Terpenoid Synthesis via Convergent Radical Annulation.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Natural Product Synthesis

Background:

• Terpenoids are complex natural products with diverse biological activities.
• Efficient synthetic routes to complex terpenoid scaffolds remain a challenge in organic chemistry.

Purpose of the Study:

• To develop a convergent radical annulation strategy for synthesizing complex terpenoids.
• To showcase the utility of this strategy through the synthesis of serratene and cyclodammarane scaffolds.

Main Methods:

• Utilized a 1,3-diradical synthon for C-ring annulation via radical couplings.
• Employed rapid alternating polarity (rAP) Kolbe electrolysis for onoceradiene assembly.
• Developed a Co-electrocatalytic metal-catalyzed hydrogen atom transfer (MHAT) for 7-endo-trig cycloisomerization.
• Applied a tandem Fe-mediated reductive olefin coupling/enolate alkylation cascade for propellane motif construction.

Main Results:

• Achieved concise syntheses of serratene and cyclodammarane scaffolds from a common intermediate.
• Demonstrated the first Co-electrocatalytic MHAT 7-endo-trig cycloisomerization to form the serratene core.
• Reported an unprecedented tandem cascade for constructing the cyclodammarane propellane motif with high diastereocontrol.
• Completed syntheses in 5-9 steps, maximizing skeletal bond-forming efficiency.

Conclusions:

• The developed radical annulation strategy offers an efficient and versatile approach to complex terpenoids.
• Highlighted the power of radical-based disconnections and cascade reactions in simplifying challenging syntheses.
• The methodology provides access to unique terpenoid skeletons with potential applications in medicinal chemistry.