Wieland-Miescher ketone

 The Wieland-Miescher ketone ^[1] is a bicyclic di-ketone (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 exceptionally promising biological properties including anticancer, antimicrobial, antiviral, antineurodegenerative and immunomodulatory activities. Examples of syntheses performed using this ketone as a starting material are that of ancistrofuran ^[2] and in the Danishefsky Taxol total synthesis. 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.^[3] Wieland-Miescher ketone contains the AB-ring structure of steroids and is for this reason an attractive starting material toward the steroid skeleton, an approach used in one successful synthesis of adrenosterone.^[4]

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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 ^[5] by hydrogenation over Raney nickel to dihydroresorcinol as the enolate followed by alkylation with methyl iodide.

An enantioselective synthesis employs L-proline as a chiral auxiliary in catalytic amounts ^[6]. This modification is called the Hajos-Parrish-Eder-Sauer-Wiechert reaction ^[7].

References