Bifunctional Organocatalytic Strategy for Inverse-Electron-Demand Diels-Alder Reactions: Highly Efficient In Situ Substrate Generation and Activation to Construct Azaspirocyclic Skeletons

摘要

The catalytic asymmetric Diels-Alder reaction (DAR) is among the most powerful protocols for the stereoselective construction of six-membered functionalized cyclic frameworks. Its versatility in the synthesis of diverse natural products provides organic chemists with a prodigious starting point to discover new reaction modes for this cycloaddition. In the wake of the emergence of the first metal complexes for the Lewis acid catalyzed asymmetric inverse-electron-demand Diels-Alder reactions (IEDDAR) through the LUMO-lowering strategy reported by the group of Kobaya-shi, several remarkable studies have been presented involving the activation of dienes through lowering of the LUMO energy by Lewis acidic metal complexes or organic molecules [Eq. (1), Scheme 1]. Recently, amine organocatalysis has been attracting considerable interest since the development of the highly enantioselective organocatalytic DAR by MacMillan and co-workers. Alternatively, J0rgensen and co-workers reported the first organocatalytic asymmetric IEDDAR with dienophiles whose HOMO energy has been raised by an enamine activation [Eq. (2)], and considerable advances in this field have recently been achieved by the Chen group Bifunctional organocatalysis has emerged as a potentially powerful tool in catalytic asymmetric synthesis. This concept aims to efficiently achieve asymmetric transformations that cannot be approached by using either a Lewis acid or base catalyst alone. To the best of our knowledge, there is no report to date of an asymmetric IEDDAR that is controlled with a single reactive catalyst through a bifunctional activation strategy; that is simultaneous activation of the HOMO of the dienophile and the LUMO of the diene [Eq. (3)]. There is a report on the use of a combination of an enamine with metal Lewis acid activation that proved to have potential for this transformation. Herein, we introduce a bifunctional catalyst for an in situ substrate generation/ activation strategy as a new platform for the design of organocatalytic intermolecular cycoaddition processes. In this context, we document the first highly enantioselective bifunctional catalytic IEDDAR that involves dual control of the HOMO_(dienophiles) and LUMO_(dienes) energies of the substrates.