Activating Aldehyde C-H Bonds: Applications to Hydroacylation and Transfer Hydroformylation

Cross-couplings that proceed via C-H bond activation streamline the synthesis of complex molecules. Rhodium complexes are promising catalysts for these reactions and they readily activate aldehyde C-H bonds to generate acyl-rhodiumIII-hydrides. Developing strategies to control the reactivity of these oxidative addition products enables developments in hydroacylation and hydroformylation. Chapter 1 describes a cooperative catalysis strategy for branched-selective hydroacylation of alkenyl alcohols with salicylaldehydes. A phosphinite ligand reversibly binds the alkenyl alcohol to promote an intermolecular coupling and override the inherent linear selectivity of hydroacylation. Chapter 2 expands branched-selective hydroacylation to non-chelating aldehydes through the advent of an electron rich rhodium catalyst with a small-bite angle diphosphine. This enabled an intermolecular olefin hydroacylation with the most broad substrate scope with respect to the aldehyde component reported to date. Mechanistic studies shed light on the rate limiting step of the reaction and the unique properties of the substrates and catalyst. Chapter 3 describes the use of bifunctional ruthenium catalysts for intramolecular ketone hydroacylation. This strategy circumvents aldehyde C-H bond activation and avoids issues of competitive aldehyde decarbonylation. γ-Butyrolactones and δ-valerolactones were generated with high enantiomeric excess by using Noyori's asymmetric transfer hydrogenation catalyst. This overall-oxidative reaction is inhibited by oxidant (acetone) and autocatalytic in a reductant (iso-propanol). Chapter 4 describes the development of a transfer hydroformylation protocol. Reactivity at room temperature was obtained with catalyst loadings as low as 0.15% by taking advantage of the unique ability of rhodium to activate typically inert C-H bonds. This method was applied to complex bioactive molecules, including macrolide antibiotics, indole alkaloids, steroids, and terpenes. Mechanistic studies revealed that a benzoate counterion acts a proton shuttle to enable transfer hydroformylation.Ph.D