Chemoenzymatic synthesis of macrocycles via dynamic kinetic resolution of secondary alcohols

Abstract

Macrolactones are privileged motifs in materials science, aromachemicals and pharmaceuticals. The pivotal ester linkage is often formed from chiral secondary alcohols, with macrolactonization using stoichiometric reagents to ensure retention or inversion of stereochemistry without compromising enantiopurity. An ideal strategy for macrolactonization is via dynamic kinetic resolution (DKR), which involves the simultaneous formation of the ester bond and introduction of a chiral centre with high stereocontrol. Surprisingly, a DKR method within the context of macrocyclization is yet to be reported. Here, using a chemoenzymatic approach, the macrocyclic DKR of seco esters affords enantioenriched macrolactones. An optimized protocol (using Candida antarctica lipase B (~0.04 mol%) and Shvo’s catalyst) forms 14–19-membered macrocycles with excellent enantioselectivities (85–99% e.e.). A variety of macrolactones were synthesized including aliphatic macrocycles, meta- and paracyclophanes as well as a macrodiolide via a dimerization protocol that was converted to the natural product macrolide (−)-pyrenophorin.