23.12 The Robinson Annulation Reaction

Robinson annulation is a powerful two-step process for building complex ring systems. It combines a Michael reaction with an intramolecular aldol condensation, creating new carbon-carbon bonds and forming cyclic structures.

This reaction is crucial for synthesizing polycyclic molecules, especially those found in steroids and other bioactive compounds. It's a versatile tool that chemists use to construct intricate molecular frameworks, making it essential in organic synthesis.

Robinson Annulation Reaction

Two-step process of Robinson annulation

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• Involves the formation of a new ring system through a two-step process
  • Step 1: Michael reaction
    • Nucleophilic addition of an enolate (nucleophile) to an $\alpha,\beta$-unsaturated carbonyl compound (electrophile) (e.g., methyl vinyl ketone)
    • Creates a new carbon-carbon bond and generates a 1,5-dicarbonyl intermediate
  • Step 2: Intramolecular aldol reaction
    • The 1,5-dicarbonyl intermediate undergoes an intramolecular aldol condensation
    • Forms a new carbon-carbon bond and a cyclic $\beta$-hydroxyketone or $\beta$-hydroxyaldehyde (e.g., Wieland-Miescher ketone)
    • Dehydration of the $\beta$-hydroxyketone or $\beta$-hydroxyaldehyde yields an $\alpha,\beta$-unsaturated cyclic ketone or aldehyde

Reactants and products in Robinson annulation

• Reactants
  • An enolate or enamine derived from a ketone or aldehyde (e.g., 2-methylcyclohexane-1,3-dione)
  • An $\alpha,\beta$-unsaturated carbonyl compound, such as an $\alpha,\beta$-unsaturated ketone or aldehyde (e.g., methyl vinyl ketone)
• Products
  • A cyclic $\beta$-hydroxyketone or $\beta$-hydroxyaldehyde intermediate
  • An $\alpha,\beta$-unsaturated cyclic ketone or aldehyde as the final product (e.g., Wieland-Miescher ketone)

Applications for polycyclic molecule synthesis

• Enables the synthesis of polycyclic molecules, especially those with a six-membered ring fused to a five-membered ring
  • This ring system is prevalent in steroid hormones and other biologically active compounds (e.g., testosterone, progesterone)
• Example: Synthesis of the Wieland-Miescher ketone, a key intermediate in the synthesis of various steroids
  1. Michael reaction between 2-methylcyclohexane-1,3-dione (an enolate) and methyl vinyl ketone (an $\alpha,\beta$-unsaturated ketone)
  2. Intramolecular aldol reaction and dehydration to form the bicyclic Wieland-Miescher ketone
• Can be further extended to synthesize more complex polycyclic systems by using the product as a reactant in subsequent annulation reactions (e.g., synthesis of tetracyclic steroid core)

Mechanistic considerations

• The Michael reaction proceeds through conjugate addition, where the nucleophile attacks the β-carbon of the α,β-unsaturated carbonyl compound
• The intramolecular aldol reaction involves cyclization of the 1,5-dicarbonyl intermediate
• Stereochemistry of the product is influenced by the reaction conditions and substrate structure