The Direct Catalytic Asymmetric Three-Component Mannich Reaction

Homoenolate, a species containing anionic carbon β to a carbonyl group or a moiety that can be transformed into a carbonyl group, is a potential three carbon synthon. Recent introduction of a protocol for the generation of homoenolate directly from enals by NHC (nucleophilic heterocyclic carbene) catalysis has made it possible to explore the synthetic utility of this unique reactive intermediate. The versatility of NHC-bound homoenolate is illustrated by its annulation with various carbonyl compounds leading to γ-butyrolactones, spiro-γ-butyrolactones, and δ-lactones. Interception of homoenolate with imines afforded γ-lactams and bicyclic β-lactams. Formation of cyclopentenes and spirocyclopentanones respectively by reaction with enones and dienones is also noteworthy. This tutorial review focuses on these and other types of reactions which attest to the synthetic potential of NHC-bound homoenolates in organic synthesis.

Recent advances in carbon–carbon bond-forming reactions involving homoenolates generated by NHC catalysis

We have developed proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines. Several of the studied reactions provide β-amino carbonyl compounds (Mannich products) in excellent enantio-, diastereo-, regio-, and chemoselectivities. The scope of each of the three components and the influence of the catalyst structure on the reaction are described. Reaction conditions have been optimized, and the mechanism and source of asymmetric induction are discussed. We further present application of our reaction to the highly enantioselective synthesis of 1,2-amino alcohols.

The proline-catalyzed direct asymmetric three-component Mannich reaction: Scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols

Asymmetric synthesis of amines by nucleophilic 1,2-addition of organometallic reagents to the CN-double bond

Synthesis of optically active pheromones

Synthesis of diastereo- and enantiomerically pure α-amino-γ-oxo acid esters by reaction of acyliminoacetates with enamines derived from 6-membered ketones

Asymmetric syntheses via metalated chiral hydrazones : Overall enantioselective α-alkylation of acyclic ketones

Asymmetric synthesis of β-substituted δ-ketoesters via michael-additions of samp/ramp-hydrazones to α,β-unsaturated esters, virtually complete 1.6-asymmetric induction

EFFICIENT PREPARATION OF THE CHIRAL AUXILIARIES SAMP and RAMP. N-AMINATION via HOFMANN DEGRADATION

Enantioselective Synthesis of β‐Substituted Primary Amines; α‐Alkylation/Reductive Amination of Aldehydes via SAMP‐Hydrazones

Dieter Enders

Papers

Synthesis of diastereo- and enantiomerically pure α-amino-γ-oxo acid esters by reaction of acyliminoacetates with enamines derived from 6-membered ketones

Asymmetric syntheses via metalated chiral hydrazones : Overall enantioselective α-alkylation of acyclic ketones

Asymmetric synthesis of β-substituted δ-ketoesters via michael-additions of samp/ramp-hydrazones to α,β-unsaturated esters, virtually complete 1.6-asymmetric induction

EFFICIENT PREPARATION OF THE CHIRAL AUXILIARIES SAMP and RAMP. N-AMINATION via HOFMANN DEGRADATION

Enantioselective Synthesis of β‐Substituted Primary Amines; α‐Alkylation/Reductive Amination of Aldehydes via SAMP‐Hydrazones