Strategic application of C-H oxidation in natural product total synthesis

The oxidation of unactivated C-H bonds has emerged as an effective tactic in natural product synthesis and has altered how chemists approach the synthesis of complex molecules. The use of C-H oxidation methods has simplified the process of synthesis planning by expanding the choice of starting materials, limiting functional group interconversion and protecting group manipulations, and enabling late-stage diversification. In this Review, we propose classifications for C-H oxidations on the basis of their strategic purpose: type 1, which installs functionality that is used to establish the carbon skeleton of the target; type 2, which is used to construct a heterocyclic ring; and type 3, which installs peripheral functional groups. The reactions are further divided based on whether they are directed or undirected. For each classification, examples from recent literature are analysed. Finally, we provide two case studies of syntheses from our laboratory that were streamlined by the judicious use of C-H oxidation reactions. Strategies that utilize the oxidation of unactivated C-H bonds are becoming increasingly popular in natural product total synthesis. This Review classifies and highlights the different strategic use-cases of oxidation reactions as they were applied in recent total syntheses. C-H oxidation reactions of unactivated bonds have found increased application as key enabling steps in complex molecule synthesis.Strategically, C-H oxidation reactions can serve the purpose of making, breaking or rearranging skeletal bonds (type 1), forming heterocyclic rings (type 2), and introducing peripheral functional groups (type 3).From the many C-H bonds in a molecule, site-selectivity for oxidations can be guided by substrate sterics and electronics and/or supramolecular control (undirected) or by inherent functional groups (directed).C-H oxidation reactions enable conversion of structurally complex, but readily available, starting materials to useful intermediates through introduction of remote functionalization.Remote functionalization can be further leveraged to generate target-oriented complexity, that is, elimination, rearrangement, C-C bond formation and so on.The logic of C-H oxidation reactions can be combined with traditional synthetic planning strategies to devise highly efficient and divergent syntheses.