Aminocatalytic Asymmetric Diels–Alder Reactions via HOMO Activation

Abstract

In the first successful catalytic asymmetric Diels-Alder reaction in 1979, Koga and colleagues used a chiral aluminum complex as a Lewis acid catalyst, but since then, researchers have developed numerous catalytic systems for these reactions. By 2000, several chiral organic compounds, such as the salts of imidazolidinones or TADDOLs, emerged as robust catalysts in the asymmetric Diels-Alder reactions. According to frontier molecular orbital theory, most of these catalysts employ a LUMO-lowering strategy as a means of activating electron-deficient dienophiles. Only rarely do chiral catalysts take advantage of the alternative strategy of activating the HOMO. In this Account we will discuss the development of asymmetric Diels-Alder reactions based on the HOMO-raising effects of chiral amines. First, we show that enamine intermediates formed in situ between an amine catalyst and enolizable aliphatic aldehydes can act as electron-rich dienophiles in inverse-electron-demand Diels-Alder reactions. We describe the preparation of a variety of oxygen- or nitrogen-containing heterocycles with high optical purity. Then, we demonstrate that the dienamine species from α,β-unsaturated aldehydes can act either as electron-rich dienes in normal-electron-demand Diels-Alder reactions or as dienophiles in inverse-electron-demand Diels-Alder reactions. These reactions generally occur with high chemo-, regio-, and stereoselectivity. Finally, we introduce a new activation mode for Diels-Alder reactions, in which reactive trienamine intermediates derived from 2,4-dienals or even 2,4-dienones play a key role. Notably, we observe remarkable β,ε-regioselectivity and obtain excellent stereocontrol even at the very remote ε-reactive center-up to seven bonds away from the chiral center of the amine catalyst. These results demonstrate that a HOMO-activation strategy via aminocatalysis could become a significant tool in asymmetric Diels-Alder reactions. In addition, these reactions using enamine, dienamine, or trienamine intermediates produce a diverse array of densely functionalized cyclic scaffolds, which may serve as valuable structures in drug discovery and natural product synthesis.

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.…”

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“…Further, aminocatalytic DAR and DAR inv via HOMO activation were documented using dienamine species from α, β-unsaturated aldehydes which act either as electron-rich dienes in normal-electrondemand DAR or as dienophiles in DAR inv . All these reactions occur with high chemo-, regio-, and stereoselectivity as mentioned above 56 .…”

One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael–Hemiaminalization Sequence

“…Over the past decade, asymmetric organic catalysis [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], quite powerful for synthesizing various heterocyclic molecules, has formed the basis of several elegant approaches to construct chiral single-heterocycle piperidine skeletons with high efficiency and low toxicity under environmentally friendly conditions . In contrast, relatively few organocatalytic methods have been described to stereo-selectively form spirocyclic piperidine derivatives [30][31][32][33][34][35][36], particularly ones with a quaternary stereocenter [37][38][39].…”

“…Strong electron-withdrawing aryl groups on enal 3 (entries 8-9) gave slightly higher 91 yields and stereoselectivities than electron-donating aryl groups (entries [10][11][12] Using these optimized conditions (Table 1, entry 12), we explored the scope and limitations of this method using α,β-unsaturated aldehyde 3, cyclic 2-diazo-1,3-diketone 1 and primary amine 2 (Table 2). Generally, the reaction was flexible in affording the desired spirocyclic piperidones.…”

“…Halogen substitutions such as -F, -Cl, and -Br at the meta or para positions of aryl groups in enal 3 (entries 2-5) gave better yields and stereoselectivities than such substitutions at the ortho position (entries 6 and 7). Strong electron-withdrawing aryl groups on enal 3 (entries 8 and 9) gave slightly higher yields and stereoselectivities than electron-donating aryl groups (entries [10][11][12]. The heteroaromatic group furan led to the desired product 5m with high ee and good dr value (entry 13).…”