The enzymatic β-C–H hydroxylation of the feedstock chemical isobutytic acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transitionmetal catalyzed enantioselective β-C–H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline (MPAO) ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation and -alkynylation of isobutyric acid/2-amino-isobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

2-Carbomethoxynorbornene is identified as a more effective transient mediator to promote a Pd(II)-catalyzed meta-C(sp2)–H alkylation of amides with various alkyl iodides as well as arylation with previously incompatible aryl iodides. The use of a tailor-made quinoline ligand is also crucial for this reaction to proceed.

Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C–H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C–H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C–H arylation of a lenalidomide derivative. The first steps towards a silver free protocol for this reaction are also demonstrated.

Meta-C–H amination and meta-C–H alkynylation of aniline and phenol substrates using a modified norbornene (methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate) as a transient mediator has been developed for the first time. Both the identification of a mono-protected 3-amino-2-hydroxypyridine/pyridone type ligand and the use of a modified norbornene as a mediator are crucial for the realization of these two unprecedented meta-C–H transformations. A variety of substrates are compatible with both meta-C–H amination and meta-C–H alkynylation. Amination and alkynylation of heterocyclic substrates including indole, indoline, and indazole afford the desired products in moderate to high yields.

A monoprotected aminoethyl amine chiral ligand based on an ethylenediamine backbone was developed to achieve Pd-catalyzed enantioselective C(sp)-H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids without using exogenous directing groups. This new chiral catalyst affords new disconnection for preparing diverse chiral carboxylic acids from simple starting materials that are complementary to the various ring forming approaches.