Robinson annulation

The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds. The method uses a ketone and a methyl vinyl ketone to form an α,β-unsaturated ketone in a cyclohexane ring by a Michael addition followed by an aldol condensation. This procedure is one of the key methods to form fused ring systems. Formation of cyclohexenone and derivatives are important in chemistry for their application to the synthesis of many natural products and other interesting organic compounds such as antibiotics and steroids. Specifically, the synthesis of cortisone is completed through the use of the Robinson annulation. The initial paper on the Robinson annulation was published by William Rapson and Robert Robinson while Rapson studied at Oxford with professor Robinson. Before their work, cyclohexenone syntheses were not derived from the α,β-unsaturated ketone component. Initial approaches coupled the methyl vinyl ketone with a naphthol to give a naphtholoxide, but this procedure was not sufficient to form the desired cyclohexenone. This was attributed to unsuitable conditions of the reaction. Robinson and Rapson found in 1935 that the interaction between cyclohexanone and α,β-unsaturated ketone afforded the desired cyclohexenone. It remains one of the key methods for the construction of six membered ring compounds. Since it is so widely used, there are many aspects of the reaction that have been investigated such as variations of the substrates and reaction conditions as discussed in the scope and variations section. Robert Robinson won the Nobel Prize for Chemistry in 1947 for his contribution to the study of alkaloids. The original procedure of the Robinson annulation begins with the nucleophilic attack of a ketone in a Michael reaction on a vinyl ketone to produce the intermediate Michael adduct. Subsequent aldol type ring closure leads to the keto alcohol, which is then followed by dehydration to produce the annulation product. In the Michael reaction, the ketone is deprotonated by a base to form an enolate nucleophile which attacks the electron acceptor (in red). This acceptor is generally an α,β-unsaturated ketone, although aldehydes, acid derivatives and similar compounds can work as well (see scope). In the example shown here, regioselectivity is dictated by the formation of the thermodynamic enolate. Alternatively, the regioselectivity is often controlled by using a β-diketone or β-ketoester as the enolate component, since deprotonation at the carbon flanked by the carbonyl groups is strongly favored. The intramolecular aldol condensation then takes place in such a way that installs the six-membered ring. In the final product, the three carbon atoms of the α,β-unsaturated system and the carbon α to its carbonyl group make up the four-carbon bridge of the newly installed ring. In order to avoid a reaction between the original enolate and the cyclohexenone product, the initial Michael adduct is often isolated first and then cyclized to give the desired octalone in a separate step. Studies have been completed on the formation of the hydroxy ketones in the Robinson annulation reaction scheme. The trans compound is favored due to antiperiplanar effects of the final aldol condensation in kinetically controlled reactions. It has also been found though that the cyclization can proceed in synclinal orientation. The figure below shows the three possible stereochemical pathways, assuming a chair transition state.