Lipase-catalyzed macrocyclization of heteroatom-linked diaryl compounds

Heteroatom-linked diaryl compounds are important structural motifs found in numerous biologically active molecules. Their macrocyclic counterparts, such as Pacritinib and Combretastatin D-2, have demonstrated promising anticancer activity.^1,2 Lipases are versatile biocatalysts widely employed in organic synthesis because of their remarkable enzymatic promiscuity. These enzymes have been shown to efficiently catalyze macrocyclization reactions and can therefore be applied to the synthesis of diaryl macrocycles through esterification processes.³ Herein, we report a series of heteroatom-linked diaryl macrocycles synthesized via a lipase-catalyzed esterification strategy. We further investigate the key factors influencing the efficiency of the macrocyclization process, including the diacid chain length, the nature of the diaryl linker, and the steric effects of bulky aryl substituents. A clear trend was observed in which longer diacid chain lengths favored macrocycle formation over dimerization. Sulfone linkers proved to be the most effective, and when combined with phenyl substituents, the macrocycle was obtained in quantitative yield.