Synthesis of the Spirocyclic Framework of Sesterterpenoid Natural Products

Abstract

A convergent synthetic route to the sesterterpenoid framework of the bioactive phorbaketal and alotaketal natural product families has been established. The synthetic approach hinges on a Hosomi-Sakurai coupling of complex acetal and allylsilane coupling partners, followed by DDQ-promoted oxidative cyclization of highly unsaturated advanced intermediates. This robust synthetic approach enables further investigations into the members of these natural product families and readily provides access to analogues for biological testing.

Unified Asymmetric Total Syntheses of (−)‐Alotaketals A–D and (−)‐Phorbaketal A

“…The groups of Yang, and Dalby accomplished the elegant total synthesis of 1 by similar strategies, which involved late‐stage construction of the C ring through a Barbier‐type reaction and spiroketalization. Recently, the groups of Brimble and Bray disclosed two efficient strategies for the tricyclic spiroketal core, which unfortunately could not be elaborated to the natural products. It remains an unmet challenge to synthesize two or more members of this family, using reported strategies which cannot create the structural variations at both the C ring and the side chains.…”

Synthetic applications of hydride abstraction reactions by organic oxidants

“…Hubert and co-workers provided an excellent example of this in their studies on sesterterpenoid spiroketals (Scheme 29). 87 This process employed the conversion of dihydropyran 144 to oxocarbenium ion 145 . The pendent alcohol nucleophile coupled with this electrophile to form spiroketal 146 with complete stereocontrol.…”

Collective Syntheses of Eight Phorbaketals via Total Synthesis of Phorbaketal A

“…Thus, with the accumulated knowledge of reactivities of synthetic intermediates during the total synthesis of both natural products, we envisioned that direct transformation of alotaketal A into phorbaketal A via isomerization of two‐exo‐olefins of alotaketal A to corresponding trisubstituted olefins of phorbaketal A (Table 1) could be possible, though challenging [4d,g] and tricky, [4c] as there are many reports of olefin isomerizations toward more substituted isomers [5] . Herein, we would like to report an efficient synthesis of phorbaketal A through olefin isomerization and diversification of phorbaketal A into phorbaketal B, D, E, F, H, I, J and M.…”