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Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.

The Ru-S bond in Ohki-Tatsumi complexes breaks oligomeric DIBAL-H structures into their more reactive monomer. That deaggregation is coupled to heterolytic Al-H bond activation at the Ru-S bond, formally splitting the Al-H linkage into hydride and an alumenium ion. The molecular structure of these Lewis pairs was established crystallographically, revealing an additional Ru-Al interaction next to the Ru-H and Al-S bonds. That bonding situation was further analyzed by quantum-chemical calculations and is best described as a three-center-two-electron (3c2e) donor-acceptor σ(Ru-H) → Al interaction. Despite the extra stabilization of the aluminum center by the interaction with both the sulfur atom and the Ru-H bond, the hydroalane adducts are found to be stronger Lewis acids and electrophiles than the free ruthenium catalyst and DIBAL-H in its different aggregation states. Hence, the DIBAL-H molecule and its Al-H bond are activated by the Ru-S bond, but these hydroalane adducts are not to be mistaken as sulfur-stabilized alumenium ions in a strict sense. The Ohki-Tatsumi complexes catalyze C(sp 3 )-F bond cleavage with DIBAL-H, and the catalytic setup is applied to hydrodefluorinative Friedel-Crafts alkylations. A broad range of CF 3 -substituted arenes is efficiently converted into unsymmetrical diarylmethanes with various arenes as nucleophiles. Computed fluoride-ion affinities (FIAs) of the hydroalane adducts as well as DIBAL-H in its aggregation states support this experimental finding.

Combined experimental and theoretical analysis of the carbonyl hydrosilylation catalysed by an iron(0) pincer complex reveals an unprecedented mechanism of action. The iron(0) complex is in fact a precatalyst that is converted into an iron(ii) catalyst through oxidative addition of a hydrosilane. Neither the hydrogen atom nor the silicon atom bound to the iron(ii) centre are subsequently transferred onto the carbonyl acceptor, instead remaining at the sterically inaccessible iron(ii) atom throughout the catalytic cycle. A series of labelling, crossover and competition experiments as well as the use of a silicon-stereogenic hydrosilane as a stereochemical probe suggest that the iron(ii) site is not directly involved in the hydrosilylation. Strikingly, it is the silyl ligand attached to the iron(ii) atom that acts as a Lewis acid for carbonyl activation in this catalysis. The whole catalytic process occurs on the periphery of the transition metal. Computation of the new peripheral as well as plausible alternative inner and outer sphere mechanisms support the experimental findings.

New experimental findings suggest partial revision of the currently accepted mechanism of the carbonyl hydrosilylation catalyzed by the iridium(III) pincer complex introduced by Brookhart. Employing silicon-stereogenic silanes as a stereochemical probe results in racemization rather than inversion of the configuration at the silicon atom. The degree of the racemization is, however, affected by the silane/carbonyl compound ratio, and inversion is seen with excess silane. Independently preparing the silylcarboxonium ion intermediate and testing its reactivity then helped to rationalize that effect. The stereochemical analysis together with these control experiments, rigorous multinuclear NMR analysis, and quantum-chemical calculations clearly prove that another silane molecule participates in the hydride transfer. The activating role of the silane is unexpected but, in fact, vital for the catalytic cycle to close.