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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 1970's it is considered an important contribution to asymmetric organocatalysis. It has been used extensively as a tool in steroid synthesis.
Additional recommended knowledge
In the original reaction 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. The asymmetric synthesis of the Wieland-Miescher ketone (1985) is another intramolecular reaction also based on proline, a reaction revisited by the Barbas group in 2000 
The authors noted the similarity of proline with the enzyme aldolase A which both 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.
The List group expanded the utility of this reaction to the synthesis of 1,2-diols :
In a screening program, 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 
This reaction is unusual because in general aldehydes will self-condense.
Several reaction mechanisms for the triketone reaction have been proposed over the years. The one put forward by Hajos (1974) features a hemiaminal intermediate. The Agami mechanism (1984) has an enamine intermediate with two proline units involved in the transition state (based on experimental reaction kinetics)  and according to a mechanism by Houk (2001)   a single proline unit suffices with a cyclic transition state and with the proline carboxyl group involved in hydrogen bonding.
The reaction mechanism as proposed by the Barbas/List group in 2000 for the intermolecular reactions  is based also on enamine formation and the observed stereoselectivity based on the Zimmerman-Traxler model favoring Re face approach:
This enamine mechanism also drives the original Hajos-Parrish triketone reaction but the involvement of two proline molecules in it as proposed by Agami  is disputed by List also based on reaction kinetics . The general mechanism is further supported (again by List) by the finding that in a reaction carried out in labeled water (H218O), the oxygen isotope finds its way into the reaction product . This rules out the non-enamine Hajos mechanism. In the same study the reaction of proline with acetone to the oxazolidinone (in DMSO) was examined:
The equilibrium constant for this reaction is only 0.12 leading List to conclude that the involvement of oxazolidinone is only parasitic. This view is contested by Seebach and Eschenmoser who in 2007 published a 47 page (!) article  in which they argue that oxazolidinones in fact play a pivotal role in proline catalysis. One of the things they did was reacting a oxazolidinone with the activated aldehyde chloral in an aldol addition:
In 2008, Barbas in an essay addressed the question why it took until the year 2000 before interest regenerated for this seemingly simple reaction 30 years after the pioneering work by Hajos and Parrish and why the proline catalysis mechanism appeared to be an enigma for so long . One explanation has to do with different scientific cultures: a proline mechanism in the context of aldolase catalysis already postulated in 1964 by a biochemist  was ignored by organic chemists. Another part of the explanation was the presumed complexity of aldolase catalysis that dominated chemical thinking for a long time.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Hajos-Parrish-Eder-Sauer-Wiechert_reaction". A list of authors is available in Wikipedia.|