Question

Show the two (neutral) organic starting materials that would be used to synthesize the following compound via a Robinson Annulation reaction.

Answer 1

Concepts and reason

Retrosynthetic approach: It is a technique used for the synthesis of organic compounds. In this approach, a target molecule is transformed into a simple precursor molecule and each precursor molecule is treated by the same method until the final compound is formed.

Aldol condensation: Aldol condensation is defined as a condensation reaction that involves the nucleophilic addition of an enolate ion to another carbonyl group to form a ${\rm{\beta }} -$ hydroxy ketone or aldehyde. The final product is commonly known as aldol because it contains both an aldehyde group and a hydroxy group of an alcohol.

Michael addition: When the double bond of an ${\rm{\alpha }},{\rm{\beta }} -$ unsaturated carbonyl compound or any other electron-deficient double bond undergoes conjugate addition through carbanion, the reaction is known as Michael addition. An electrophile or an ${\rm{\alpha }},{\rm{\beta }} -$ unsaturated carbonyl compound that accepts a pair of electrons is known as the Michael acceptor. The attacking nucleophile that donates a pair of electrons is known as the Michael donor.

Robinson annulation: The Michael addition of a ketone enolate to an ${\rm{\alpha }},{\rm{\beta }} -$ unsaturated ketone gives ${\rm{\delta }} -$ diketone as a final product. When conjugate addition takes place under strongly acidic or basic conditions, then ${\rm{\delta }} -$ diketone undergoes a spontaneous intramolecular aldol condensation followed by dehydration to form a six-membered ring compound commonly known as cyclohexenone. This synthesis is known as Robinson annulation.

Fundamentals

Robinson annulation is a combination of aldol and Michael reaction followed by cyclization. Robinson annulation makes a new ring in the compound. The retrosynthetic approach of Robinson annulation reaction is shown below:

In the above figure, tri-ketone 2 has $1,3$ and $1,5$ dicarbonyl relationships. The disconnection at $1,3$ position does not remove any carbon atom but $1,5$ position at the branch point forms a symmetrical ${\rm{\beta - diketone}}$ , which is a good conjugate addition.

The target compound can be retro synthetically cleaved to attain the organic starting materials as given below:

The given molecule can be synthesized by using a $\alpha ,\beta$ -unsaturated carbonyl and an active methylene carbonyl compound.

The mechanistic pathway for the synthesis of desired $\alpha ,\beta$ -unsaturated cyclic carbonyl compound is given as follows:

Michael addition:

Aldol condensation :

The overall Robinson annulation can be written as follows.

Ans:

The structures of two organic starting molecules for the given target compound are shown as follows: