Asymmetric inverse-electron-demand hetero-Diels-Alder reaction of six-membered cyclic ketones: an enamine/metal Lewis acid bifunctional approach.

The combination of organocatalysis with metal catalysis has emerged as a potentially powerful tool in organic synthesis. This new concept aims to achieve organic transformations that cannot be accessed by organocatalysis or metal catalysis alone. In our effort to combine organo-enamine catalysis with metal Lewis acid catalysis, we have developed a new class of bifunctional enamine/metal Lewis acid catalysts. These bifunctional catalysts displayed unusually high activity and high stereoselectivity in asymmetric direct aldol reactions. The challenge in the development of Lewis acid/Lewis base catalytic systems lies in the acid-base quenching reaction that leads to catalyst inactivation. A common and elegant approach to solving this problem is the use of a soft acid along with a hard base, or vice versa. Based on this approach, organo-enamine catalysis has been successfully combined with Cu, Ag, Pd, and Au. We use a different strategy to solve the acid-base problem. This new strategy complements the mixed soft/hard approach. In our system, the Lewis base (primary or secondary amine) is tethered to a chelating ligand, which serves as a “trap” for the incoming metal. In this way, the base and the metal Lewis acid are brought into close proximity in one molecule without interacting with each other (Figure 1). The bifunctional enamine/metal Lewis acid catalysts have two unique advantages. First, a large number of metals can be introduced. The Lewis acidity can be easily tuned by simply using a different metal, thereby offering great flexibility to this system. For example, stronger Lewis acids, such as La, can be used to activate the enamine acceptor more strongly. Second, the bifunctional catalysts can potentially convert an intermolecular reaction into a much more efficient intramolecular reaction. In addition, the intramolecular bifunctional nature of the catalysts would also enhance the stereoselectivity of the reaction. With these catalysts, we intend to develop new carbon–carbon or carbon–heteroatom bond-forming reactions involving difficult organic transformations. Herein, we report the first example of a highly chemoand enantioselective inverse-electron-demand hetero-Diels–Alder (HDA) reaction of cyclic ketones with b,g-unsaturated-a-ketoesters catalyzed by primary-amine-based enamine/metal Lewis acid bifunctional catalysts. Asymmetric inverse-electron-demand hetero-Diels– Alder (IED/HDA) reactions of electron-rich alkenes with an electron-deficient a,b-unsaturated ketone offers a valuable synthetic entry into dihydropyran derivatives, which are chemically and biologically of significant importance, allowing the construction of up to three stereogenic centers in one operation. In most of the inverse-electron-demand HDA reactions, enol ethers derived from aldehydes act as the electron-rich alkenes (dienophiles). Very recently, enaminebased organocatalytic asymmetric inverse-electron-demand HDA reactions, in which an in situ formed enamine from a chiral pyrolidine and an aldehyde serves as the dienophile, have been made possible. Ketones are much less reactive compared to aldehydes because of electronic and steric reasons. Asymmetric HDA reactions of ketones, in particular cyclic ketones, have remained a long-standing challenge. We are interested in developing a catalytic asymmetric enamine-based IED/HDA reaction of simple ketones with enones, as it would greatly generalize this method, and open it up to much wider exploitation. To achieve this we believe that the activation of enones should extend beyond hydrogen-bond methods, 8] for example, by using a strong metal Lewis acid. In contrast, the formation of a less congested enamine intermediate using a primary amine catalyst may also contribute to or facilitate this transformation. The primary-amine-based enamine/metal Lewis acid bifunctional catalysts developed in our laboratory appear to be ideal candidates to tackle this difficult problem. We envision that the primary amine/metal Lewis acid bifunctional catalyst would engage enone 3 and the cyclic ketone 2 intramolecularly (Scheme 1). The primary amine would form an enamine in situ with the ketone (A) and the Figure 1. Illustration of primary amine/metal Lewis acid bifunctional catalysts.