A Cooperative Participation of the Amido Group in the Organocatalytic Construction of All-Carbon Quaternary Stereocenters by Michael Addition with β-Ketoamides

Abstract

The secondary amido group of α-substituted β-ketoamides plays a crucial role in the control of the reactivity and spatial arrangement (selectivity) in the organocatalyzed Michael addition to unsaturated carbonyls. This results in an unprecedented activation mode of substrates through H-bonding interactions allowing the construction of enantiomerically enriched functionalized all-carbon quaternary centers and spiroaminals of high synthetic potential.

Organocatalytic Enantio‐ and Diastereoselective Conjugate Addition to Nitroolefins: When β‐Ketoamides Surpass β‐Ketoesters

“…The first challenge of our study was to identify acyclic methylene β‐ketoamide substrates that could combine both good reactivity and selectivity. Our former studies of the organocatalytic Michael addition of cyclic α‐substituted β‐ketoamides to α,β‐unsaturated carbonyl compounds7d, 8a, d–e or nitroolefins6g highlighted the importance of the presence of a proton on the nitrogen atom. Its absence generally resulted in no reactivity and the acidity of the secondary amide could be correlated with the observed enantioselectivities.…”

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].…”

Enantioselective Organocatalytic Multicomponent Synthesis of 2,6‐Diazabicyclo[2.2.2]octanones

“…In contrast, with crotonaldehyde (7), the 2,6-DABCO 5 q was obtained with encouraging yield and diastereoselectivity, but surprisingly as a virtually racemic product. As presented in our preliminary work on the conjugate addition of b-ketoamides to a,bunsaturated carbonyl compounds, [15] the Michael adduct readily cyclizes to give the hemiaminal A. Its dehydration can afford the iminium ion B, for which a racemization pathway via a retro-Michael and uncatalyzed intramolecular Michael addition sequence can be envisaged.…”

“…[12,13] This also constitutes a proof of concept that very complex transformations are amenable to enantioselective control by hydrogen-bonding activation, even in the presence of substrates containing acidic hydrogen atoms. The targeted bridged pentacyclic scaffolds [14] were obtained in excellent chemical yields along with high enantioand diastereoselectivities by assembling three simple polyfunctionalized starting materials in a very chemoselective manner while creating very efficiently a large number of new bonds and stereogenic centers.Based on our preceding studies on the enantioselective Michael addition of b-ketoamides to a,b-unsaturated carbonyl derivatives, [15] we started our investigations by mixing the N-tosyl-b-ketoamide 1 a, 2-aminophenol (2 a), and acrolein (3) in the presence of bifunctional Takemoto catalyst (R,R)-4 and crushed 4 molecular sieves in dry toluene at room temperature (Table 1, entry 1). Pleasingly, the expected DABCO 5 a was formed as the only product and isolated in 74 % yield with 14:1 d.r.…”

“…Based on our preceding studies on the enantioselective Michael addition of b-ketoamides to a,b-unsaturated carbonyl derivatives, [15] we started our investigations by mixing the N-tosyl-b-ketoamide 1 a, 2-aminophenol (2 a), and acrolein (3) in the presence of bifunctional Takemoto catalyst (R,R)-4 and crushed 4 molecular sieves in dry toluene at room temperature ( Table 1, entry 1). Pleasingly, the expected DABCO 5 a was formed as the only product and isolated in 74 % yield with 14:1 d.r.…”