Late‐Stage Oxidation of C( <i> sp ³ </i> )─H Bonds with High Efficiency and Alkyl Group Dihydroxylation of Complex Molecules

Abstract The late‐stage oxidation of C( sp 3 )─H bonds is highly valuable for modulating the solubility and binding of bioactive compounds and for diversification of complex molecules. Undirected methods for C( sp 3 )─H oxidation are valuable for the installation of hydroxyl groups at sites remote from other functional groups present in the molecule, but existing catalysts are limited by low turnover numbers and lengthy ligand syntheses. Perfluorinated ruthenium porphyrins are highly active catalysts for the oxidation of alkyl C─H bonds, but the scope of the transformation with complex molecules under conditions of limiting substrate has not been investigated. We report that carbonylruthenium(II) tetrakis(pentafluorophenyl)porphyrin [Ru(TPFPP)(CO)] catalyzes the selective oxidation of tertiary C( sp 3 )─H bonds in a broad range of complex natural products and drugs, with turnover numbers as high as 1000, and the tolerance of the reaction to various functional groups was rapidly assessed by performing a model reaction in the presence of additives. We show how the combination of this undirected C( sp 3 )─H oxidation and a directed C( sp 3 )─H silylation and oxidation provides rapid access to highly oxidized, 1,2‐diol derivatives of natural products by a formal dihydroxylation of an alkyl group.