Title: Skeletal Editing Facilitates One-Pot Isomerisation of Dihydrobenzofurans for Enhanced Drug Discovery
In the relentless quest for more effective drug discovery techniques, chemists are perpetually inventing novel methods to refine the structures of bioactive compounds. One noteworthy breakthrough in this field is the application of skeletal editing—a potent synthetic strategy that allows for precise alterations in the fundamental framework of molecules. A recent development by Richmond Sarpong and his research team at the University of California, Berkeley, broadens the capabilities of skeletal editing within pharmaceutical chemistry by introducing a one-pot approach to generate functionalized constitutional isomers from dihydrobenzofurans. This ingenious method presents a fresh strategy to optimize drug candidates more effectively through structure-activity relationship (SAR) investigations.
Recognizing the Challenge: Functional Group Shifting in Drug Candidates
Dihydrobenzofuran frameworks are common in a variety of therapeutically significant compounds. Minor modifications in the locations of functional groups within these core structures—which yield constitutional isomers—can result in significantly different biological activity, pharmacokinetics, or toxicity profiles. Consequently, creating structurally analogous compounds is an essential aspect of SAR studies in medicinal chemistry. Typically, each constitutional isomer must be crafted through tailored pathways, often necessitating multiple individual reactions from various starting materials. This method not only consumes substantial time and resources but also constrains the variety of analogs that can realistically be investigated.
Photochemical Skeletal Editing: An Innovative Route
Sarpong and his team proposed a more streamlined method: why not “reorganize” the molecule to relocate functional groups to neighboring positions employing a skeletal editing technique? Their approach utilizes a photochemical reaction to transform acyl-substituted dihydrobenzofurans into new constitutional isomers, effectively switching the core C2 and C3 carbons—alongside their functional groups.
The procedure commences with UV irradiation of the initial dihydrobenzofuran, which initiates the formation of an unusual spiro-cyclopropane intermediate. This intermediate, transient and highly reactive, is captured with dilute hydrochloric acid in one variant of the protocol. The subsequent elimination and cyclization phases—conducted under meticulously controlled acidic or basic conditions—close the molecular ring anew, but now with the substituted carbons exchanged. In a complementary approach, the team also crafted a neutral pathway using a metal halide salt, facilitating the same end transformation through a more direct route.
Two Paths, One Outcome
Each of the two reactive conditions—acidic and neutral—displayed unique reactivity characteristics, providing useful flexibility based on the substrate. The acid-mediated conditions demonstrated broad functional group compatibility, accommodating electron-donating and electron-withdrawing groups as well as carboxylic acids, esters, and amides. The neutral method, which eschews severe conditions, was particularly efficient when more sensitive, basic functional groups were involved.
Crucially, both techniques preserve the molecular complexity of the initial material while securing stringent control over core skeletal rearrangement—a rarity in synthetic organic chemistry. The researchers validated the utility of their method by successfully synthesizing isomeric analogs of two pharmacologically relevant compounds encountered in recent SAR studies.
A New Frontier for Molecular Editing
This adaptable one-pot approach signifies a major advancement in molecular editing, especially for swiftly generating matching analog pairs—a vital aspect of contemporary drug discovery frameworks. By simplifying the access to constitutional isomers from common intermediates, the method could significantly lessen the synthetic burden in SAR campaigns.
“We envisioned a scenario where a peripheral substituent could be formally relocated to an adjacent position by cleaving and reforming bonds at the core of the molecule,” comments Sarpong, emphasizing the conceptual shift this reaction embodies.
While the method’s range is already remarkable, the team is further investigating its mechanistic aspects and substrate tolerance, with the ambition of extending the approach to other heterocyclic structures—such as indolines—that are prevalent in pharmaceuticals and natural products.
Community Reception and Future Prospects
Experts in the domain have welcomed the innovation. Bill Morandi, an organic chemist at ETH Zürich, regards it as a significant contribution to an underrepresented area of synthetic chemistry: “Functional group transpositions are substantially underdeveloped, but I believe they could have a transformative effect on molecular editing,” he notes. “The reaction formulated by Sarpong is exceptionally creative and is set to open new pathways to vital compounds.”
As chemists increasingly embrace skeletal editing to address fundamental challenges in synthesis and drug design, the work of Sarpong and his collaborators illustrates that even complex structural rearrangements can be conquered with inventive design and a photochemical impetus. Their approach exemplifies not just a synthetic achievement, but a precursor to faster, smarter methodologies for navigating chemical spaces in the service of human health.