Total Synthesis of (-)-Glaucocalyxin A
Jiuzhou Guo1, Bo Li1, Weihao Ma1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing, 100191, China.
Angewandte Chemie (International Ed. in English)
|May 20, 2020
Summary
A new manganese(III)-mediated radical cyclization method efficiently forms highly oxygenated bicyclo[3.2.1]octane systems. This breakthrough enabled the first total synthesis of the complex natural product (-)-glaucocalyxin A.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Natural Product Synthesis
Background:
- The bicyclo[3.2.1]octane core is a key structural motif found in numerous biologically active natural products, particularly highly oxidized diterpenoids.
- Developing efficient synthetic routes to access these complex oxygenated frameworks remains a significant challenge in organic synthesis.
Purpose of the Study:
- To develop a novel and practical method for constructing the highly oxygenated bicyclo[3.2.1]octane ring system.
- To apply this new methodology towards the total synthesis of (-)-glaucocalyxin A, a representative highly oxidized diterpenoid.
Main Methods:
- Manganese(III) acetate-mediated radical cyclization of alkynyl ketones was employed as the key step for forming the bicyclo[3.2.1]octane core.
- The synthesis also incorporated a highly enantioselective conjugate addition/acylation cascade, a Yamamoto aldol reaction, and an intramolecular Diels-Alder reaction for assembling the molecular framework.
Main Results:
- A practical and efficient method for the formation of the target bicyclo[3.2.1]octane system was successfully developed.
- The first total synthesis of (-)-glaucocalyxin A was achieved, demonstrating the utility of the developed methodology.
- The synthetic strategy effectively integrated multiple complex reactions to build the intricate structure of the natural product.
Conclusions:
- The developed Mn(OAc)3-mediated radical cyclization provides a new and valuable approach for synthesizing highly oxygenated bicyclo[3.2.1]octane derivatives.
- This methodology significantly advances the total synthesis of complex diterpenoids, exemplified by the successful synthesis of (-)-glaucocalyxin A.
- The synthetic route highlights the power of combining cascade reactions and cycloadditions for efficient construction of intricate natural product architectures.
