Total synthesis of biologically intriguing drimane-type sesquiterpenoids via intramolecular diels–alder approaches

Abstract

The total syntheses of three drimane-type sesquiterpenoids, (–)-mniopetal E, (–)-mniopetal F, and (–)-kuehneromycin A, are described. These natural products inhibit the enzymatic activity of RNA-directed DNA-polymerases (reverse transcriptases) of the human immunodeficiency virus (HIV)-1. Our enantiospecific total syntheses of these target molecules in naturally occurring forms commenced with a known 2,3-anhydro- d -arabinitol derivative, which was prepared using the Sharpless asymmetric epoxidation strategy. A combination of highly stereocontrolled inter- and intramolecular Horner–Emmons carbon elongations led to the two butenolides tethering 1,2,4,9- and 1,4,9-functionalized nona-5,7-diene moieties at the β-carbon. The key step in mniopetal E synthesis is a stereoselective thermal intramolecular Diels–Alder reaction of the former butenolide compound, providing a highly oxygenated tricyclic skeleton with the desired endo and π-facial selections. The intramolecular Diels–Alder reaction of the latter butenolide compound for the syntheses of other two drimanes also proceeded with the desired stereoselectivity, which is controlled by a balance of the steric effect and the stereoelectronic effect of a trialkylsilyloxy substituent existing adjacent to the dienophile in accordance with Cieplak’s theory. The transformation of the γ-lactone moiety in the cycloadducts to the γ-hydroxy-γ-lactone part was efficiently achieved via a tetracyclic intermediate. Our total syntheses of (–)-mniopetal E, (–)-mniopetal F, and (–)-kuehneromycin A established the unsettled absolute stereochemistries of the antibiotics. In addition, the reported total syntheses by Jauch are briefly reviewed.