Palladium Catalyzed Aerobic Dehydrogenation: From Alcohols to Indoles and Asymmetric Catalysis

Catalytic aerobic dehydrogenation of organic substrates is going through a Renaissance. Recent advances in this area have led to the discovery of palladium-catalyzed alcohol dehydrogenations and oxidative heteroand carbocyclizations. The development of asymmetric catalytic dehydrogenations is the latest advance in a long line of catalytic asymmetric oxidation reactions. Introduction Asymmetric catalytic oxidation chemistry has profoundly impacted organic synthesis. Some reactions of particular consequence are shown in Figure 1 and include the Katsuki-Sharpless asymmetric epoxidation (KSAE) and dihydroxylation, the Katsuki–Jacobsen and Shi epoxidations, and the Evans and Jacobsen aziridinations. There is no doubt that the KSAE reaction not only paved the way for future directions in enantioselective oxidation chemistry, but also opened the door to a wide range of other catalytic asymmetric reactions. Moreover, the introduction of the KSAE and the other reactions listed in Figure 1 led to innumerable advances in the construction of complex molecules by de novo asymmetric synthesis. All of the reactions shown in Figure 1 are examples of oxidations by virtue of heteroatom transfer. As a result, these reactions may be classified in a simplistic sense as belonging to a family of similar oxidations characterized by the stylized reaction in Figure 2. In contrast, asymmetric oxidation chemistry that does not involve heteroatom transfer has been relatively less explored (e.g., the dehydrogenations shown in Figure 3). Until recently, few methods existed for catalytic asymmetric dehydrogenation chemistry, despite the ubiquity of such processes in nature (e.g., oxidases and dehydrogenases) and for racemic scenarios in the chemistry laboratory (e.g., alkane ! alkene and alcohol ! carbonyl). For instance, seminal contributions for the asymmetric dehydrogenation of alcohols were provided by Rychnovsky and Noyori only in the last decade. In part, it may be possible to understand the relatively slow nature with which developments along these lines have proceeded, by the subtle nature of the problem. Dehydrogenation is, by definition, a complexity-minimizing event. Thus, in the case of an enantioselective oxidation of a secondary alcohol, the product ketone arises by destruction of the asymmetric center (as opposed to asymmetric induction). Recently, increasing interest in the use of palladium catalyzed aerobic dehydrogenation chemistry as a broad platform for asymmetric oxidation has surfaced. This highlight review will focus on these developments, Highlight Review R2 R3 R1 H OH HO R2 R1 H R3 R2 R3 R1 H R2 R3 R1 H O R2 R3 R1 H R2 R3 R1 H R4 N R1 R2 OH R3 O R1 R2 OH R3 Katsuki-Sharpless Asymmetric Epoxidation Sharpless Asymmetric Dihydroxylation Katsuki-Jacobsen and Shi Epoxidations Evans and Jacobsen Aziridinations Figure 1. Heteroatom transfer asymmetric oxidation reactions. LnM Y LnM Y Heteroatom Transfer (reduced state) Figure 2. General heteroatom transfer mechanism.