Intramolecular Aldol Reactions Using Enamine Catalysis

2 Intramolecular Aldol Reactions Using Enamine Catalysis 

The first example of an organocatalytic enantio-group-differentiating intramolecular G-endo aldol reaction catalyzed by (S)-proline was the Hajos-Parrish-Eder-Sauer-Wiechert cyclization [24]. Although impressive, the synthetic scope of the 

Pioneering work in this field has been independently reported based on two distinct strategies. Designed small diamine catalyst 54 (10mol%) in the presence of trifluoroacetic acid in an emulsion system catalyzes the direct cross-aldol reaction of cyclohexanone (51, 2 equiv.) with p-nitrobenzaldehyde (52) in bulk water (111 equiv.), giving the anti-aldol product 53 in quantitative yield with 94% ee 

A great number of direct aldol reactions in aqueous media with no organic solvent have now been reported. Several of these reports are summarized in Table 28.3 [35]. Based on investigations of different salting-out and salting-in conditions, brine is clearly a unique aqueous media that accelerates the rate of reaction and affects the stereochemical outcome of the aldol reactions due to hydrophobic aggregation (entries 7 and 8). 

D Donor, A Acceptor. W Water, P Product C or Qwwww Catalyst, Qvwww, Enamine intermediate 

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Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

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]. 

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