Yamaguchi esterification

The Yamaguchi method, also referred to as Yamaguchi cyclization Yamaguchi or esterification, is a name of reaction in organic chemistry. It is used for the production of macrolides (also macrolactones ) from readily available hydroxycarboxylic acids. Macrolides have a variety of applications, such as macrolide antibiotics or antifungals. The reaction of the hydroxycarboxylic acid with 2,4,6- trichlorobenzoyl chloride in the presence of a stoichiometric amount leads to an intermediate of DMAP which performs the elimination of 2,4,6- trichlorobenzoic acid intramolecular ring closure to give the final product; the method was discovered by Masaru Yamaguchi and co-workers.

Mechanism

The acid group is deprotonated by triethylamine. In a nucleophilic substitution reaction, the activated ω -hydroxycarboxylic now attacks the acid chloride of 2,4,6- trichlorobenzoic. In the reaction is formed on the tetrahedral intermediate mixed anhydride. The case liberated chloride is bound by triethylammonium formation of triethylammonium chloride.

The addition of DMAP to the carbonyl group of the sterically unhindered anhydride effects the cleavage of benzoic acid as a byproduct. The hydroxy group of the reactant nucleophilic attack on the heavily positivised carbon of the original acid group of the compound. The ring closure to the lactone ( lactonization ) with elimination of catalytic DMAP used.

Application

The macrolactonization is an important step in the synthesis of many natural products or synthetic macrolides, which are used as drugs. A practical example is to be found in the synthesis of the cancer drug epothilone A.