Dispersion Interactions in Asymmetric Induction for Constructing Vicinal Stereogenic Centers

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information CONSPECTUS: Vicinal stereogenic centers are prevalent structural motifs of primary functional relevance in natural products and bioactive molecules. The quest for the rapid and controllable construction of vicinal stereogenic centers stands as a frontier endeavor in asymmetric organic synthesis. Over the past decade, stereodivergent synthesis has been intensely researched within the realm of bimetallic catalysis, aiming at establishing novel transition-metal dual-catalytic reactions that efficiently generate all stereochemical combinations of multichiral molecules from identical starting materials, thus offering new opportunities toward rapid complexity building and diversity-oriented chiral compound library generation. In this Account, we summarize our recent advancements in computational investigations of stereodivergent asymmetric allylic alkylation, an important reaction class heavily studied for the purpose of constructing vicinal stereogenic centers. Our discussions focus on synergistic bimetallic catalysis for the syntheses of α,α-disubstituted α-amino acids and cascade allylation/cyclization toward enantiomerically enriched indole-containing heterocycles. We describe our series of studies that converge in establishing the molecular mechanism of asymmetric induction for chiral copper−azomethine ylide, a nucleophile that holds widespread utility and is characterized by a distinctive, sterically biased surrounding enveloping the prochiral center. Notably, our studies revealed that attacks at the prochiral site by allylmetal species are significantly favored by dispersion attraction from one face (−PPh 2 ) but blocked by steric repulsion and associated structural distortions on the opposite face (oxazoline), therefore building up a multimodal and highly robust face-selective stereoinduction. We showcase how a suite of systematic computational analyses generates precise atomistic insights into a number of systems of relevance. We also discuss how the same methodologies can be applied to chiral intermediates with shared interaction patterns, including the rhodium−Josiphos catalyst in asymmetric hydrogenation to create two continuous stereocenters. In the selectivity-controlling migratory insertion step, our computational models unveiled that the reaction is favored by ligand−substrate dispersion attraction on the −PPh 2 side and hindered by steric repulsion on the opposite −P t Bu 2 side. These noncovalent interactions along with the distal ligand−auxiliary structural distortions enable strictly oriented three-dimensional stereoinduction. Our analysis of ligand−substrate dispersion interactions and steric effects in competing pathways highlights certain interaction-level similarities between PHOX-type and Josiphos-type ligands in asymmetric induction. In summary, this Account underscores the foundational significance and broad applicability of nonbonded dispersion interactions in asymmetric inductions for the construction of vicinal stereogenic c...

Iridium-Catalyzed Enantioselective Transfer Hydrogenation of 1,1-Dialkylethenes with Ethanol: Scope and Mechanism

“…Notably, when London dispersion interactions are omitted from the calculations, the calculations fail to reproduce the observed enantioselectivity (Figure a). This underscores the significance of London dispersion interactions in enantioface discrimination . An independent gradient model based on Hirshfeld partition analysis (IGMH) reveals the presence of London dispersion interactions between the Cy and Ad in the TS-ax-S-cyclohexyl .…”

Interception of Transient Allyl Radicals with Low-Valent Allylpalladium Chemistry: Tandem Pd(0/II/I)–Pd(0/II/I/II) Cycles in Photoredox/Pd Dual-Catalytic Enantioselective C(sp3)–C(sp3) Homocoupling

“…Our computations unambiguously predicted the formation of branched/branched products with the correct stereochemistry. A more detailed examination allowed us to identify steric hindrance as a prominent contributor to the observed selectivity. , …”

“…Intriguingly, we found that the flexible alkyl group adaptively avoids potential steric conflicts with the ligand, allowing for a congested linear-branched transition state. Moreover, the alkyl group allows extensive dispersion attraction within the inner pocket of the sizable chiral ligand. − Collectively, these analyses reveal a substrate-dependent interplay between dispersion and steric effects that dictate regio- and stereoselectivities in the current inner-sphere bond-formation mechanism.…”

“…This effectively avoids nonselective radical–radical coupling pathways, − underscoring the promising use of low-valent allylpalladium chemistry in intercepting transient radicals for selective C­(sp 3 )–C­(sp 3 ) bond constructions . We have also established predictive models for regio- and stereoselectivities, which feature a substrate-dependent interplay between dispersion effects and steric repulsion. , In summary, the study is anticipated to find values in the design and rationalization of synergistic photoredox/transition-metal dual catalysis.…”