Organocatalysis intermolecular reactions

In our illustration of the graphical manipulations of data using reaction progress kinetic analysis, we will make use of the example of a model reaction, the intermolecnlar aldol reaction between acetone 1 and aldehyde 2 to form the aldol addition product 3, mediated by proline 4, as shown in Scheme 27.1. The demonstration by List, Lemer, and Barbas in 2000 that proline mediates intermolecular aldol reactions with a high degree of asymmetric induction heralded a revolution in the field of organocatalysis, encompassing the discovery of new catalysts and new catalytic transformations." ... 

Prior to the advent of organocatalysis, the asymmetric direct a-allqtlation reaction was relatively unknown. Classical methods to access a-allq lated carbonyl products required stoichiometric amounts of preformed aldehyde metal enolates. Additionally, side reactions such as aldol, Canizzaro- or Tischenko-type processes diminished the efficiency of these reactions. In this sense the asymmetric intermolecular Sjj2 a-alkylation of aldehydes with simple allq l halides has been a difficult feat to achieve. 

The extremely high interest in asymmetric organocatalysis today has been driven by the seminal publications of Eder et al. in 1971 and of List et al. in 2000 who recognised that the natural amino acid (S)-proline acted as an efficient catalyst in asymmetric intra- or intermolecular aldol reactions. Subsequently, numerous proline derivatives (amides, ... 

Probably (5)-proline (1) is the most used organocatalyst, being applied in ample spectra of asynunetric reactions with excellent results in a variety of reaction conditions. Its application in the intermolecular direct aldol reaction marked a breakthrough in the organocatalysis research area. In this section the use of proline in different aldol processes will be divided according to the nature of the nucleophilic and electrophilic partner used. 

Although asymmetric organocatalysis is now considered as a powerful tool for the synthesis of chiral compounds this research held experimented its own revolution. It was restricted after the seventies only to the nse of simple a-amino acids as catalyst for the Robinson annulations and above all with the application of proline to the enantioselective intermolecular aldol reaction. 

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

Nicewicz and MacMillan reported an elusive asymmetric intermolecular a-alkylation of aldehydes by elegantly merging Ru photoredox catalysis with chiral amine organocatalysis [30]. The reaction mechanism proposed for the synergistic catalysis is illustrated in Scheme 2. 

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