Publisher: National Key Laboratory of Bioactive Molecules and Drug Optimization  

Date: January 24, 2025

A research team led by Ye Wencai, Wang Ying, and Hu Lijun from the College of Pharmacy has successfully completed the total synthesis of a new class of alkaloids, secupyritines A-C, utilizing an innovative synthesis strategy based on biogenic building blocks. This significant achievement was published in Angewandte Chemie International Edition (DOI: 10.1002/anie.202423900).

Background

Plants are remarkable natural chemical reactors, capable of synthesizing complex natural products from limited biogenic blocks. In previous work, the team developed a synthesis strategy that integrates systematic chemical composition studies, biosynthetic pathway analysis, and biogenic block evaluation. This approach was first reported in 2023, demonstrating its effectiveness in the cluster synthesis of active natural products, particularly triphenylphenols from various medicinal plants in the Rosaceae family.

Key Findings

The recent research focuses on the total synthesis of secupyritines A-C, unique polycyclic Securinega alkaloids isolated from the medicinal plant Flueggea suffruticosa. These alkaloids are characterized by a distinctive pentacyclic ring system featuring a highly strained 2-oxa-6-aza[4.4.3]propellane core.

1. Synthesis Strategy: The team employed their biogenetic building block strategy, achieving the total synthesis of secupyritines A-C in 14 to 16 steps. This method showcases high efficiency, simplicity, and diversity in synthetic pathways.

2. Synthetic Procedures: Key reactions involved in the synthesis include:

   - Vinylogous Mannich-type Reaction: Used to construct the sp3-sp2 attached ring system.

   - Suzuki Coupling Reaction: Employed to form the piperidine ring.

   - Intramolecular Aza-Michael Addition Reaction: Established the propellane skeleton.

3. Structure Elucidation: The absolute configurations of secupyritines A-C were determined using a combination of nuclear magnetic resonance (NMR) spectroscopy, single-crystal X-ray crystallography, and electronic circular dichroism (ECD) calculations.

4. Asymmetric Synthesis: The research also presents a formal asymmetric synthesis of the secupyritines, adding to the complexity and significance of the findings.

Conclusion

This breakthrough in the total synthesis of secupyritines A-C not only highlights the team's innovative approach to natural product synthesis but also contributes valuable insights into the synthesis of complex alkaloids. Doctoral students Qin Guanqiu and Dr. Wang Guiyang are co-first authors of the published paper, which underscores the collaborative efforts within the research group.

For further details, access the full paper here: Angew Chem Int Ed

(https://doi.org/10.1002/anie.202423900).