Published: 10 September 2024
Skeletal editing has recently surfaced as a powerful strategy for precise and selective deletion, insertion or swapping of atoms in core ring structures of complex molecules. The term ‘skeletal editing’ was introduced by Prof. Mark Levin to distinguish specific atom changes to the cyclic core of a scaffold from its peripheral editing (molecular editing). This novel approach allows for the rapid diversification of complex molecular architectures and could therefore have a huge impact on the drug discovery process, expediting the delivery of novel compounds. By minimising the number of synthetic steps versus traditional de-novo synthesis of each molecule from scratch, skeletal editing is a cost and labour efficient approach.
At BioAscent we are constantly monitoring new and emerging technologies that can be applied to our client’s projects. Recently, we have successfully applied skeletal editing in our laboratories. In the below example, a smooth ring expansion afforded rapid access to the desired bromo-substituted quinoline from the corresponding readily available indole starting material in a single step (Scheme 1).1 In this case, the application of skeletal editing avoided embarking on a possibly lengthy route optimisation to reach a key building block for which no published routes were available in the literature.
This work has inspired us to put together this blog, where we highlight some noteworthy skeletal editing reactions and their applications to the preparation of drug-like compounds.
Scheme 1. Ring expansion from indole to quinoline as carried out at BioAscent.
Ring expansion of indenes – a straightforward strategy to a library of 2-substituted naphthalenes with remarkable functional group tolerance
A useful protocol for the photoredox-enabled ring expansion of indenes to generate a library of 2-substituted naphthalenes was published by the Glorius group in 2023.2 Naphthalenes are a fundamental motif in many biologically active molecules, yet little attention has been given to developing fast and efficient methods to generate them. In this methodology, the group utilised radical carbyne precursors bearing different functional groups to access a variety of products (Scheme 2).
Scheme 2. Glorius’ photoredox ring expansion of indene to naphthalene.
The method avoids common challenges associated with carbynes such as slow reagent addition and low temperatures by using visible light to facilitate the generation of the carbyne intermediate. This ring expansion has wide applicability and tolerates a variety of both electron-withdrawing (halogens, triflate, trifluoromethyl, nitro, cyano and phenylsulfonyl) and electron-donating (thiomethyl) functional groups. Moreover, common heterocyclic rings, such as thiophene and pyridine, and aliphatic chains bearing diverse functionalities were tolerated with the corresponding products being obtained in moderate to good yields (Figure 1).
Figure 1. Selected scope of the ring expansion reaction.
A highly selective silver carbene-mediated ring hop from indazole to 1,2-dihydroquinazoline
Earlier this year, Xihe Bi’s group published an interesting addition to a ring hopping technique that employs donor-type carbenes for a straightforward carbon atom insertion into the N–N bond in the five-membered ring of an indazole.3 This high-yielding silver catalysed approach demonstrated not only introduction of mono- and di-aromatic, arylalkyl, or alkenyl groups into 1H-indazoles but has proven to be widely applicable to more complex pharmaceutically relevant structures. The authors showed that a range of biologically active molecules underwent carbon insertion to afford the relevant quinazolines with good to excellent yields (Scheme 3).
Scheme 3. Silver-catalysed ring expansion and application to biologically relevant scaffolds.
Bi’s group also demonstrated that PROTAC-like molecules containing two ring expansion reaction sites led to the corresponding double-site ring-expanded 1,2-dihydroquinazoline products with excellent yields (Figure 2).
Figure 2. Application of the ring expansion methodology to PROTAC-like molecules.
C(sp3)–C(sp3) coupling via nitrogen deletion and its application in library synthesis
Compared to atom insertion, fewer protocols describing atom deletion have been reported to date. One prominent publication from the group of Grygorenko, in collaboration with Levin, describes the synthesis of a library of pharmaceutically relevant compounds via a two-step one-pot parallel synthesis that includes reductive amination followed by nitrogen deletion.4 The methodology utilises anomeric amide 1 previously described by Levin (Scheme 4).
Scheme 4. Nitrogen deletion in secondary amines.
The authors demonstrated the suitability of this method for early drug discovery by generating a library of 25 compounds (including drug-like molecules) with a 76% synthesis success rate (Figure 3).
Scheme 5. Parallel synthesis setup.
By mindfully designing a set of initial validation experiments the group was able to quickly determine functionalities which were badly tolerated in the reaction or not at all. For example, 2-substituted azines, 1,3-azole derivatives and building blocks with multiple hydrogen bond donors were unreliable substrates leading to less than 10% yield. Surprisingly, in almost all the ineffective reactions, it was the reductive amination step that led to poor yields.
Figure 3. Selected examples of synthesised library members.
Since skeletal editing is a relatively new approach, it’s still early days to say how significant the method will become to the practical synthetic chemist. Will it become as familiar and routine as amide bond formation reactions and C–C couplings, or rather a more niche tool in the chemistry toolbox? Time will tell but given the rapid progress and growing number of publications in the area there is a hope that skeletal editing will soon become applicable to more and more complex structures, and perhaps one day it will allow for final-step modifications to pharmaceutical molecules.
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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.
I would like to express my appreciation to Lee Mitchell, Mounir Al Masri and Enrico Verpalen for introducing the skeletal editing approach into our synthetic toolbox at BioAscent.
