Hajos-Parrish reaction, enamine proline catalysis

The delicateness of the aldol protocol has perhaps been one of the factors why enamine catalysis of the aldol reaction did not emerge nntil the 1970s. The Hajos-Parrish-Eder-Sauer-Wiechert reaction [30] (Scheme 16) was an important early example of an intramolecular enamine-catalyzed aldol reaction. However, it was not nntil 2000 when List, Barbas and Lemer demonstrated that the same reaction can also be performed in an intermolecular fashion, using proline as a simple enamine catalyst [26]. 

S.C. PanandB. List s paper spans the whole field of current organocat-alysts discussing Lewis and Brpnsted basic and acidic catalysts. Starting from the development of proline-mediated enamine catalysis— the Hajos-Parrish-Eder-Sauer-Wiechert reaction is an intramolecular transformation involving enamine catalysis—into an intermolecular process with various electrophilic reaction partners as a means to access cY-functionalized aldehydes, they discuss a straightforward classification of organocatalysts and expands on Brpnsted acid-mediated transformations, and describe the development of asymmetric counteranion-directed catalysis (ACDC). 

Experiments conducted in the mid-1980s by Agami indicated a small nonlinear effect in the asymmetric catalysis in the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Agami proposed that two proline molecules were involved in the catalysis the first proline forms an enamine with the side chain ketone and the second proline molecule facilitates a proton transfer. Hajos and Parrish reported that the proline-catalyzed cyclization shown in Scheme 6.7 did not incorporate when run in the presence of labeled water. While both of these results have since been discredited—the catalysis is first order in catalyst and is incorporated into... 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

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. 

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