The catalytic, asymmetric synthesis of complex molecules has been a core focus of our research program for some time because developments in the area can have an immediate impact on the identification of novel strategies for the synthesis of value-added molecules. In concert with this central interest, we have emphasized the design of ligand scaffolds as a tactic to discover and develop novel chemistry and overcome well-recognized synthetic challenges. Based on our group's work on chiral pool-derived diolefin ligands, we designed and implemented a class of hybrid (phosphoramidite,olefin) ligands, which combines the properties of both phosphoramidite and olefin motifs to impact, fine-tune, and even override the inherent reactivity of the metal center. Specifically, we have utilized these unique modifying ligands to address several recognized limitations in the field of iridium-catalyzed, asymmetric allylic substitution. The methods we have documented typically employ branched, unprotected allylic alcohols as substrates and obviate the need for rigorous exclusion of air and moisture. Following Takeuchi's seminal report demonstrating the high aptitude of Ir(I)-phosphite catalysts for branch-selective allylic substitution, concerted efforts from numerous research laboratories have led to a broadening of the synthetic utility of this reaction class. The first section of this Account outlines the process leading to our discovery of an unprecedented (phosphoramidite,olefin) ligand and its validation in the first iridium-catalyzed amination of branched, unprotected allylic alcohols. This section continues with our work involving heteroatom-based nucleophiles within inter- and intramolecular etherification, thioetherification and spiroketalization processes. The second section highlights the use of readily available carbon nucleophiles possessing sp, sp², and sp³ hybridization in a series of enantioselective carbon-carbon bond-forming reactions. We describe how alkylzinc, allylsilane, and several classes of organotrifluoroborate nucleophiles can be coupled enantioselectively to enable construction of several key motifs including 1,5-dienes, 1,4-dienes, and 1,4-enynes. Since the unique electronic and steric properties of this class of ligands renders the (η³-allyl)-Ir(III) intermediate highly electrophilic, even weak nucleophiles such as alkyl olefins can be used. We also show that more nucleophilic alkene motifs such as enamines and in situ generated ketene acetals smoothly participate in substitution reactions with allylic alcohols to yield valuable piperidines and γ,δ-unsaturated esters, respectively. The concept of stereodivergent dual catalysis, which synergistically combines chiral amine catalysis with iridium catalysis to furnish α-allylated aldehydes containing two independently controllable stereocenters is then discussed. This process has enabled the independent, stereoselective synthesis of all four possible product stereoisomers from a single set of starting materials, and was highlighted in the stereodivergent synthesis of Δ⁹-tetrahydrocannabinol. This Account concludes with an overview of our organometallic mechanistic studies regarding relevant intermediates within the catalytic cycle of this class of allylic substitution. These studies have allowed us to better understand the origin of the unique characteristics exhibited by this catalyst in comparison to related systems.

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