The development of catalytic enantioselective C(sp3)–H metal insertion reactions has been a significant challenge. Moderate success has recently been achieved via Pd-catalyzed desymmetrization of prochiral C–H bonds located on two different carbon centers. Herein, we report the discovery of chiral acetyl-protected aminoethyl quinoline (APAQ) ligands that enables Pd(II)-catalyzed enantioselective arylation of prochiral methylene C–H bonds on the same carbon center. The feasibility of performing asymmetric Pd insertion into ubiquitous β-methylene C–H bonds of aliphatic amides offers an alternative disconnection for constructing β-chiral centers. Systematic tuning of the ligand structure reveals that a six-membered instead of a five-membered chelation of these types of ligands with the Pd(II) is essential for accelerating the C(sp3)–H activation thereby achieving enantioselectivity.

Metrics & MoreArticle Recommendations CONSPECTUS:The functionalization of unactivated carbon− hydrogen bonds is a transformative strategy for the rapid construction of molecular complexity given the ubiquitous presence of C−H bonds in organic molecules. It represents a powerful tool for accelerating the synthesis of natural products and bioactive compounds while reducing the environmental and economic costs of synthesis. At the same time, the ubiquity and strength of C−H bonds also present major challenges toward the realization of transformations that are both highly selective and efficient. The development of practical C−H functionalization reactions has thus remained a compelling yet elusive goal in organic chemistry for over a century. Specifically, the capability to form useful new C−C, C−N, C−O, and C−X bonds via direct C−H functionalization would have wide-ranging impacts in organic synthesis. Palladium is especially attractive as a catalyst for such C−H functionalizations because of the diverse reactivity of intermediate palladium−carbon bonds. Early efforts using cyclopalladation with Pd(OAc) 2 and related salts led to the development of many Pd-catalyzed C−H functionalization reactions. However, Pd(OAc) 2 and other simple Pd salts perform only racemic transformations, which prompted a long search for effective chiral catalysts dating back to the 1970s. Pd salts also have low reactivity with synthetically useful substrates. To address these issues, effective and reliable ligands capable of accelerating and improving the selectivity of Pd-catalyzed C−H functionalizations are needed.In this Account, we highlight the discovery and development of bifunctional mono-N-protected amino acid (MPAA) ligands, which make great strides toward addressing these two challenges. MPAAs enable numerous Pd(II)-catalyzed C(sp 2 )−H and C(sp 3 )−H functionalization reactions of synthetically relevant substrates under operationally practical conditions with excellent stereoselectivity when applicable. Mechanistic studies indicate that MPAAs operate as unique bifunctional ligands for C−H activation in which both the carboxylate and amide are coordinated to Pd. The N-acyl group plays an active role in the C−H cleavage step, greatly accelerating C−H activation. The rigid MPAA chelation also results in a predictable transfer of chiral information from a single chiral center on the ligand to the substrate and permits the development of a rational stereomodel to predict the stereochemical outcome of enantioselective reactions. We also describe the application of MPAA-enabled C−H functionalization in total synthesis and provide an outlook for future development in this area. We anticipate that MPAAs and related next-generation ligands will continue to stimulate development in the field of Pd-catalyzed C−H functionalization.

Herein we report acid-directed β-C(sp3)–H arylation of α-amino acids enabled by pyridine-type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc-protected unnatural amino acids in three steps. The pyridine-type ligands are crucial in the development of this new C(sp3)–H arylation.

Functionalization of the β-C-H of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions 1-5. Despite efforts on β-C-H functionalizations for carbon-carbon (C-C) and carbon-heteroatom (C-Y) bond-forming reactions, these bear numerous decisive limitations, especially for industrial-scale applications, including the lack of mono-selectivity, use of expensive oxidants, and limited scope 6-13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C-H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here, we report a Pd-catalyzed β-C(sp 3)-H lactonization of aliphatic acids enabled by a mono-N-protected β-amino acid ligand. The highly strained and reactive β-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl, and amino groups at the β position of the parent acid, thus providing a route to myriad carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide (TBHP) as the oxidant to promote the desired selective reductive elimination from the Pd(IV) center, as well as the ease of product purification without column chromatography renders this reaction amenable to ton-scale manufacturing. Main Text Alkyl carboxylic acids are ubiquitous and inexpensive reagents in organic chemistry-as such, they are privileged substrates for C-H activation reactions 4,5. The scope of these transformations is often limited due to the incompatibility of certain reaction partners. Indeed, for CC bond formations, alkylation reactions are limited to primary alkyl iodide or alkyl boron coupling partners 6-8 , olefination reactions are limited to electron-deficient olefins 9,10 , alkynylation reactions are limited to silyl acetylene bromide 11 , and arylation reactions are only compatible with aryl iodides but not the more practical aryl bromides and chlorides 12,13 despite the design of various directing groups. Most importantly, Cheteroatom bond-forming reactions (fluorination, hydroxylation, amination etc.) based on β-C-H activation of free aliphatic acids have not yet been realized. Considering these persistent limitations of the conventional β-C-H activation approach, we turned to a one-for-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp)-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp)-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple β-C-H bonds. The product γ-lactone can be readily opened to give either the highly valuable β-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.