Asymmetric Synthesis of Four Stereoisomers of 2,2-Dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane from Ageratina grandifolia and Plausible Absolute Stereochemistry of the Natural Product

Abstract

2,2-Dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane is a natural product isolated from Ageratina grandifolia that exhibits inhibitory activity against yeast α-glucosidase. Initially, its structure was proposed to be 4-hydroxy-3-((S)-1'-angeloyloxy-(R)-2',3'-epoxy-3'-methyl)butylacetophenone with an epoxide, but the structure was later revised to 2,2-dimethyl-3R-hydroxy-4S-(1-angeloyloxy)-6-acetylchromane. In this study, we present a total synthesis of 2,2-dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane from A. gradifolia and its stereoisomers. The key features of their synthesis include Sharpless asymmetric dihydroxylation of a readily available benzopyran substrate and subsequent Mitsunobu or Steglich reaction to provide both cis- and trans-isomers with chiral control. The absolute stereochemistry of the natural product was determined to be 2,2-dimethyl-3S-hydroxy-4R-(1'-angeloyloxy)-6-acetylchromane based on optical rotations of the synthesized compounds. The absolute configuration of the synthesized stereoisomers was confirmed by Mosher ester analysis. In addition, we provided ECD spectra for the four stereoisomers, which will allow verification of the absolute configuration of the natural product. Synthesis of all four stereoisomers of 2,2-dimethyl-3-hydroxy-4-(1'-angeloyloxy)-6-acetylchromane would facilitate the exploration of their potential biomedical applications.