Asymmetric Inverse-Electron-Demand Hetero-Diels–Alder Reaction of Six-membered Cyclic Ketones: An Enamine/Metal Lewis Acid Bifunctional Approach

✍ Scribed by Dr. Zhenghu Xu; Dr. Lu Liu; Prof. Dr. Kraig Wheeler; Prof. Dr. Hong Wang

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 372 KB
• Volume: 50
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/anie.201100160

✦ Synopsis

The combination of organocatalysis with metal catalysis has emerged as a potentially powerful tool in organic synthesis. [1] 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. [2] 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. [3] 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 I , [1c,d] Ag I , [1e] Pd 0 , [1f-h] and Au I . [1i,j] 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