Hajos–Parrish–Eder–Sauer–Wiechert Reaction

The Hajos–Parrish–Eder–Sauer–Wiechert reaction in organic chemistry is a proline catalysed asymmetric Aldol reaction. The reaction is named after its principal investigators from Hoffmann-La Roche and Schering AG. Discovered in the 1970s the original Hajos-Parrish catalytic procedure - shown in the reaction equation - leading to the optically active bicyclic ketol as well as the Eder-Sauer-Wiechert modification leading to the optically active enedione through the loss of water from the ketol paved the way of asymmetric organocatalysis. It has been used extensively as a tool in the synthesis of steroids and other enantiomerically pure molecules.

Figure 1.

In the original reaction shown in Figure 1. naturally occurring chiral proline is the chiral catalyst in an Aldol reaction. The starting material is an achiral triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess. As shown above, Hajos and Parrish worked at ambient temperature in dimethylformamide (DMF) solvent using a catalytic amount (3% molar equiv.) of (S)-(-)-proline enabling them to isolate the optically active intermediate bicyclic ketol. Thus, they described the first use of proline in a catalytic asymmetric aldol reaction.

The Schering group worked under non biological conditions using (S)-Proline (47 mol%), 1N perchloric acid, in acetonitrile at 80 °C. Hence, they could not isolate the Hajos, Parrish intermediate bicyclic ketol but instead the condensation product (7aS)-7a-methyl-2,3,6,7-tetrahdroindol-1,5-dione through the loss of water. Thirty-seven years later a new group at Schering AG published the continuation of the earlier Schering work . Instead of the aforementioned non biological conditions the new group used the Hajos-Parrish catalytic procedure. Thus, they could isolate the optically active 6,5-bicyclic ketol described so far only in the Hajos-Parrish publications, .

Hajos and Parrish investigated further the exact configuration of the above cis-fused-7a-methyl- 6,5-bicyclic-ketol by circular dichroism, and these results were confirmed by a single-crystal X-ray diffraction study. The centro symmetrical crystal of the corresponding racemic ketol without a heavy atom label has been obtained by the use of racemic proline. It showed by X-ray diffraction an axial orientation of the angular methyl group and an equatorial orientation of the hydroxyl group in the chair conformer of the six-membered ring. This is in good agreement with the crystal structure of the CD-ring of digitoxigenin. The structure of this ketol and its ethyl homologue are shown as follows.

Similar studies of the 7a-ethyl-homologue showed that the ethyl bicycic ketol existed in a cis conformation in which the 7a-ethyl group is equatorially oriented and the hydroxyl group is axially oriented in the chair form of the six-membered ring as shown above. The reason for a preference for this conformation could be enhanced 1,3-diaxial interaction in the other cis conformer between the angular ethyl group and the axial hydrogens at C-4 and C-6 in the six membered ring.

In a 2000 study the Barbas group found that intermolecular aldol additions (those between ketones and aldehydes) are also possible albeit with use of considerably more proline:

The authors noted the similarity of proline, the aldolase antibodies they had created and natural aldolase enzymes aldolase A all of which operate through an enamine intermediate. In this reaction the large concentration of acetone (one of the two reactants) suppresses various possible side-reactions: reaction of the ketone with proline to a oxazolidinone and reaction of the aldehyde with proline to a azomethine ylide.

Notz and List went on to expand the utility of this reaction to the synthesis of 1,2-diols:

In their full account of their 2000 Communication, the group revealed that proline together with the thiazolium salt 5,5-dimethyl thiazolidinium-4-carboxylate were found to be the most effective catalysts among a large group of amines, while catalysis with (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine salts formed the basis for the development of diamine organocatalysts that have proven effective in a wide variety or organocatalytic reactions.

The asymmetric synthesis of the Wieland-Miescher ketone (1985) is another intramolecular reaction also based on proline, that was explored by the Barbas group in 2000. In this study the Barbas group demonstrated for the first time that proline can catalyze the cascade Michael-aldol reaction through combined iminium-enamine catalysis. This work is significant because despite the 30 year history and application of the Hajos-Parrish reaction in industry, the triketone substrate for this reaction had always been synthesized in a discrete independent step, demonstrating that there was a fundamental lack of understanding of the chemical mechanism of this reaction. The Barbas group had reported the aldolase antibody catalyzed iminium-enamine Robinson annulation in their 1997 study that marked the beginning of their studies in the area now called organocatalysis. In a report published in 2002 Carlos F. Barbas III said: "Work in the 1970s on proline-catalyzed intramolecular aldol addition reactions by synthetic organic chemists Zoltan G. Hajos and David R. Parrish of the chemical research department at Hoffmann-La Roche, Nutley, N.J., inspired us to look more closely at parallels between small-molecule catalysts and enzymes".

In 2002 the Macmillan group was the first to demonstrate the proline catalyzed Aldol reaction between different aldehydes. This reaction is unusual because in general aldehydes will self-condense.

The organocatalytic intermolecular aldol reaction is now known as the Barbas-List Aldol reaction.