Synthetic Strategy as Inspiration for C-H Functionalization: Part I. Photocatalytic Dehydroformylation. Part II. 1,3-Bisdiazo Compounds and Accessing the Flavagline Core via C-H Insertion.

Abstract

C-H functionalization represents a strategically powerful class of reactions in organic synthesis. In recent years, significant efforts have been dedicated to developing new reactions which can induce reactivity at C-H bonds with great selectivity and to employing those reactions in novel synthetic contexts. As members of the NSF Center for Selective C-H Functionalization (CCHF), we have sought new opportunities to study the interplay between emerging C-H functionalization technologies and synthetic strategy.Dehydroformylation, the loss of carbon monoxide and hydrogen from aldehydes to produce alkenes, is the conceptual reverse of the widely studied hydroformylation reaction and connects two important functional group classes through the cleavage of one C-C bond and two C-H bonds. Part I describes the development of a photocatalytic dehydroformylation of aldehydes using two base-metal catalysts. The reaction is hypothesized to proceed through separate hydrogen-atom transfer steps to each of the two catalysts and the intermediacy of an acyl radical which undergoes radical decarbonylation. The flavagline family of natural products are bioactive molecules with a complex, densely substituted central core. Part II describes a strategy we envisioned to access the carbon skeleton of the flavagline family through two sequential metal-carbene C-H insertion reactions, derived from the intermediacy of a donor-acceptor-acceptor 1,3-bisdiazo compound. The general synthesis of new molecules in this class of compounds is developed and their fundamental, stepwise reactivity in the presence of dirhodium complexes is demonstrated. This stepwise carbene reactivity gives rise to new structures retaining one of the two diazo groups. Our synthetic efforts and the limitations we encountered in accessing 1,3-bisdiazo compounds which map onto the core of the flavaglines are described. A related C-H insertion reaction which closes the five-membered C-ring of the core of the flavagline family is studied, with emphasis on a key stereochemical relationship set in the course of bond-formation. Finally, our attempt to bring this C-H insertion strategy to bear on molecules with the full substitution pattern of representative members of the flavagline family is described.