General Enantioselective and Stereochemically Divergent Four-Stage Approach to Fused Tetracyclic Terpenoid Systems.

Abstract

Tetracyclic terpenoid-derived natural products are a broad class of medically relevant agents that include well-known steroid hormones and related structures, as well as more synthetically challenging congeners such as limonoids, cardenolides, lanostanes, and cucurbitanes, among others. These structurally related compound classes present synthetically disparate challenges based, in part, on the position and stereochemistry of the numerous quaternary carbon centers that are common to their tetracyclic skeletons. While de novo syntheses of such targets have been a topic of great interest for over 50 years, semisynthesis is often how synthetic variants of these natural products are explored as biologically relevant materials and how such agents are further matured as therapeutics. Here, focus was directed at establishing an efficient, stereoselective, and molecularly flexible de novo synthetic approach that could offer what semisynthetic approaches do not. In short, a unified strategy to access common molecular features of these natural product families is described that proceeds in four stages: (1) conversion of epichlorohydrin to stereodefined enynes, (2) metallacycle-mediated annulative cross-coupling to generate highly substituted hydrindanes, (3) tetracycle formation by stereoselective forging of the C9-C10 bond, and (4) group-selective oxidative rearrangement that repositions a quaternary center from C9 to C10. These studies have defined the structural features required for highly stereoselective C9-C10 bond formation and document the generality of this four-stage synthetic strategy to access a range of unique stereodefined systems, many of which bear stereochemistry/substitution/functionality not readily accessible from semisynthesis.