The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment—cone angle and % buried volume—are not equivalent, despite their treatment in the literature.

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.

The design of synthetic routes by retrosynthetic logic is decisively influenced by the transformations available. Transition‐metal‐catalyzed C−H activation has emerged as a powerful strategy for C−C bond formation, with myriad methods developed for diverse substrates and coupling partners. However, its uptake in total synthesis has been tepid, partially due to their apparent synthetic intractability, as well as a lack of comprehensive guidelines for implementation. This Review addresses these issues and offers a guide to identify retrosynthetic opportunities to generate C−C bonds by C−H activation processes. By comparing total syntheses accomplished using traditional approaches and recent C−H activation methods, this Review demonstrates how C−H activation enabled C−C bond construction has led to more efficient retrosynthetic strategies, as well as the execution of previously unattainable tactical maneuvers. Finally, shortcomings of existing processes are highlighted; this Review illustrates how some highlighted total syntheses can be further economized by adopting next‐generation ligand‐enabled approaches.

Sequence-controlled polymers are an emerging class of synthetic polymers with a regulated sequence of monomers. In the past decade, tremendous progress has been made in the synthesis of polymers, with the sophisticated sequence control approaching the level manifested in biopolymers. In contrast, the exploration of novel functions that can be achieved by controlling synthetic polymer sequences represents an emerging focus in polymer science. This Viewpoint will survey recent advances in the functional applications of sequence-controlled polymers and provide a perspective on the challenges and outlook for pursuing future applications of this fascinating class of macromolecules.

It is generally assumed that protein clients fold following their release from chaperones instead of folding while remaining chaperone-bound, in part because binding is assumed to constrain the mobility of bound clients. Previously, we made the surprising observation that the ATP-independent chaperone Spy allows its client protein Im7 to fold into the native state while continuously bound to the chaperone. Spy apparently permits sufficient client mobility to allow folding to occur while chaperone bound. Here, we show that strengthening the interaction between Spy and a recently discovered client SH3 strongly inhibits the ability of the client to fold while chaperone bound. The more tightly Spy binds to its client, the more it slows the folding rate of the bound client. Efficient chaperone-mediated folding while bound appears to represent an evolutionary balance between interactions of sufficient strength to mediate folding and interactions that are too tight, which tend to inhibit folding.