C–H Functionalization in organic synthesis

Huw M. L. Davies

Huw M. L. Davies is the Asa Griggs Candler Professor of Chemistry at Emory University. His research program covers design of chiral catalysts, development of new synthetic methodology, total synthesis of biologically active natural products, and development of chiral therapeutic agents. A major research theme in his group is catalytic asymmetric C–H functionalization and he is the Director of the National Science Foundation Center in Chemical Innovation for Stereoselective C–H Functionalization.

Justin Du Bois

Justin Du Bois is an associate professor of chemistry at Stanford. His interests are in molecular design and chemical synthesis, reaction methods development, and chemical biology. He is a founding member of the National Science Foundation Center in Chemical Innovation for Stereoselective C–H Functionalization.

Jin-Quan Yu

Jin-Quan Yu is currently Professor of Chemistry at The Scripps Research Institute. His group develops transition metal-catalyzed C–H activation reactions and applies them to synthesis and drug discovery. He is a founding member of the National Science Foundation Center in Chemical Innovation for Stereoselective C–H Functionalization.

Over the past two decades there has been an explosive growth in the development of methods for C–H functionalization and the application of these technologies for the synthesis of complex targets such as natural products and pharmaceutical agents. Today, a large and varied number of site- and stereoselective C–H functionalization methods are available that operate with a level of precision and predictability required for complex molecule assembly. These tools can dramatically streamline multi-step chemical processes by rendering functional group interconversion steps unnecessary. Thanks to the contributions of many, we have reached an era in which the C–H bond can now be considered a synthon for both C–C and C–heteroatom moieties.

One of the researchers leading the charge in C–H functionalization methods development was Keith Fagnou. In a series of seminal papers, he devised new protocols for aryl C–H bond functionalization and demonstrated the power of such processes for rapidly crafting modified arene and heteroarene derivatives. With his untimely death, the chemical community lost a highly respected and visionary leader. It is, therefore, with great respect and honor, that we dedicate this themed issue on C–H Functionalization in Organic Synthesis in memory of Keith Fagnou and in recognition of his significant accomplishments in the field.

C–H Functionalization, as a tactic applied to the synthesis of natural products, can lead to spectacular discoveries. Gutekunst and Baran (DOI: 10.1039/c0cs00182a) present a most timely review on the use of the C–H functionalization logic in total synthesis. The review places the field in historical perspective, giving case studies of natural product synthesis using C–H functionalization from 1909 to the current day. McMurray, O'Hara and Gaunt (DOI: 10.1039/c1cs15013h) focus on recent developments in natural product synthesis using metal-catalyzed C–H bond functionalization, giving a short introduction to the new methodologies and then describing specific applications.

Chemo- and stereoselectivity must be reliable and predictive for catalytic C–H functionalization methods to continue to find use in complex molecule synthesis. Hartwig (DOI: 10.1039/c0cs00156b) presents an overview of the impressive regioselectivity observed in metal catalyzed borylation of alkanes and arenes. Several of the reviews describe the status of current methodology to achieve selectivity in C–H functionalization reactions. Herrmann and Bach (DOI: 10.1039/c0cs00027b) present a critical review on diastereocontrol in C–H modification at methylene centers in chiral starting materials. Collet, Lescot and Dauban (DOI: 10.1039/c0cs00095g) describe recent advances in stereoselective catalytic C–H amination reactions. Davies and Morton (DOI: 10.1039/c0cs00217h) highlight guiding principles for site selective and stereoselective reactions by rhodium-stabilized donor/acceptor carbenes. And Zhang, Zhang and Tu (DOI: 10.1039/c0cs00063a) offer a comprehensive discussion on the available procedures for α-C–H functionalization of ethers and alcohols. Nature is capable of truly spectacular site selective C–H bond oxidation; Lewis, Coelho and Arnold (DOI: 10.1039/c0cs00067a) have beautifully illustrated the awesome potential of enzymatic C–H functionalization as a synthetic tool.

Further advances in the application of C–H functionalization to organic synthesis requires the development of more effective catalyst designs. Reviews by Che, Lo, Zhou and Huang (DOI: 10.1039/c0cs00142b) and by Lu and Zhang (DOI: 10.1039/c0cs00070a) detail the exceptional range of C–H functionalization reactions that can be achieved with metalloporphyrin complexes. These processes include C–H oxidation, C–H amination and carbenoid induced C–H insertion. Zhou and Crabtree (DOI: 10.1039/c0cs00099j) offer a fascinating look at the oxidation chemistry of platinum group metal oxo or peroxo species, whereas Borovik (DOI: 10.1039/c0cs00165a) gives an insightful mechanistic perspective on metal–oxo reactivity. Boorman and Larrosa (DOI: 10.1039/c0cs00098a) illustrate a range of gold-catalyzed C–H functionalization reactions emphasizing the uniqueness of this chemistry for a variety of synthetic applications.

The development of selective processes for C–H functionalization and their use in organic synthesis is rapidly evolving. The field is burgeoning and will continue to expand given the opportunities afforded for creative invention both in methods development and chemical (and materials) synthesis. We have only just started to realize the revolutionary impact that C–H functionalization can have to redefine the logic of chemical synthesis.

Footnote

† Part of a themed issue on C–H functionalisation in organic synthesis dedicated in memory of Keith Fagnou.

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