Yamaguchi esterification

What is Yamaguchi esterification?

The Yamaguchi esterification, also known as the Yamaguchi lactonization or Yamaguchi macrocyclization, is a regioselective synthesis of highly functionalized esters from carboxylic acids and alcohols using 2,4,6-trichlorobenzoyl chloride as the condensation reagent and a stoichiometric amount of 4-N,N-dimethylamino pyridine (DMAP).

Yamaguchi esterification - general reaction scheme - Yamaguchi lactonization - Yamaguchi macrocyclization
Yamaguchi esterification

R, R’ = alkyl, aryl (see list of acronyms)

The Yamaguchi reagent is used to form a mixed anhydride with the carboxylic acid, which is subsequently esterified with DMAP and the alcohol. The reaction is carried out in two steps to ensure the regioselectivity of the ester products due to the steric hindrance at the aromatic counterparts of the mixed anhydride.

The intramolecular version of the Yamaguchi esterification is carried out under highly diluted conditions to form medium-sized lactones, such as solandelactones and halicholactones, and macrolactones, including macrolides. The formation of macrolactones under the Yamaguchi condition is called the Yamaguchi macrocyclization or Yamaguchi’s macrocyclization.

Different results may be obtained at various temperatures and with a different order of mixing reactants due to the high reactivity of the mixed anhydride, which is thermally unstable.

It is suggested that the Yamaguchi esterification can be performed in a one-pot reaction, and an excess amount of DMAP is not necessary. The acyl-pyridinium or triethylammonium salt of 2,4,6-trichlorobenzoyl chloride reacts differently from an unhindered acyl chloride, and the former salt does not react with the Yamaguchi reagent to form the anhydride due to steric hindrance.