At BioAscent we are thinking differently about making molecules.  By encouraging our chemists to disconnect targets in new ways, we have successfully synthesised novel compounds more efficiently.  One important technology which has enabled us to realise this is photochemistry.

Photochemistry involves the use of light (typically visible or ultraviolet light) to activate a substrate or catalyst that, in turn, facilitates a chemical reaction. This field has gained significant attention from researchers in recent years, and emerged as a valuable synthetic strategy, due to its mild reaction conditions, selectivity, and the ability to access new reaction pathways.

Photochemistry opens up a wealth of novel disconnections

Traditionally, transition metal mediated cross-coupling reactions have been utilised to form C(sp²)-C(sp³) bonds. Although an essential reaction in the medicinal chemist’s toolbox, most chemists will have experienced the problems which cross-coupling reactions between an aromatic and aliphatic partner can suffer from. These can include competitive side reactions (eg. β-hydride elimination), sluggish reaction rates and lack of commercial availability of reagents.

By employing photochemistry, it has been possible for our chemists to rapidly obtain products that would otherwise be more time-consuming or challenging to access.  In 2021, MacMillan and co-workers reported a novel photochemical method for the direct use of alcohols in deoxygenative C(sp²)-C(sp³) cross-coupling reactions with aryl halides (scheme 1A).¹   With a large and ever-increasing feedstock of commercially available alcohol building blocks, this methodology opens up the possibility to access diverse chemical space and quickly introduce sp³-character to compounds.  The reaction compliments previous methodology published by the same group for the photochemical decarboxylative C(sp²)-C(sp³) cross-coupling of carboxylic acids with aryl halides (scheme 1B).²

Our New Technologies team investigated MacMillan’s deoxygenative coupling, with good yields achieved across a range of substrates.  The application of this reaction to a client project enabled access to a highly functionalised intermediate in 1 step, considerably expediting the synthesis of the target compound as using traditional chemistry would have required an 8-step route.

Scheme 1a. Representative reaction scheme for deoxygenative C(sp²)-C(sp³) cross coupling; 1b. Representative reaction scheme for decarboxylative C(sp²)-C(sp³) cross coupling.

Rapid access to key compounds is enabled by photocatalysis

We have found this cross-coupling chemistry to be highly applicable to the synthesis of drug-like molecules and have been able to rapidly prepare further key building blocks for our projects which would have been challenging and time consuming using classical methods.  Using a batchwise approach, 3 g of intermediate 1 was successfully produced (scheme 2A).  The MacMillan group has recently expanded this methodology to include C(sp³)-C(sp³) couplings, which will further increase the utility of the reaction.³

Photochemical methods developed by the MacMillan group have also been employed by chemists at BioAscent to carry out operationally simple decarboxylative C(sp³)-C(sp³) cross coupling reactions in a single step and high yield.  For example, intermediate 2 (scheme 2B) was synthesised in one step from cheap and readily available starting materials, without the need for pre-functionalisation of either substrate.⁴ The reaction employs a dual nickel/iridium catalyst system which enables the catalytic activation of both coupling partners upon excitation of the iridium catalyst by visible light. 

Scheme 2a. 3 g of key building block 1 was prepared using a photocatalytic reaction; 2b. Quick and high-yielding sp³-sp³ cross coupling to access intermediate 2.

Mild and predictable C–H functionalisation using photocatalysis

In a C–H functionalisation reaction, a relatively inert C–H bond is selectively cleaved and replaced with a C–X bond.  This can streamline syntheses by removing the need for pre-functionalisation of the reactive site.  Photochemistry is well suited to C–H functionalisation as reactions can be fine-tuned by changing the catalyst, wavelength of light or other factors.  This can favour reaction at a single site in a molecule, leading to high levels of site-specific selectivity.

Nicewicz and co-workers have developed a predictive model for the photochemical site selective C–H functionalisation of aromatic heterocycles.⁵ Using electron density calculations, the group were able to predict the site of reaction for the C–H functionalisation of a number of heterocycles and to identify general trends across different classes of heterocycles.

BioAscent chemists employed this methodology to selectively functionalise a single position on the heterocyclic core of a late-stage intermediate on a client project (scheme 3).  This afforded access to a key compound for which traditional synthetic routes had proved to be poorly yielding.  The conditions employed are mild, meaning sensitive functional groups can be incorporated into the molecule prior to the C–H functionalisation step.

Scheme 3. Site selective C–H activation of aromatic (hetero)-cycles

Access to our benchtop photoreactors allows the chemistry team at BioAscent to implement these and other versatile strategies as part of the synthesis of compounds we design and make for our clients.

For more information on how BioAscent can support your chemistry requirements please get in touch.

References

1.         Nature, 2021, 598, 451–456.

2.         Science, 2014, 345, 437−440.

3.         J. Am. Chem. Soc., 2023, 145, 7736-7742.

4.         Nature, 2016, 536, 322-325.

5.         J. Am. Chem. Soc., 2017, 139, 11288–11299

About the author

Kirsten Deytrikh is a Senior Scientist in chemistry and a Business Development Associate at BioAscent.  Prior to joining BioAscent she gained experience in fragment- and structure-based drug discovery as a medicinal chemist at Vernalis in Cambridge, UK.  Kirsten holds a PhD in synthetic chemistry from the University of Cambridge.