Robinson annulation

Robinson annulation is a comprehensive chemical reaction that combines aspects of both the Michael addition and aldol condensation in a sequential manner to construct complex cyclic structures, specifically cyclohexenones. This reaction is named after Sir Robert Robinson, who first reported it in 1935, making it a cornerstone in the field of organic chemistry for the synthesis of complex, ring-containing molecules, particularly steroids and other cyclic compounds.

Overview

The Robinson annulation begins with a Michael addition, where a nucleophile (often an enolate) attacks an α,β-unsaturated ketone to form a Michael adduct. This is followed by an intramolecular aldol condensation, where the adduct undergoes dehydration to form a new carbon-carbon bond, resulting in the formation of a cyclohexenone ring. The overall process is highly valued for its ability to efficiently build complex molecular architectures from simpler precursors.

Mechanism

The mechanism of the Robinson annulation can be divided into two main steps:

1. Michael Addition: The reaction starts with the deprotonation of a ketone to form an enolate, which then attacks an α,β-unsaturated ketone at the β-carbon, leading to the formation of a Michael adduct.
2. Aldol Condensation: The Michael adduct undergoes an intramolecular aldol condensation. This step involves the nucleophilic attack of the enolate formed from the Michael adduct on the carbonyl group of the same molecule, followed by dehydration to yield the cyclohexenone ring.

Applications

The Robinson annulation has found widespread application in the synthesis of natural products and pharmaceuticals. Its ability to construct complex cyclic structures from simpler components makes it a valuable tool in the synthesis of steroids, terpenes, and other biologically active molecules.

Limitations

Despite its utility, the Robinson annulation has some limitations. The reaction conditions can be harsh, and the reaction may not proceed efficiently if the starting materials are not properly chosen or if steric hindrance is significant. Additionally, controlling the stereochemistry of the reaction can be challenging.

Variants

Several variants of the Robinson annulation have been developed to overcome its limitations, including the use of different catalysts and conditions that allow for milder reaction conditions and better control over stereochemistry.

See Also

• Michael reaction
• Aldol reaction
• Cyclohexenone
• Stereochemistry