Total Synthesis of Diterpene (?)-Aspewentin A via a Michael/Aldol Cascade

Abstract

Diverse natural product carbocycles and heterocycles are continuously of interest to the biochemical, synthetic, and medicinal communities. The biosynthetic pathways that lead to structurally diverse diterpenes, and other natural products, involve genes that are both highly conserved and mutable in their characteristic. These properties help ensure that healthy ecosystems continue generating novel complex molecules with diverse biological activity. Many synthetic approaches towards these natural products have been described, however, as known structural diversity in nature increases so does the need for novel methods to access the relevant structural analogues. The total synthesis of (±)-aspewentin A via a tandem Michael-aldol reaction approach has been developed and described herein. The key Michael reaction can be accomplished using copper (II)-catalysis of a ketoester and enone to provide an aldol substrate needed for a key carbocyclization to yield a desired complex intermediate. The first chapter will introduce the broad relevance of natural products to medicine and society. Then, tricyclic diterpene natural products that have been described and feature the fused bicyclic scaffold related to isopimaranes will be highlighted. Numerous syntheses that together encapsulate the breadth of synthetic approaches to access the isopimarane-like bioactive scaffolds have been organized and presented herein. Synthetic approaches may mimic natural biosynthesis or be derived from de novo approaches in synthetic connectivity. In the second chapter, the accepted biosynthetic pathway leading to (±)-aspewentin A is presented beginning from common metabolites. A precedent total synthesis will be introduced before the introduction of the novel, concise synthetic approach developed herein. The failed synthetic strategies that provided unexpected, but often in synthetically interesting, carbocycles have also been presented. In the third chapter, the synthetic developments for the Cu(II)-Michael process implementing gem-dimethyl donors, that rapidly enable the formation of a highly congested intermediate are described. Synthetic access to these hindered intermediates enable the concise total synthesis of (±)-aspewentin A.