Robinson Annulation

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Chapter: Organic Chemistry : Planning Organic Syntheses

Another example of a very common ring-forming sequence is the Robinson annulation. This sequence allows a six-membered ring to be appended to an existing carbonyl group.


ROBINSON ANNULATION

Another example of a very common ring-forming sequence is the Robinson annulation. This sequence allows a six-membered ring to be appended to an existing carbonyl group.


The strategy of the sequence is a Michael addition to an α,β-unsaturated ketone followed by an intramolecular aldol reaction. Treatment of a ketone enolate with a Michael acceptor gives a diketone intermediate which is poised to produce a six-membered ring if an enolate is produced and it intramolecularly adds to the carbonyl group.


This process nicely accounts for formation of product, but if we consider intermediate I, we see that there are several different α protons that could be removed by base, Ha , Hb , and Hc . Furthermore the acidities of these various α protons should be comparable so all should be removed to similar extents under the reaction conditions. If we sequentially remove each proton and write the product from an intramolecular carbonyl addition, the following products could be produced. The fact is that only P is produced to any extent. This is due to the preference of six-membered ring formation over the formation of the more strained four-membered ring product or the more strained bridged product. Thus the enolate formed by the removal of Ha closes faster than the enolates formed by removal of Hb or Hc .


Furthermore, since the aldol reaction is reversible, if any of these higher energy products were formed, they could open back up under the reaction conditions. The exclusive formation of P is an example of kinetic as well as thermodynamic control as the more stable product is formed fastest.

For the purposes of retrosynthetic analysis, a six-membered ring in a target can be related to a Robinson annulation of an existing ketone with an α,β-unsaturated ketone. Normally α,β-unsaturated methyl ketones are used to facilitate the ring closure, but this is not an absolute requirement. Thus the target steroid S could potentially be constructed by a series of Robinson annulations as shown. The last retrosynthetic step (the first synthetic step) could be problematic as a mixture of regioisomers would be formed.


Furthermore the bicyclic starting material could also be constructed by a Robinson annulation on a cyclopentanedione. In this case the final functionality must be achieved by selective reductions of the olefin and ketone functions at appropriate stages in the synthesis.


A great many complex multicyclic targets have been synthesized by the Robinson annulation attesting to its generality and versatility.

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