Conspectus By using transition metal catalysts, chemists have altered the “logic of chemical synthesis” by enabling the functionalization of carbon–hydrogen bonds, which have traditionally been considered inert. Within this framework, our laboratory has been fascinated by the potential for aldehyde C–H bond activation. Our approach focused on generating acyl-metal-hydrides by oxidative addition of the formyl C–H bond, which is an elementary step first validated by Tsuji in 1965. In this Account, we review our efforts to overcome limitations in hydroacylation. Initial studies resulted in new variants of hydroacylation and ultimately spurred the development of related transformations (e.g., carboacylation, cycloisomerization, and transfer hydroformylation). Sakai and co-workers demonstrated the first hydroacylation of olefins when they reported that 4-pentenals cyclized to cyclopentanones, using stoichiometric amounts of Wilkinson’s catalyst. This discovery sparked significant interest in hydroacylation, especially for the enantioselective and catalytic construction of cyclopentanones. Our research focused on expanding the asymmetric variants to access medium-sized rings (e.g., seven- and eight-membered rings). In addition, we achieved selective intermolecular couplings by incorporating directing groups onto the olefin partner. Along the way, we identified Rh and Co catalysts that transform dienyl aldehydes into a variety of unique carbocycles, such as cyclopentanones, bicyclic ketones, cyclohexenyl aldehydes, and cyclobutanones. Building on the insights gained from olefin hydroacylation, we demonstrated the first highly enantioselective hydroacylation of carbonyls. For example, we demonstrated that ketoaldehydes can cyclize to form lactones with high regio- and enantioselectivity. Following these reports, we reported the first intermolecular example that occurs with high stereocontrol. Ketoamides undergo intermolecular carbonyl hydroacylation to furnish α-acyloxyamides that contain a depsipeptide linkage. Finally, we describe how the key acyl-metal-hydride species can be diverted to achieve a C–C bond-cleaving process. Transfer hydroformylation enables the preparation of olefins from aldehydes by a dehomologation mechanism. Release of ring strain in the olefin acceptor offers a driving force for the isodesmic transfer of CO and H2. Mechanistic studies suggest that the counterion serves as a proton-shuttle to enable transfer hydroformylation. Collectively, our studies showcase how transition metal catalysis can transform a common functional group, in this case aldehydes, into structurally distinct motifs. Fine-tuning the coordination sphere of an acyl-metal-hydride species can promote C–C and C–O bond-forming reactions, as well as C–C bond-cleaving processes.

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)‐[5]‐ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.

In this article, we advance Rh-catalyzed hydrothiolation through the divergent reactivity of cyclopropenes. Cyclopropenes undergo hydrothiolation to provide cyclopropyl sulfides or allylic sulfides. The choice of bisphosphine ligand dictates whether the pathway involves ring-retention or ring-opening. Mechanistic studies reveal the origin for this switchable selectivity. Our results suggest the two pathways share a common cyclopropyl-Rh(III) intermediate. Electron-rich Josiphos ligands promote direct reductive elimination from this intermediate to afford cyclopropyl sulfides in high enantio-and diastereoselectivities. Alternatively, atropisomeric ligands (such as DTBM-BINAP) enable ring-opening from the cyclopropyl-Rh(III) intermediate to generate allylic sulfides with high enantio-and regiocontrol.

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)‐[5]‐ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.

Level anticrossings (LACs) are ubiquitous in quantum systems and have been exploited for spin-order transfer in hyperpolarized nuclear magnetic resonance spectroscopy. This paper examines the manifestations of adiabatic passage through a specific type of LAC found in homonuclear systems of chemically inequivalent coupled protons incorporating parahydrogen (pH 2 ). Adiabatic passage through such a LAC is shown to elicit translation of the pH 2 spin order. As an example, with prospective applications in biomedicine, proton spin polarizations of at least 19.8 ± 2.6% on the methylene protons and 68.7 ± 0.5% on the vinylic protons of selectively deuterated allyl pyruvate ester are demonstrated experimentally. After ultrasonic spray injection of a precursor solution containing propargyl pyruvate and a dissolved Rh catalyst into a chamber pressurized with 99% para-enriched H 2 , the products are collected and transported to a high magnetic field for NMR detection. The LAC-mediated hyperpolarization of the methylene protons is significant because of the stronger spin coupling to the pyruvate carbonyl 13 C, setting up an ideal initial condition for subsequent coherence transfer by selective INEPT. Furthermore, the selective deuteration of the propargyl side arm increases the efficiency and polarization level. LAC-mediated translation of parahydrogen spin order completes the first step toward a new and highly efficient route for the 13 C NMR signal enhancement of pyruvate via side-arm hydrogenation with parahydrogen.