Site-selective functionalization of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, developing strategies to activate C–H bonds that are distal from a functional group is essential. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukemia agent, and hydrocinnamic acid substrates.

One of the core challenges in developing C-H activation reactions is to distinguish multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp 2)-H bonds have been selectively activated in the presence of proximate ones 1-2. Yet achieving such unconventional site selectivity with C(sp 3)-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid derived directing group and a 2-pyridione ligand that enables the preferential activation of the distal γ-C(sp 3)-H bond over the proximate β-C(sp 3)-H bonds for a wide range of alcohol derived substrates. Competition experiment of five-and six-membered cyclopalladation step as well as kinetic experiments demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp 3)-H activation. Developing C-H activation reactions as new retrosynthetic disconnections could offer a multitude of novel synthetic strategies due to the abundance of positionally diverse C-H bonds 3-4. On the other hand, the great resemblance between these C-H bonds in terms of bond strength and electronic properties presents a tremendous challenge for achieving regioselectivity. This difficulty escalates with metalation chemistry because in such processes, the numerous primary or secondary C-H bonds are nearly indistinguishable by the metal. For example, despite the recent advances in developing a wide range of Pdcatalyzed C(sp 3)-H activation reactions, their regioselectivity is largely restricted to the cleavage of the C-H bond that will result in five-membered cyclopalladation 5-12. Therefore, it is fundamentally important to develop strategies to switch the selectivity of the key metalation step from five-membered to six-membered cyclopalladation (Fig. 1b). Such Reprints and permissions information is available at www.nature.com/reprints.

Achieving p-CAr–H site selectivity is one of the major challenges in direct carbon–hydrogen (C–H) functionalization reactions. Herein, the copper-catalyzed and picolinamide-assisted remote p-C–H sulfonylation of 1-naphthylamides was realized. The synthetic utility of this method was further examined by sequential functionalizations and the efficient synthesis of the pharmaceutically useful 5-HT6 serotonin receptor ligand. This approach also provided a general strategy for other p-C–H bond functionalization, such as highly selective constructions of C–O, C–Br, C–I, C–C, and C–N bonds. Control experiments and theoretical calculations suggested that this C–H sulfonylation reaction might proceed through a single-electron-transfer process.

A short and practical synthesis of oseltamivir was accomplished in 11 steps from inexpensive and abundant diethyl D-tartrate starting material. This azide-free route featured an asymmetric aza-Henry reaction and a domino nitro-Michael/Horner-Wadsworth-Emmons (HWE) reaction as the key steps to construct the relevant cyclohexene ring of the product, which provided an economical and practical alternative for the synthesis of oseltamivir.