Hajos-Parrish-Eder-Sauer-Wiechert reaction

What is Hajos-Parrish-Eder-Sauer-Wiechert reaction?

In 1971, two separate groups, namely Hajos and Parrish, and Eder, Sauer, and Wiechert, independently reported on an enantioselective Aldol reaction. This reaction is catalyzed by (S)-proline and is considered to be one of the earliest reactions to be enantioselectively catalyzed and practically used in synthetic organic chemistry. Due to its widespread use in organic synthesis, it has been extensively researched and expanded to include asymmetric Aldol reaction, α-alkylation, Mannich reaction, Michael addition, and α-amination of carbonyl compounds.

Hajos-Parrish-Eder-Sauer-Wiechert reaction - general reaction scheme
Hajos-Parrish-Eder-Sauer-Wiechert reaction

This reaction has been given various names in the literature, including the Hajos-Parrish-Eder-Sauer-Wiechert reaction, Hajos-Eder-Sauer-Wiechert reaction, Hajos-Wiechert reaction, and Hajos-Parrish-Wiechert reaction.

The asymmetric version of the Robinson annulation, catalyzed by (S)-proline, is referred to as the Hajos-Parrish reaction, Hajos-Parrish-Robinson annulation, or Hajos-Wiechert aldol reaction.

The resulting cyclic aldol product is known as the Hajos-Parrish ketol, and the cyclic (S)-enedione “(7aS)-2,3,7,7a-tetrahydro-7a-methyl-1H-indene-1(5,6H)-dione” is referred to as the Hajos-Parrish ketone, Hajos-Parrish diketone, or Hajos-Wiechert ketone.

Initially, it was believed that this reaction involved the formation of a carbinolamine intermediate, followed by the displacement of the proline moiety by nucleophilic attack of the enol from ketone. However, more experimental and theoretical evidence suggests that this reaction involves the nucleophilic addition of the neutral enamine to the carbonyl group, together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide.