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A wish list for organic chemistry

Why do so many drugs have structural similarities? If you look at many of the best-
selling and most-prescribed medicines – like hepatitis C treatment sofosbuvir,
antihypertensive lisinopril or asthma drug fluticasone – they have a few things in
common: they are densely functionalised, have at least one ring and some
unprotected amines or alcohols, and often a scattering of fluorine atoms.

Part of the answer is that drug discovery chemists are limited to a chemical space
that can be accessed by known reactions and the available building blocks. They
also need to consider biology, so reactions that tolerate basic nitrogen atoms are a
must since they feature in almost every single biologically active compound.
Reactions using only off-the-shelf reagents that don’t catch fire when they’re
exposed to air are also a big plus as there’s often no easy access to specialist
equipment like glove boxes.

A 2014 analysis1 showed that only two reactions make up over half of all those used
in synthesis to discover and develop drugs: the amide formation and the Suzuki–
Miyaura cross coupling. ‘The reason these have contributed so much to medicinal
chemistry is that they are the most robust reactions,’ says György Keserű, who
leads a medicinal chemistry group at the Hungarian Academy of Sciences.
The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

Ranging from the seemingly simple to potential Nobel-winning transformations,

every medicinal chemist has a list of reactions they wished existed. Here’s what
this list might look like.

The wish list at a glance

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.

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.

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.

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.

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.

1. Fluorination everywhere, anytime

Perhaps unsurprisingly, a reaction that could convert a C–H into C–F bond is high
on the wish list. More than 20% of all commercial pharmaceuticals contain
fluorine.2 The antidepressant fluoxetine – better known as Prozac – is a prominent
example.

Source: Adapted from DOI: 10.1038/s41557-018-0021-z

To make this fluorinated aggrecanase inhibitor – a compound that stops cartilage

The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

breakdown in osteoarthritis – chemists have to start with a fluoropyridine. A direct

fluorination reaction would give researchers access not only to one but multiple
fluorinated versions of a drug to for testing.

Adding even a single fluorine atom onto a molecule can increase its metabolic
stability and lipophilicity. A reaction to quickly fix radioactive fluorine-18 onto
molecules could also be a boon for medical positron-emission tomography.

But there’s no straightforward way to replace a specific hydrogen atom with a

fluorine once the molecular structure has been assembled, explains Astex’s chief
scientific officer David Rees. ‘If you ask a drug discovery chemist when they’ve got
their lead molecule: “Can you put a fluorine in each of these positions?” The
answer, in general, would be: “I have to go back to the beginning of the synthesis
and start with fluorinated starting materials.”’

There are quite a few ways to fluorinate molecules.3 But they all require installing
another reactive group – like a tin or boron fragment in aromatics, or a double
bond or oxirane in aliphatics – and exchanging it for fluorine. What medicinal
chemists are really after is a robust way to directly exchange an H for an F.

But these direct fluorination reactions often struggle with selectivity issues, giving
mixtures of regioisomers or over-fluorinating compounds. And since a single
fluorine barely changes a molecule’s reactivity or physical properties, removing
excess starting material or side-products after a reaction isn’t trivial.

A lot of the same things are true for reactions that install difluoromethyl groups.
The CF2H group is a bioisostere of thiols or alcohols – it has similar biological
properties to these groups but can lower a drug’s toxicity and increase its
bioavailability. ‘We’re more and more designing them into molecules, but the
chemistry hasn’t quite caught up,’ says Christopher am Ende, senior principal
scientist at Pfizer.

One of the few ways to install a CF2H group uses diethylaminosulfur trifluoride
(DAST), a liq uid that turns into explosive bis-(diethylamino)sulfur difluoride
when heated. Whether this is better than working with the alternative – gaseous
sulfur tetrafluoride, which releases highly corrosive hydrofluoric acid upon contact
with moisture – is questionable. ‘Having that nice solid that you can grab off the
shelf to install a difluoromethyl group would be a great advance,’ says am Ende.

2. Alkylating heteroatoms when there’s

several
The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

‘It might be so mundane that most people don’t even want to think about it, but if
it could be done that would be incredibly useful,’ says am Ende about the reaction
at the top of his personal wish list: pyridone alkylation.

Source: Adapted from DOI: 10.1038/s41557-018-0021-z

Trying to functionalise the 2-pyridone on the left leads to a roughly 1:1 mixture of
products (DOI: 10.1016/j.tetlet.2013.05.054) A reaction that selectively alkylates
one specific heteroatom would be great for tackling the nitrogen-heavy molecule
on the right.

Attaching anything selectively to either the nitrogen or the oxygen in 2- or

4-pyridones is, so far, impossible. Chemists usually end up with wild mixtures of
N-alkylpyridones and alkoxypyridines. ‘It’s such a common and simple
transformation, I find it hard to believe there isn’t a general fix for this yet with
how often pyridones show up in drug discovery,’ am Ende says.

Attempts have been made to figure out the rules behind pyridones’ two-faced
reactivity.4,5 But there are so many individual factors, including the pyridone’s
substitution pattern, the alkylating agent, the base used for deprotonation, the
temperature and even the solvent, it’s still hard to predict – or control – what a
reaction will produce.

There are many heterocycles in drug discovery libraries that suffer from similar
problems. Pyrazoles and triazoles, for example, have two and three nitrogen atoms,
respectively. There’s no reagent combination to selectively modify one of them –
they are just too similar in reactivity. And perish the thought of trying to do a
selective alkylation on a compound that has several of those heterocycles.

The reason heteroatom alkylation is among medicinal chemists’ most wanted is

that these scaffolds make good drugs. The anticancer medications topotecan and
irinotecan feature N-alkylated pyridones; O-alkylated pyridones can be found in
antimalarial drugs. There is also a whole host of antifungal drugs, like fluconazole,
with alkylated triazole units.

3. Powered-up carbon coupling

Cross coupling reactions have enjoyed huge success since their discovery in the
The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

1970s. The reactions that join two – aromatic or other sp2 – carbon atoms together
with the help of a palladium catalyst have become essential for building organic
scaffolds. But the flat biaryls traditional cross coupling reactions are so good at
making are becoming increasingly limited – chemists want their couplings to go
3D.

Source: Adapted from DOI: 10.1038/s41557-018-0021-z

In the synthesis of antidepressant paroxetine, the fluorobenzene ring needs to be

attached in the very first step. Chemists would have to repeat the entire sequence
every time they wanted to test different substitution patterns around the benzene
ring. A robust carbon–carbon coupling would solve this problem. Although there
are reactions that can do similar connections, they are hindered by paroxetine’s
amine group.

‘Pharmaceuticals are evolving towards higher sp3 carbon content,’ explains organic
chemist Mary Watson from the University of Delaware, US. ‘Saturated carbons let
you tune a third dimension, which lets you mitigate off-target effects without
dramatic changes in other drug-like properties.’ A robust reaction that connects
aromatic and aliphatic carbon atoms – or even two aliphatic fragments – is what
medicinal chemists are after.

‘Part of the reason people love palladium is that they know what’s going to happen,
its oxidation states and redox reactions are well controlled,’ says Watson. But while
palladium’s catalytic cycle is perfect for sp2 fragments, it doesn’t do well with
aliphatic coupling partners. Undesirable side reactions can takeover, other times
the reaction shuts down entirely. What might be needed is a different metal
entirely.

Nickel, for example, allows unusual transformations like cross coupling between
alkyl amines and alkylzinc halides.6 Other metals might be able to do even more
exotic transformations. But ‘how, for example, do you control iron and its wide
variation in redox activity?’ Watson asks. ‘What are the right ligands, the right
conditions to get it to do what you want it to do?’

But no matter the metal, all cross couplings need pre-functionalisation. Attaching
reactive groups onto the coupling partners lets the catalyst know where to join the
carbon atoms. Sometimes, for example with pyridines, making these precursors is
a big sticking point. So some chemists want to rid themselves entirely of the need
The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

to pre-functionalise. The goal is to convert C–H directly into C–C bonds.

The problem is that organic molecules are all about C–H bonds. With so many of
them around it’s difficult to tell a catalyst what to do. Currently, reactions rely on
workarounds, like the substrate’s inherent reactivity bias or a directing group, to
guide the catalyst to a specific C–H bond.

Even if a universal C–H activation reaction becomes a reality one day, ‘I think
there will still be times when it will be easier to pre-install a functional group or to
take advantage of existing functional groups,’ says Watson. ‘The beauty of organic
chemistry is that we created options so we can choose the one that makes the most
sense for an application.’

4. Making and editing rings

Heterocycles are medicinal chemists’ bread and butter. Around 60% of all small
molecule drugs have a heterocyclic core. By far the most common ones are
piperidines, pyridines and pyrrolidines, but there’s also penams, morphinans and
isoxazoles among the 25 most frequent nitrogen heterocycles.7

Source: Adapted from DOI: 10.1038/s41557-018-0021-z

This substituted piperazine is a precursor for a cancer drug candidate. Because

there’s no reaction that can install the methoxymethyl directly, chemists have to
make the ring from scratch (DOI: 10.1021/acs.jmedchem.5b00706). Making the
same molecule without the methoxymethyl group takes only three steps. Wouldn’t
it be nice if there was a reaction that could directly manipulate such rings?

Many small heterocycles are commercially available, but the ones that aren’t can
become a major synthesis headache. ‘If you have multi-substituted pyridines,
something that may look quite simple on the surface, sometimes you realise that
just to make the starting material for your synthesis could take seven, eight, nine
steps,’ says am Ende.

Many reactions designed for all-carbon aromatics don’t translate well to

heteroaromatics. Fluorinating reagents can react with heterocycles and oxidise
rather than fluorinate them. Cross coupling catalysts are often poisoned by
heterocycles as they stick to the metal permanently.

There are some ways to install functional groups on aromatic heterocycles late in a
The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

synthesis though, like iridium-catalysed borylation. It installs a boron group that

can be replaced with a substituent of choice. But figuring out where the reaction
might occur – a mix of steric and electronic effects play a role in heteroaromatics –
is the subject of entire publications.8 ‘If you could start with pyridine, which is
cheap and you can get litres of it, or other simple, abundantly available
heterocycles, and you could just go round the ring and selectively install different
groups, I’d be out of a job,’ laughs am Ende.

When chemists want an aliphatic heterocycle with unusual substitution patterns, it

gets even more complicated. Usually, this means starting from an acyclic
precursor. The substituents are installed on the acyclic molecules, which are then
painstakingly cyclised later in the synthesis. If the cyclisation fails, it’s back to the
beginning.

‘That hurts us because it’s slow,’ says Rees. ‘Frequently, we don’t have time to
make those compounds so don’t explore this chemical space even if it might make
for really interesting drugs.’

In 2009, chemists at a British biotech company published a paper called

Heteroaromatic rings of the future. Hiding behind this poetic title is a list of over
3000 small heterocycles that, although they seem ‘synthetically viable’, had never
been made.

Ten years on, a group of French researchers revisited the state of synthesis by
looking at the 22 examples the 2009 study had selected as representative.9 Nine of
the small bicycles have been synthesised as exact rings. Six have been made as part
of larger scaffolds. Another seven have still not been described.

5. Atom swapping

‘For me [it] would be the single most useful new reaction for drug discovery
chemistry and might rank alongside Nobel prize winning synthesis,’ says Rees
about a carbon–nitrogen swap reaction. This transformation could revolutionise
medicinal chemistry if it were possible.

Source: Adapted from DOI: 10.1038/s41557-018-0021-z

The moonshot synthesis: single atom exchanges, particularly to convert rings into
heterocycles, would have the potential to revolutionise medicinal chemistry.
The five reactions on every organic chemist’s wish list | Research | Ch... https://www.chemistryworld.com/news/the-five-reactions-on-every-org...

Syntheses like that of anti-cancer drug crizotinib – currently done in at least six
steps – might look quite different if chemists could simply edit in the nitrogen ring
atoms at the end of the synthesis.

Chemists wouldn’t need to worry any more about how to functionalise heterocycles
or how to do a cross coupling in the presence of a few amine groups. Like a
chemical version of gene editing, the reaction could take a finished molecule, target
a specific carbon atom and exchange it for a nitrogen, oxygen or sulfur.

‘That’s of course unprecedented, and some people don’t like talking about this
because they say it’s just unrealistic,’ Rees says. But before Crispr–Cas9, people
didn’t think targeted gene editing would be possible either. ‘Science moves very
fast and there are a lot of creative people in organic chemistry,’ Rees says. ‘I’m sure
it will be done, it’s just a question of when.’

The Baeyer–Villinger oxidation and the Beckmann rearrangement are the two
reactions that come closest to a hypothetical atom swap. Both were discovered
more than 100 years ago, and both are straightforward: they insert an oxygen or a
nitrogen into a cyclic ketone. But both add an atom rather than replacing one.

Acknowledgements

Thank you to Constanze Neumann from the Massachusetts Institute of

Technology, and Ben Glasspoole, Kaelyn Wilke and Kenneth Schwieter from
Millipore Sigma for helpful discussions.

References

1 D G Brown and J Boström, J. Med. Chem., 2016, 59, 4443 (DOI:

10.1021/acs.jmedchem.5b01409)

2 G K Surya Prakash and F Wang, Chemistry Today, 2012, 30, 30

3 C N Neumann and T Ritter, Angew. Chem. Int. Ed., 2015, 54, 3216 (DOI:
10.1002/anie.201410288)

4 M Breugst and H Mayr, J. Am. Chem. Soc., 2010, 132, 15380 (DOI:
10.1021/ja106962u)

5 M C Torhan, N P Peet and J D Williams, Tetrahedron Lett., 2013, 54, 3926 (DOI:
10.1016/j.tetlet.2013.05.054)

6 S Plunkett et al, J. Am. Chem. Soc., 2019, DOI: 10.1021/jacs.9b00111

7 E Vitaku, D T Smith and J T Njardarson, J. Med. Chem., 2014, 57, 10257 (DOI:
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10.1021/jm501100b)

8 M A Larsen and J F Hartwig, J. Am. Chem. Soc., 2014, 136, 4287 (DOI:
10.1021/ja412563e)

9 K Passador, S Thorimbert and C Botuha, Synthesis, 2019, 51, 384 (DOI:

10.1055/s-0`037-1611279)

Further reading

D C Blakemore et al, Nat. Chem., 2018, 10, 383 (DOI: 10.1038/s41557-018-0021-

z)

J Boström et al, Nat. Rev. Drug Discov., 2018, 17, 709 (DOI:
10.1038/nrd.2018.217)

K R Campos et al, Science, 2019, 363, eaat0805 (DOI: 10.1126/science.aat0805)

T Cernak et al, Chem. Soc. Rev., 2016, 45, 546 (DOI: 10.1039/C5CS00628G)

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