Lignans are plant-based natural substances with complex ring-shaped structures that serve as defence substances in many species. Furofuran lignans, which contain a characteristic bicyclic ring system, are particularly significant. The plant Phryma leptostachya contains numerous representatives of this class of substances, including the chemically sophisticated and biologically highly active haedoxanes and phrymarolines. Phrymarolines and related natural substances exhibit antibacterial and antiviral effects, for example against the tobacco mosaic virus. In addition, some representatives act as highly potent insecticides even in very low concentrations. Particularly noteworthy is haedoxane A, a trimeric lignan with exceptional activity against pests such as Culex pipiens, Musca domestica and the fall armyworm (Mythimna separata). Studies show that Haedoxan A is even more effective than the commercial insecticide indoxacarb – possibly due to a previously unknown mechanism of action. However, the natural yield is extremely low: in 1989, only 83 milligrams of the substance could be isolated from 36 kilograms of root material. Magauer emphasises the fundamental value of these natural substances: ‘Bio-inspired strategies not only enable efficient synthesis routes, but also open up great innovation potential for follow-up projects.’
Bio-inspired synthesis as the key to sustainable solutions
In order to make the promising molecules available in relevant quantities, the working group developed a strategy based on biosynthesis. Both the characteristic furofuran core and the 1,4-benzodioxane system were constructed via cyclisations modelled on natural processes. This made it possible to produce haedoxane A and haedoxane D in just 13 steps, an exceptionally short synthesis sequence for such complex natural substances. The project was developed in close collaboration with an agrochemical industry partner. For Magauer, this exchange is crucial: ‘Long-standing collaboration with industrial partners strengthens our own research and at the same time promotes the development of ideas within the working group.’ At the same time, the collaboration opens up valuable perspectives for students and young researchers: ‘Direct exchange with the chemical industry offers exciting insights into research and development beyond basic research, highlights current challenges at an early stage and optimally prepares the participating young scientists for their future careers.’ The new synthesis route not only enables a better understanding of natural biosynthesis, but also lays the foundation for the development of highly effective natural product analogues. The research thus makes an important contribution to more effective and sustainable strategies in plant protection, an urgent concern in view of globally increasing resistance and the need for more environmentally friendly active ingredients.
Publication: Unified Total Synthesis of Phrymarolin and Haedoxan Natural Products. Paciorek, Jan; Guy, Antoine; Sudau, Alexander; Barber, David; Magauer, Thomas. Journal of the American Chemical Society
Link to Thomas Magauer's working group: Magauer Laboratory
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