Researchers at Busan National University have successfully controlled the positional selectivity of the 'aryne reaction,' known for its high reactivity, to achieve the total synthesis of complex natural products derived from the polyphenol resveratrol found in grapes and wine.
On August 20, the university announced that a research team led by Professor Yoon Hwa-young from the Department of Pharmacy has successfully synthesized laetevirenol A and isoampelopsin D, both natural products derived from resveratrol.
Total synthesis refers to the complete creation of complex natural products starting from basic precursor materials through a series of chemical reactions.
The aryne reaction is an organic chemistry process that generates a highly reactive intermediate between two adjacent carbons in an aromatic ring, forming new bonds. Its high reactivity has made it challenging to control the formation of bonds at desired locations.
Natural products derived from resveratrol have attracted attention due to their diverse structures and potential medicinal applications, but their complex structures have made it difficult to synthesize them in desired forms or obtain various derivatives. Laetevirenol A, in particular, is noted for its complex structure as a resveratrol dimer with a phenanthrene skeleton formed by three bent benzene rings, making it a challenging natural product to synthesize.
The research team compared the reactivity of aryne with various substituents and confirmed that using specific halogen-substituted aryne allows for the preferential formation of products at desired positions. Based on this, they constructed the phenanthrene skeleton and completed the total synthesis of laetevirenol A in nine steps from commercially available starting materials. For isoampelopsin D, they controlled the positional selectivity of the aryne-ene reaction to synthesize the target structure.
The study was conducted with Professor Yoon Hwa-young as the corresponding author and Nguyen Huong as the first author, with contributions from Professor Lee Seok-woo of Chungnam National University, Professor Kim Yeon-jun of Pukyong National University, and Professor Jeong Gi-woong of Busan National University.
The research teams from Chungnam National University and Pukyong National University conducted computational chemical analyses to investigate the reasons behind the controlled positional selectivity. They found that the reaction pathways and the stability of transition states vary depending on the substituents introduced to the aryne, and these differences influence the positional selectivity of the final products.
The distortion energy of molecular structures and intermolecular interactions occurring at the transition state were identified as key variables.
Professor Jeong Gi-woong's team at Busan National University evaluated the biological activity of the derivatives obtained during the total synthesis process and found that most of the synthesized derivatives exhibited significant antioxidant activity, with some showing higher activity than the natural product itself.
However, the research team clarified that the core achievement of this study lies not in proving the efficacy of new substances but in the advancement of synthetic techniques for creating complex compounds.
Professor Yoon Hwa-young stated, "The antioxidant data is an additional result confirming the potential for various derivatives during the synthesis process," adding, "The main academic significance of this paper is establishing methodologies for controlling challenging chemical reactions."
He emphasized that the essence of the research is to lay the groundwork for freely creating these derivatives rather than focusing solely on the antioxidant effects of specific substances.
Professor Yoon further highlighted, "This research successfully applied the established positional selectivity of the highly reactive aryne in the total synthesis of complex natural products, and I expect that the methodologies developed will serve as a crucial foundation for future synthesis research of various natural products and derivatives using aryne, as well as exploring new medicinal applications."
This research, supported by the Ministry of Science and ICT's research and development project, was published in the online edition of the Journal of the American Chemical Society (JACS) on August 4.
* This article has been translated by AI.
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