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. Stereochemistry 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. It has been postulated that the difference in the formation of these transition states and their corresponding products is due to solvent interactions. Scanio found that changing the solvent of the reaction from dioxane to DMSO gives different stereochemistry in step D above. This suggests that the presence of protic or aprotic solvents gives rise to different transition states. Mechanistic classification Robinson annulation is one notable example of a wider class of chemical transformations termed Tandem Michael-aldol reactions, that sequentially combine Michael addition and aldol reaction into a single reaction. As is the case with Robinson annulation, Michael addition usually happens first to tether the two reactants together, then aldol reaction proceeds intramolecularly to generate the ring system in the product. Usually five- or six-membered rings are generated. Scope and variations Reaction conditions Although the Robinson annulation is generally conducted under basic conditions, reactions have been conducted under a variety of conditions. Heathcock and Ellis report similar results to the base-catalyzed method using sulfuric acid. The Michael reaction can occur under neutral conditions through an enamine. A Mannich base can be heated in the presence of the ketone to produce the Michael adduct. Successful preparation of compounds using the Robinson annulation methods have been reported. The Michael acceptor A typical Michael acceptor is an α,β-unsaturated ketone, although aldehydes and acid derivatives work as well. In addition, Bergmann et al. reports that donors such as nitriles, nitro compounds, sulfones and certain hydrocarbons