macrolactonization

Macrolactonization is the chemical process of forming a macrolactone, a large-ring ester, by cyclizing a molecule that contains both a carboxyl group and a proximal hydroxyl group. The reaction closes a macrocycle and creates the characteristic ester linkage that defines macrolides and related large-ring lactones. It is a central step in the synthesis of many natural products and in the construction of complex macrocyclic architectures.

Most macrolactonizations rely on activating the carboxyl moiety to promote intramolecular attack by an alcohol. Classical approaches include carbodiimide-mediated dehydrations, often in the presence of additives such as DMAP or HOBt, under high-dilution conditions to minimize intermolecular ester formation. The Yamaguchi method is a notable example, using a 2,4,6-trichlorobenzoyl mixed anhydride activation followed by intramolecular esterification to deliver the macrolactone.

In recent years, alternative activation strategies have enhanced scope and tolerance. The Shiina method employs an activated anhydride such as MNBA (2-methyl-6-nitrobenzoic anhydride) with a catalytic base, enabling milder, more selective macrolactonizations for sensitive substrates. The Mitsunobu approach can also be used to effect intramolecular esterification, often with inversion at the alcohol center, but is less common for very large rings due to stoichiometry and byproducts.

Practical aspects include high-dilution techniques to favor intramolecular over intermolecular reactions, choice of solvent and temperature, and careful handling of sensitive functional groups. Limitations arise from ring-size effects, competing polymerization, and potential epimerization or side reactions. Macrolactonization remains a fundamental tool in the synthesis of macrolide antibiotics, polyketides, and other macrocyclic natural products.