology is a very exciting field right now: data is easy to acquire, there are lots of problems to work on, and there seems to be genuine interest from adjacent fields about the technologies being developed. Still, if the toughest challenges in the field’s imagination can be solved in under a decade, it makes you wonder what organic methodology will look like in 20–30 years.
As methods get faster to develop and more and more methods are published, what will happen? Will chemists employ an exponentially growing arsenal of transformations in their syntheses, or will the same methods continually be forgotten and rediscovered every few decades? Will computers be able to sift through centuries of literature and build the perfect synthesis—or will the rise of automation mean that we have to redesign every reaction to be “dump and stir”? Or will biocatalysis just render this entire field obsolete? The exact nature of synthesis’s eschatology remains to be determined.