Expanding Natural Diversity: Tailored Enrichment of the 8,12-Sesquiterpenoid Lactone Chemical Space through Divergent Synthesis.

The divergent synthesis of a non-natural 8,12-sesquiterpenoid lactone collection is described. The synthesis relies on a rationally designed guaianolide scaffold bearing a tertiary hydroxyl as the pinpoint for inducing its selective diversification. Key reactions include an unprecedented Suarez-type CH lactonization and a highly diastereoselective oxy-Cope/ene cascade that allows the introduction of three stereocenters in a single operation. Selective oxidative/reductive and redox neutral transformations follow to highlight the synthesis of naturally unpresented highly substituted 8,12-guaianolides.

Combining the best of both worlds: radical-based divergent total synthesis.

A mature science, combining the art of the total synthesis of complex natural structures and the practicality of delivering highly diverged lead compounds for biological screening, is the constant aim of the organic chemistry community. Delivering natural lead compounds became easier during the last two decades, with the evolution of green chemistry and the concepts of atom economy and protecting-group-free synthesis dominating the field of total synthesis. In this new era, total synthesis is moving towards natural efficacy by utilizing both the biosynthetic knowledge of divergent synthesis and the latest developments in radical chemistry. This contemporary review highlights recent total syntheses that incorporate the best of both worlds.

Short Scalable Route to Apiaceae Sesquiterpene Scaffolds: Total Synthesis of 4-epi-Epiguaidiol A.

The oxy-Cope/ene reaction cascade to form a locked elemane conformer allows the short scalable synthesis of versatile Apiaceae scaffolds. The divergent fate of the obtained macrocyclic germacrane is surveyed under cationic and dioxygen-induced Prins-type reaction conditions to allow the diastereoselective synthesis of oxidized Apiaceae guaiane congeners and the total synthesis of 4-epi-epiguaidiol A. Additionally, the unprecedented reduction of a hydrogen-bond-biased guaiane substrate permits the chemoselective synthesis of desoxo-jungiaguaiane.

A multifunctional divergent scaffold to access the formal syntheses of various sesquiterpenoids.

The development of a divergent scaffold able to access an array of diverse natural sesquiterpenoids is described. The route unifies the scope of previously reported plans of our group to allow the scalable synthesis of 8,12-furo and lactone sesquiterpenoid carbocyclic cores of elemanes, germacranes, guaianes, cadinanes, lindenanes and myliols. The formal syntheses of furogermenone, methyl-curdionolide, zedoarol, qweicurculactone, lindenene and sarcandralactone A are reported.