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

Abstract

The catalytic asymmetric Diels-Alder reaction (DAR) [1] 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-electrondemand Diels-Alder reactions (IEDDAR) through the LUMO-lowering strategy reported by the group of Kobayashi, [2] several remarkable studies have been presented involving the activation of dienes through lowering of the LUMO energy by Lewis acidic metal complexes [3] or organic molecules [4] [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.[5] Alternatively, Jørgensen and co-workers [6] 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. [7] Bifunctional organocatalysis has emerged as a potentially powerful tool in catalytic asymmetric synthesis. [8] 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.[9] 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.The spirocyclic core is a privileged structural element that is featured in a large number of naturally occurring bioactive alkaloids. Although the significant bioactivity and preparation methods of such motifs attract the interest of chemists, as reported in some elegant works including intramolecular alkylation, metal-based cyclization, intermolecular cycloaddition, rearrangements, and other reactions, [10] the enantioselective catalytic approach to access chiral spiro architectures containing all-carbon quaternary stereocenters still remains challenging. As an important skeleton in the larger spirocycle family, the spirolactam scaffold not only often shows interesting biological activities, but it can also act as an intermediate in the synthesis of more s...

Zn-Catalyzed Enantio- and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitro-Alkenes

“…12 More recently, Masson disclosed an asymmetric cycloaddition of N -aryl-1-azadienes and enecarbamates catalyzed by chiral phosphoric acid (eq 2). 13 Various groups have also reported the cycloaddition of N -sulfonyl-1-azadienes with highly electron-rich alkenes generated from the activation of aldehydes with organocatalysts, such as NHCs, 14 secondary amines, 15,16 thioureas 17 and isothioureas. 18 It is noteworthy that all these examples involve electron-rich alkenes.…”

Magnetic nanoparticle-supported organocatalysis

“…Well-known bifunctional organocatalysts such as the cinchona alkaloid/thiourea system have been developed for a broad range of asymmetric reactions [25][26][27][28]. The Connon group reported the synthesis of Fe 3 O 4 -supported bifunctional catalyst cat-6 through a thiol linker (Scheme 11) [29].…”

5.10 Hetero-Diels–Alder Reactions

“…The chiral primary amine/thiourea 184 (10 mol%), a bifunctional organocatalyst, in combination with acetic acid (20 mol%) promotes the inverse electron-demand aza-Diels-Alder reaction of N-tosylazadienes 185 with cyclic keto/enolate salts 186 (Scheme 42, Table 32). 95 When the reaction is conducted in a biphasic mixture of toluene and water (1:1) at À 13 1C, the corresponding azaspirocyclic compounds 187 are obtained with high diastereo-and enantioselectivities. With regard to the absolute stereochemistry of the inverse electron-demand aza-Diels-Alder reaction, it has been proposed that the azadiene 185 is fixed and activated by the two thiourea hydrogen atoms through weak hydrogen bonding (lowering of the LUMO energy), whereas the cyclic keto/enolate salt 186 is activated by the formation of a ketimine (increase in the HOMO energy), as shown in Scheme 42.…”