Hajos-Parrish-Eder-Sauer-Wiechert Reaction

What Is Hajos-Parrish-Eder-Sauer-Wiechert Reaction?

The Hajos-Parrish-Eder-Sauer-Wiechert (HPESW) reaction is a pioneering example of asymmetric organocatalysis, enabling the synthesis of enantiomerically enriched bicyclic ketols through proline-catalyzed intramolecular aldol reactions. Researchers Hajos and Parrish initially reported this reaction in the 1970s before Eder, Sauer, and Wiechert independently discovered the same process which became the first successful metal-free catalytic asymmetric aldol reaction. The reaction uses (S)-proline as a chiral catalyst to convert non-chiral triketones into bicyclic ketols which show remarkable enantioselectivity (up to 93% ee) and reach high yields (100% under optimal conditions).

• Catalyst: (S)-Proline
• Solvents: Dimethylformamide (DMF) for aldol cyclization; acetonitrile with HClO₄ (acidic conditions) for dehydration.
• Reactants: Triketones (e.g., 2-methyl-1,3-cyclopentanedione derivatives); Precursors for fused bicyclic systems (e.g., methyl vinyl ketone + 2-methyl-1,3-cyclohexanedione in Wieland-Miescher ketone synthesis).
• Products: Enantiomerically enriched bicyclic ketols (e.g., Hajos-Parrish ketone [5,6-fused system], Wieland-Miescher ketone [6,6-fused system]); Dehydrated aldol condensation products under acidic conditions.
• Reaction Type: Asymmetric intramolecular aldol reaction.
• Related Reactions: Robinson annulation, List-Barbas intermolecular aldol reaction.
• Experimental Tips:

1) Optimal proline loading is 3 mol%, though higher concentrations (e.g., 47 mol%) under acidic conditions shift the pathway toward dehydration products.

2) Proline derivatives (e.g., 5,5-dimethylthiazolidine-4-carboxylic acid) may enhance selectivity in specific cases.

3) DMF is preferred for intramolecular aldol reactions, while acetonitrile with HClO₄ promotes dehydration.

4) High substrate concentrations minimize undesired pathways (e.g., oxazolidinone or iminium ylide formation).

Fig 1. HPESW reaction and its mechanism. [1]

Mechanistic Insights of HPESW Reaction

The mechanism of the HPESW reaction has been extensively debated, with three primary hypotheses:

Ketone Hemiaminal Transition State (Hajos, 1974):

Initially proposed by Hajos, this pathway involves a hemiaminal intermediate formed between proline and the carbonyl group, facilitating stereoselective cyclization.

Enamine-Mediated Pathway (Agami, 1988; List & Barbas, 2000):

Agami suggested an enamine intermediate, where proline condenses with the ketone to form a nucleophilic enamine. Subsequent aldol cyclization is stereocontrolled by proline's carboxyl group via hydrogen bonding. List and Barbas provided experimental support using H₂¹⁸O isotopic labeling, confirming the enamine mechanism by detecting ¹⁸O incorporation in the product.

Oxazolidinone Intermediate (Seebach & Eschenmoser, 2007):

Recent studies propose oxazolidinone intermediates as key species, particularly in reactions involving activated aldehydes.

Application Examples of HPESW Reaction

• Example 1: Wieland-Miescher ketone is a synthetic precursor for many steroids and terpenoids. Since the Wiechert and Hajos groups reported their proline-catalyzed synthesis method, it has been widely used in the synthesis of steroids and terpenoids. For example, Danishefsky used Wieland-Miescher ketone as a starting material to complete the synthesis of Baccatin Ⅲ and Taxol. [2]
• Example 2: Omayra H. Rubio et al. synthesized several bifunctional organic catalysts based on the carbazole skeleton (containing chiral amines and synthetic oxygen anion holes) and successfully applied them to the synthesis of Hajos-Wiechert ketone and Wieland-Miescher ketone (ee value up to 99%). [3]

Fig 2. Synthetic examples via HPESW reaction.

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116569-09-6		5-Hydroxyisatin
117-78-2		Anthraquinone-2-Carboxylic Acid
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References

1. Wang, Hg. Comprehensive organic name reactions. Vol. 2. New York, NY, USA: Wiley, 2010.
2. Danishefsky, Samuel J., et al. Journal of the American Chemical society, 1996, 118(12), 2843-2859.
3. Rubio, Omayra H., et al. Tetrahedron, 2015, 71(8), 1297-1303.
4. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 238-240.

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