Skeletal Modification via Activation of Relatively Unstrained C-C Bonds

ConspectusMethods that can directly modify the skeletons of complex molecules have become increasingly attractive for preparing novel analogues without the need for de novo synthesis in drug discovery processes. Among the various skeletal modification approaches, those targeting unstrained C-C bonds are particularly challenging to realize, owing to the relative inertness of these bonds toward common reagents. Compared to C-H or C-X (X: heteroatom) bonds, the activation of unstrained C-C bonds is often not thermodynamically and/or kinetically favorable. As a result, strategies relying on highly strained substrates or oxidative conditions are generally employed, which inevitably limit the scope and applications of C-C bond activation reactions. Hence, the development of redox-neutral catalytic C-C activation methods remains highly sought after for late-stage skeletal modification of complex bioactive compounds.In this Account, we summarize our recent progress in skeletal modifications through the catalytic activation of relatively unstrained C-C bonds. Enabled by transient or removable directing groups (DGs), the scope of C-C bond activation can be greatly expanded, encompassing a wide range of substrates, including ketones, amides, lactams, and biaryls. Consequently, different types of skeletal modification transformations have been developed. The major topics covered include the following: (1) Skeletal rearrangement and "cut-and-sew" transformations of cyclic ketones: we developed an aminopyridine/Rh-N-heterocyclic carbene (NHC) cooperative catalysis system that specifically targets the α-C-C bond of cyclic ketones. For substrates bearing a β-aryl substitution, the rhodacycle formed after the C-C bond activation can undergo an intramolecular C-H activation, resulting in the skeletal rearrangement from cyclopentanones/cyclohexanones to 1-tetralones/1-indanones. Additionally, the "cut-and-sew" transformations between indanones and ethylene or alkynes have been realized to offer a two-carbon ring expansion. (2) Chain homologation of linear amides and downsizing of lactams: the Rh-NHC activation system can be extended to the linear amides and lactams through preinstalling removable DGs. This approach has provided some new tools for precise amide modifications, including tunable homologation of tertiary amides via a "hook-and-slide" strategy and the downsizing transformation of lactams. (3) "Cut-and-sew" transformations of biphenols: using the preinstalled phosphinite DGs, unstrained 2,2'-biphenols can undergo split cross-coupling with various aryl iodides. When diiodide coupling partners are used, an interesting phenylene insertion into the aryl-aryl bond of biphenols can be achieved, which represents another type of "cut-and-sew" transformation.Collectively, these methods provide a reliable means to manipulate inert molecular scaffolds and offer new bond-disconnecting strategies to access useful structural motifs. The applications of these methods in the synthesis of bioactive natural products and complex analogues underscore their practical significance. Mechanistic insights gained from these studies are also discussed, which are expected to inspire future endeavors in this field.