Intramolecular aldol condensation is between two aldehyde groups or ketone groups in the same molecule. Five- or six-membered , -unsaturated ketone or aldehydes are formed as products. This reaction is an important approach to the formation of carbon-carbon bonds in organic molecules containing ring systems. As an example, under strong basic conditions (e.g. sodium hydroxide), hexane-2,5-dione (compound A in Figure 1) can cyclize via intramolecular aldol reaction to form the 3-methylcyclopent-2-en-1-one (compound B).
The mechanism of the intramolecular aldol reaction involves formation of a key enolate intermediate followed by an intramolecular nucleophilic addition process.
First, hydroxide abstracts the α-hydrogen on a terminal carbon to form the enolate. Next, a nucleophilic attack of the enolate on the other keto group forms a new carbon-carbon bond (red) between carbons 2 and 6. This forms the Adol addition product.
Then, usually under heating conditions, the elimination of water molecule yields the cyclized α,β-unsaturated ketone, the aldol condensation product.
Intramolecular aldol reactions have been widely used in total syntheses of various natural products, especially alkaloids and steroids. An example is the application of an intramolecular aldol reaction in the ring closure step for total synthesis of (+)-Wortmannin by Shigehisa, et al. (Figure 2).