Diversity-Generating Skeletal Editing Transformations

ConspectusSkeletal editing, as a synthetic tool, offers the unique potential to selectively and efficiently modify the core skeleton of a target molecule at a late-stage. The main benefit of such transformations is the rapid exploration of the chemical space around lead compounds without necessitating a de novo synthesis for each new molecule. However, many skeletal editing transformations are inherently restricted to generating a single product from a single starting compound, limiting the potential for diversification, a concept central to expediting structure-activity relationship (SAR) investigations. In this Account, we describe our efforts to develop novel skeletal editing transformations in which a modification to the central motif of a molecule is performed simultaneously with the incorporation of additional functionality that can be easily varied through a judicious choice of the reagents. Specifically, we successfully developed an α-iodonium diazo-based carbynyl radical equivalent reagent that, under photoredox conditions, could facilitate the ring-expansion of indene scaffolds while enabling the insertion of over ten different functionalized carbon atoms into the corresponding naphthalene products. This concept was later extended to the design of an atomic carbon equivalent reagent that could promote mild and selective Ciamician-Dennstedt-type indole ring-expansion reactions, while simultaneously installing an oxime ester handle that could undergo further functionalization. Furthermore, we highlight recent work from our group on multiple-atom insertion reactions, namely, the development of a photocatalyzed De Mayo reaction for the ring-expansion of cyclic ketones and a photocatalyzed dearomative ring-expansion of thiophenes via small-ring insertion. In both of these cases, multiple products can be potentially accessed from a single starting material upon variation of the insertion reagent. The diversity-generating skeletal editing strategy could also be applied to single-atom transmutation, as demonstrated by the development of a nitrogen-to-functionalized carbon atom transmutation reaction to convert pyridine to benzene rings. Here, the desired transformation was achieved via a sequence of pyridine ring-opening, Horner-Wadsworth-Emmons (HWE) olefination, and ring-closure, with a judicious choice of the HWE reagent allowing the installation of a wide variety of versatile functional groups. Finally, an energy transfer-mediated quinoline ring-contraction is discussed, specifically with reference to the ways in which it does and does not fit the criteria of a skeletal editing reaction. Although formal atom deletion transformations are typically restricted to single products from each discrete substrate, this 2 + 2 cycloaddition/rearrangement cascade also involves the incorporation of an alkene into the molecule and introduces a point of variation that can be exploited for diversity generation. We hope to not only highlight the transformations reported herein but also inspire further research into this synthetic strategy to access new classes of skeletal editing transformations that, through rapid diversity generation, provide the potential to expedite SAR investigations.