Divergent Synthetic Approach to Grayanane Diterpenoids

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Grayanane diterpenoids are a class of natural products with complex structures.
• These compounds exhibit a wide range of biological activities.
• Previous synthetic efforts have been limited in scope and efficiency.

Purpose of the Study:

• To develop a divergent synthetic strategy for accessing diverse grayanane diterpenoids.
• To achieve the total synthesis of nine grayanane diterpenoids, including six novel compounds.
• To elucidate the biosynthetic relationships between different grayanane skeletons.

Main Methods:

• Oxidative dearomatization-induced [5 + 2] cycloaddition/pinacol rearrangement cascade for CD ring assembly.
• Photosantonin rearrangement for constructing the 5/7 bicycle (AB rings) of 1-epi-grayanoids.
• Grob fragmentation/carbonyl-ene process for accessing additional grayanane skeletons.

Main Results:

• Total synthesis of nine grayanane diterpenoids (GTX-II, GTX-III, rhodojaponin III, GTX-XV, principinol D, iso-GTX-II, 1,5-seco-GTX-Δ1,10-ene, leucothols B and D) achieved.
• Six of the synthesized compounds represent the first reported total syntheses.
• The divergent approach successfully generated five distinct grayanane subtypes.
• Density functional theory calculations provided mechanistic insights into key transformations.

Conclusions:

• A concise and divergent synthetic strategy was established for grayanane diterpenoids.
• The methodology allows for the efficient construction of complex grayanane skeletons.
• The study provides valuable insights into the biosynthesis of these natural products.