A Direct Route to Habiterpenol Synthesis Using Anticopalic Acid as a Chiral Pool Template

The concise total synthesis of habiterpenol utilizing the highly abundant natural product, anticopalic acid, as a chiral pool starting material is presented. The synthesis was completed in 10 steps with a 17.3% overall yield. DFT calculations to interpret reaction outcomes and cancer chemopreventive properties of habiterpenol and related pentacyclic derivatives are also reported in this study.

Abstract

The concise total synthesis of habiterpenol utilizing the highly abundant natural product, anticopalic acid, as a chiral pool starting material is presented in this work. The key synthetic transformations involved the acid-induced cyclization of the bicyclic anticopalic acid to directly construct the C-ring of the habiterpenol framework and the aromatic Nazarov cyclization to afford the pentacyclic ring-fused indane core structure. The synthesis was completed in 10 steps with an overall yield of 17.3%. All carbon atoms present in anticopalic acid were incorporated into the habiterpenol structure, highlighting the atom economy of this synthesis. Density functional theory (DFT) calculations were performed to gain insight into and explain specific reaction outcomes. Additionally, various assays were conducted to evaluate the chemopreventive properties of habiterpenol and related pentacyclic derivatives, providing new biological insights into these compounds. This study demonstrates the effectiveness of the chiral pool approach, using a high-abundance natural product as a starting material to access a low-abundance natural product valuable for biological activity exploration. The potential application of this strategy to the total synthesis of similar terpenoid scaffolds offers valuable opportunities for medicinal chemistry and drug development.

Zum Volltext