Published: 11 December 2024
Skeletal editing is a completely new paradigm in organic chemistry that allows for rapid modification of the core of a complex molecule without having to synthesise each analogue from scratch.
A growing number of publications on atom insertion/deletion are highlighting new strategies and attempts to involve more and more complex structures, manifesting the great potential for adjusting atomic make-up and therefore, the chemical and physical properties of drug candidates. In our previous blog, we discussed the successful application of ring expansion in our labs at BioAscent.
However, skeletal editing is not limited to atom insertion or deletion - atoms in a complex molecule’s skeleton can also be swapped removing the requirement for a new synthesis from scratch. As we near the 2024 festive season a fun comparison could be - imagine if you had to redecorate your entire Christmas tree in order to swap out a single bauble?! By its very nature, atom swapping methodology is quite a complex process because the selected atom (and not any other one) must be extracted first without affecting other atoms and then a new atom must be reintroduced at that exact location leaving the original molecular architecture undisturbed.
Balancing innovation and practicality in skeletal editing
To date, the number of publications on skeletal editing via atom swapping is quite limited and we have not yet had a suitable opportunity to apply this approach to benefit a customer’s project. At this point, the methodology is a brand-new concept that has great potential but to what extent this approach can be applicable in a commercial laboratory has yet to be determined. The lion’s share of drug molecules rarely contains only one potentially exchangeable atom so there is the distinct possibility of an undesired atom being swapped or unclear situations, for example, in the case of competing multiple atom swaps. In such scenarios, it might well be more time efficient at the end of the day to follow an unambiguous multistep protocol rather than try to cut corners - albeit rationally!
At BioAscent we understand that the fast-paced business environment is not always the place to take a risk and employ highly novel and innovative techniques in their early stage of advancement. On a case-by-case basis and through dialogue with our customers we pragmatically weigh out the benefits and drawbacks of any technology to apply in our labs from ‘Pool and Split’ to photochemistry in order to efficiently deliver on projects.
Highlighted below are publications that might accelerate the introduction of atom swap chemistry into commercial laboratories as a routine methodology.
One-pot access to pyridine derivatives of drug precursors via nitrogen scanning
Nitrogen scanning is quite an intriguing concept in drug discovery. What if it was possible to simply swap carbon atoms of choice for nitrogen atoms in advanced building blocks or even final pharmaceutical molecules (Figure 1)?
Figure 1. Examples of nitrogen scans applied in the discovery of recently approved pharmaceuticals.
In 2023, another seminal publication from the pioneering lab in skeletal editing field came to light.1 Mark Levin’s group reported an elegant way to introduce a nitrogen atom into various aromatic rings by a carbon to nitrogen site-directed swap reaction that could potentially avoid the bottom-up synthesis of each pyridine containing advanced building block. Inspired by earlier studies2,3 Levin’s team suggested that the challenges encountered previously such as lack of selectivity and formation of multiple products can be tackled by selective ipso-carbon deletion in azepine molecules. This would allow for a single pyridine isomer formation without any skeletal or functional group disruption and made nitrogen scanning possible (Scheme 1).
Scheme 1. General outline and reaction scope of nitrogen scanning reaction.
This two-step one-pot swap reaction was found to apply to a more complex structure, female hormone estrone (Figure 2). The pyridine analogue of estrone was obtained with 10% yield over 4 steps, whereas the previously published approach required 11 steps and resulted in less than 1% yield starting from significantly more expensive nor-Testosterone.
Figure 2. Comparison of the published route towards aza-estrone derivative vs. atom swap approach.
Scaffold hopping through atom pair swap: from pyridines to benzenes and naphthalenes
An intriguing method for precise atom pair swap in substituted pyridine scaffolds was reported in 2023 by Studer’s group4. The atom pair swap was performed in a one-pot multistep fashion: dearomatisation of pyridines, followed by [4+2] cycloaddition with dienophiles, and rearomatising retrocycloaddition. This allowed for the conversion of a C=N duo of the pyridine core into a C=C bond under mild conditions and without any catalyst present (Scheme 2).
Scheme 2. Studer’s atom pair swap. General outline.
Initial evaluation of one-pot atom pair swap in various substituted pyridines with benzyne as dienophile was successful, therefore the authors went on to explore other potential dienophiles such as alkenes and alkynes and found that they were also well tolerated in the dearomatisation, cycloaddition and retrocyclisation sequence. Notably, the presence of various heterocycles (pyrazoles, benzofurans, pyridines, indoles and thiophenes) in pyridine scaffolds did not have any negative effect and swap occurred chemoselectively (Figure 3).
Figure 3. Selected examples of initial evaluation of atom pair swap in substituted pyridine.
Synthetic utility of this method was further demonstrated on multiple drug molecules. For example, several benzene and naphthalene derivatives of acyl-protected tropicamide were generated via one-pot atom pair swap in the pyridine scaffold in good yields. This robust atom swap strategy can also be used to introduce medicinally relevant functionalities such as carboxylate, phosphonate and trifluoromethoxy groups by derivatisation of pyridine–stanolone, pyridine–indomethacin and pyridine–probenecid conjugates (Figure 4).
Figure 4. Atom pair swap and its application to biologically relevant scaffolds.
Single step access to benzimidazoles from N-alkyl indoles via carbon-to-nitrogen atom swap
A very practical route to benzimidazoles has recently been published in ChemRxiv®5. This publication (though not yet peer-reviewed) has drawn our attention due to the method’s applicability to a variety of complex drug-like molecules. Bill Morandi and his team developed C to N swap based conversion of various indoles to the corresponding benzimidazoles using readily available commercial phenyliodine(III) diacetate (PIDA) and ammonium carbamate (Scheme 3).
Scheme 3. General scheme for benzimidazoles synthesis via atom swap.
Multiple functional groups used in drug discovery were found to be tolerant to these conditions. For example, indoles bearing methoxy, amide, halogens, esters, and sulfones were successfully converted into benzimidazoles with moderate to good yields. Benzyl-protected indole was engaged in atom swap-deprotection sequence resulting in unprotected free NH benzimidazole with 47% yield over two steps, allowing for further functionalisation (Figure 5).
Figure 5. Selected examples for the synthesis of benzimidazoles via carbon to nitrogen atom swap.
To the author’s delight, the atom swap worked very well when applied to more complex building blocks i.e. indoles with substituents in proximity to the reactive centre (substituents in 4- or 7-positions) or various aza-indoles (Figure 6).
Figure 6. Selected examples for the synthesis of benzimidazoles from indoles with substitution in proximity to the reactive centre.
The scope of this elegant atom swap protocol was expanded to late-stage diversification of multiple drug-like molecules. The benzimidazole core of a precursor for a PFKFB3 kinase and PTK6 inhibitor was obtained in 41% yield, demonstrating excellent chemoselectivity and leaving the benzopyrazine intact under the reaction conditions. A series of other compounds containing multiple heterocycles led to corresponding benzimidazoles in good yields showcasing the reaction’s compatibility with oxazoles, pyrimidines and pyridines (Figure 7).
Figure 7. Carbon to nitrogen swap application for the synthesis of benzimidazole cores in the advanced drug-like molecules.
The future potential of atom swapping in drug discovery
Based on the above publications we can surely see that atom swapping chemistry is being developed using complex architectures and relatively simple reaction conditions. This gives us hope that the atom swap will, at some point, have a substantial impact on drug discovery programmes. Our chemistry team is eagerly waiting for an opportunity to apply atom swap techniques to advance our customers’ projects.
To find out more about our services or to enquire about working with BioAscent, contact a member of the team.
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About the author
Olga Gozhina is a Senior Scientist in the Chemistry Department at BioAscent. She earned her PhD in organic chemistry from The Arctic University of Norway, focusing on synthesis of short boron-containing antimicrobial peptidomimetics. Upon completion of her postdoctoral studies at the University of São Paulo (Brazil) she made a career shift into industry. Prior to working at BioAscent she worked for several CRO’s and Biotech businesses in Canada, Russia and Norway.
