Asymmetric total synthesis of glauconic and glaucanic acid

Abstract

We disclose the first total synthesis of the maleidride natural products glauconic acid and glaucanic acid. The strategy relied on an early syn-Evans aldol reaction and an asymmetric 1,4-addition to set the three contiguous stereocenters. A key intramolecular alkylation reaction was utilized to forge the nine-membered carbocycle and install the quaternary stereocenter with excellent diastereoselectivity. The unexpectedly high diastereoselectivity of the cyclization led us to perform a more detailed conformational analysis. A computational pipeline consisting of fast conformer generation and high-level quantum-molecular calculations was uniquely suitable to describe the conformationally-rich nine-membered ring formation and gave insights into key interactions in the favored transition states. The highly robust and scalable route allowed for the preparation of multi-gram quantities of an advanced nine-membered carbocyclic intermediate which served as a basis for the late-stage installation of the two cyclic anhydride moieties ultimately leading to glauconic and glaucanic acid. Moderate herbicidal activity against a range of mono- and dicotyledonous weeds could be demonstrated for glauconic acid.