Neha Patil (Editor)

Wieland–Miescher ketone

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Formula
  
C11H14O2

ChemSpider ID
  
80553

Molar mass
  
178.23 g/mol

Wieland–Miescher ketone orgsynorgcontentfiguresCV7P0368gif

The Wieland–Miescher ketone is a racemic bicyclic diketone (enedione) and is a versatile synthon which has so far been employed in the total synthesis of more than 50 natural products, predominantly sesquiterpenoids, diterpenes and steroids possessing possible biological properties including anticancer, antimicrobial, antiviral, antineurodegenerative and immunomodulatory activities. The reagent is named after two chemists from Ciba Geigy, Karl Miescher and Peter Wieland (not to be confused with Heinrich Otto Wieland). Examples of syntheses performed using the optically active enantiomer of this diketone as a starting material are that of ancistrofuran and the Danishefsky total synthesis of Taxol.

Wieland–Miescher ketone WielandMiescher ketone Wikipedia

Most advances in total synthesis methods starting from Wieland–Miescher ketone were fueled by the search for alternative methods for the industrial synthesis of contraceptive and other medicinally relevant steroids, an area of research that flourished in the 1960s and 1970s. Wieland–Miescher ketone contains the AB-ring structure of steroids and is for this reason an attractive starting material for the steroid skeleton, an approach used in one successful synthesis of adrenosterone.

Wieland–Miescher ketone WielandMiescher ketone Wikipedia

The original Wieland–Miescher ketone is racemic and prepared in a Robinson annulation of 2-methyl-1,3-cyclohexanedione and methyl vinyl ketone. The intermediate alcohol is not isolated. The required 2-methyl-1,3-cyclohexanedione can be prepared from resorcinol by hydrogenation over Raney nickel to dihydroresorcinol as the enolate followed by alkylation with methyl iodide.

Wieland–Miescher ketone Illustrated Glossary of Organic Chemistry WielandMiescher ketone

An enantioselective synthesis employs L-proline as an organocatalyst:

This reaction appeared in 1971 in the patent literature by Z. G. Hajos and D. R. Parrish. In this patent, the isolation and characterization of the above pictured optically active intermediate bicyclic ketol (in parentheses) has also been described, because they worked at ambient temperature in anhydrous dimethylformamide (DMF) solvent. Working in DMSO solvent does not allow isolation of the bicyclic ketol intermediate, it leads directly to the optically active bicyclic dione. The reaction is called the Hajos-Parrish reaction or the Hajos-Parrish-Eder-Sauer-Wiechert reaction.

Wieland–Miescher ketone modern steroid science February 2012

This reaction has also been performed in a one-step procedure, leading to 49% yield and 76% Enantiomeric excess (ee):

Wieland–Miescher ketone Illustrated Glossary of Organic Chemistry WielandMiescher ketone

Other proline-based catalysts have been investigated

Wieland–Miescher ketone WielandMiescherKeton Wikipedia

References

Wieland–Miescher ketone Wikipedia