Biocatalysis as a versatile tool for macrolactonization: comparative evaluation of catalytic and stoichiometric approaches†

Abstract

Macrolactonization is a challenging process where high dilution and temperatures can extend reaction times and promote reagent degradation. Biocatalysis is a versatile strategy for synthesis but not traditionally associated within the toolbox of organic chemists for macrocyclization. Macrolactonization has been investigated using modern methods employing both catalysis and stoichiometric activation strategies on 20 different substrates with differing ring sizes and types (cyclophanes, macrolactones, macrodiolides) and structural features at the reaction site (central vs. planar chirality; primary vs. secondary alcohols). The data demonstrates that of all protocols examined, the biocatalytic route was superior, providing the highest average yields across all classes of macrocycles studied. From the stoichiometric activation strategies investigated, the Yamaguchi macrolactonization was the most versatile in terms of ring size and nature. Despite the advantages of biocatalytic macrolactonization, advances in developing supported, versatile non-enantioselective lipases would actually represent a useful tool in molecular synthesis.