Catalytic, Asymmetric, Intramolecular Carbon–Hydrogen Insertion

Doyle, M. P.; Liu, Y.; Ratnikov, M.


The insertion of a chiral-ligated metal carbene into an aliphatic C–H bond to construct a carbon-carbon bond imparts asymmetry into the resultant molecule to form enantiomerically enriched lactones, lactams, and cycloalkane derivatives and returns the chiral-ligated metal to its catalytically active state. Insertion is favored by electron-donating groups adjacent to the C–H bond that undergoes insertion, and is disfavored by electron-withdrawing groups. Chiral dirhodium(II) carboxamidates have proven to have the greatest breadth of high selectivities, but other classes of catalysts are selective in specific cases. Although there are examples of iodonium ylides as reactants, diazo compounds are the reactants of choice for these reactions. Diazocarbonyl compounds, especially diazoacetates and diazoacetamides, have reactivities and selectivities that are most suitable for high product yields and high stereoselectivities. This reaction is optimally designed for the formation of five-membered ring compounds using diazoacetates and diazoacetamides and of four-membered ring products with constrained diazoacetamides. Access to lignan lactones, baclofen, deoxyxylolactone, and rolipram, among others, exemplify the efficiencies of this methodology relative to other synthetic approaches.