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This book will focus on direct asymmetric C–H bond functionalization reactions. The direct functionalization of inert C–H bonds is of great importance in modern synthetic chemistry since it can employ the readily available hydrocarbons (or any C–H bond-containing compounds) as the starting material to construct the molecular complexity without “pre-activation” of the C–H bonds and thus meets the criteria of atom economy and step economy. Among all the great challenges that accompany the C–H bond functionalization process, one of the most significant challenges is how to distinguish the reactivity among the numerous C–H bonds in one single molecule and achieve the versatile transformations in a highly efficient way. In recent years, several novel types of methodology have emerged for the direct enantioselective functionalization of inert C–H bonds by chiral organometallic complexes or organocatalysts. In general, these novel reactions point out a promising direction for the development of the next generation of asymmetric synthesis. The emerging methods for direct asymmetric functionalization of inert C–H bonds reveal novel reactivity of fundamental chemical feedstocks. The deep understanding of their mechanisms is beneficial for the design and development of highly efficient chiral catalytic systems applicable for asymmetric catalysis. In addition, these reactions provide unprecedented retro-synthetic disconnection strategies for the synthesis of complex targets and will definitely stimulate further advances in organic chemistry.

My personal interest in asymmetric catalysis can be dated back to my graduate study under the supervision with Professor Li-Xin Dai at the Shanghai Institute of Organic Chemistry, where my Ph.D. thesis had been focused on the synthesis of (planar) chiral ferrocene ligands and their application in Pd-catalyzed allylic substitution reactions. Since my independent research was started in 2006, our group has been focusing on asymmetric direct functionalization reactions of various C–H bonds, including Pd-catalyzed asymmetric synthesis of planar chiral ferrocenes via C–H bond functionalization reactions, asymmetric Friedel–Crafts type reactions, and N-heterocyclic carbene (NHC) catalyzed aldehyde C–H bond functionalization. Through the years, I have been amazed by the fast development of this field. The asymmetric C–H bond direct functionalization reactions have emerged very rapidly in the last decade and now receive increasing attention in the areas of organic chemistry, medicinal chemistry, materials science, and many more. There are quite a few review articles covering this fast growing field.1  Our motivation to write a book on the topic of asymmetric C–H bond functionalization reactions originated from the time when we wrote a review on such a topic.2  It is amazing to see the fast development of this field; there have been many new papers published during every stage of the production of that review, such as submission, revision and proof. On the other hand, despite these existing reviews, many of them were written with the focus on one subject of the asymmetric C–H bond functionalization reactions. A comprehensive review covering the whole field has not appeared yet. In addition, given the rapidly increased number of papers in this field, it is not possible to cover it within one review article. A book summarizing the origin, mechanism, scope, and application of the asymmetric C–H bond functionalization reaction should be timely and highly useful.

The nine chapters of this book have been designed to cover the majority of asymmetric C–H bond functionalization reactions. In the Chapter 1, asymmetric insertion reactions into C–H bonds by metal carbenoids, metal nitrenoids, and metal-oxo species are summarized. This kind of reaction is probably the more traditional (or earlier) method to realize asymmetric C–H bond functionalization. The results are classified according to carbene (or equivalents) precursors such as metal carbenoids, metal nitrenoids, and metal-oxo species. The application of these methods in total synthesis are also briefly discussed. In Chapter 2, asymmetric cross-dehydrogenative coupling (CDC) reactions are discussed, offering a general picture of this powerful method which could couple one C(sp3)–H bond α to a nitrogen, oxygen atom, or a carbonyl group and various C(sp)–H, C(sp2)–H or C(sp3)–H bonds under oxidative conditions. In Chapter 3, asymmetric oxidative biaryl coupling reactions are introduced in detail as they provide the most atom-economical way to synthesize axially chiral biaryl compounds. In Chapter 4, we have summarized the asymmetric [1,5]-hydride transfer reactions, which represent an important method to realize the asymmetric functionalization of C(sp3)–H bonds in a redox-neutral fashion. Both transition metal complexes and small molecule organocatalyst-catalyzed transformations are introduced. In Chapter 5, asymmetric C–H bond functionalization involving a transient C–M (carbon–metal) species is summarized. The asymmetric C–H bond functionalization involving a transient M–C species has witnessed significant development in recent years. Various transition metal complexes are found capable of promoting the reactions. Compared with traditional cross-coupling reactions, these transformations do not require pre-activation and lead to less salt wastes. The discussion in this chapter is classified according to the metal catalysts as well as the reaction mechanism. In Chapter 6, a brief overview on asymmetric Friedel–Crafts reactions is presented. Asymmetric Friedel–Crafts reactions are important methods to realize the functionalization of various electron-rich arenes. However, given the existence of elegant reviews and books on this topic,3  this chapter only focuses on the recent progress in this field, mainly those contributions made after 2009. In Chapter 7, NHC-catalyzed asymmetric functionalization reactions of aldehyde C–H bonds is presented. N-Heterocyclic carbenes (NHC) are unique organocatalysts that enable the functionalization of aldehyde C–H bonds. The rapid development in recent years results in various novel asymmetric transformations. This chapter is intended to give the readers a general picture of this area. In Chapters 8 and 9, asymmetric hydroacylation and hydrovinylation reactions are presented, respectively. Asymmetric hydroacylation and hydrovinylation reactions of olefins are undoubtedly among the most important methods to functionalize alkene C–H bonds and have been applied successfully in the bulk chemical industry. Recent developments in these fields are discussed in these two chapters. Notably, enzyme-catalyzed asymmetric C–H functionalization reactions have also progressed rapidly.4  However, these are not covered in this book. To be noted, the term “CH bond functionalization”, a more accurate and general definition in my opinion, was chosen to describe the inert C–H bond-related transformations instead of the somewhat controversial term “C–H bond activation” throughout the book.

I would like to express my great gratitude to those who have made the book possible. The book has been written by my current group members and three former co-workers, who are now professors at the Fujian Institute of Research on the Structure of Matter (Professor Qiang Kang), Fuzhou University (Professor Yi Li), and China Pharmaceutical University (Professor Qing-Long Xu). Particularly, Professor Chao Zheng is acknowledged for his careful proofreading of all the drafts. Professor Kuiling Ding and Professor Li-Xin Dai have been highly encouraging through the whole writing process. Professor Jin-Quan Yu is very supportive about this book and his kindness to write the foreword is also highly appreciated. People from RSC Publishing, Dr. Quanqun Song, Dr. Leanne Marle, Alice Toby-Brant, and Lindsay Stewart, are most appreciated for their kind assistance and great patience.

Our work that appears in this book is supported by the National Basic Research Program of China (973 Program 2015CB856600) and the National Natural Science Foundation of China (21332009).

Shu-Li You

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