Total Syntheses of Shizukaols A and E

Today, biologically active natural products act as starting points for drug discovery and potential sources of new medicines, along with being critical tools to learn about biologically important processes.
Published in Chemistry
Total Syntheses of Shizukaols A and E

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Unfortunately, the potential natural product is only found in very low quantities in nature, so that supplies, with which to carry out a full physiological and biological assessment, are very scarce; if potential leads or drugs of these natural products were found to be effective, the lack of availability and scalability would be a significant impediment to their further development and evaluation in drug discovery. Therefore, chemical synthesis can solve the supply problem by synthesis of quantities of natural product and analogs in a more efficient manner. Furthermore, the chemical synthesis allows verification of the primary structure proposed on the basis of studies of natural product and biomimetic analogs, and it presents opportunities for modifying their structures, with the ultimate aim of improving activity or the physicochemical/biological properties of these lead molecules, which would also allow us to have a better understanding of their biological action and biogenetic synthetic approach. Due to the biological importance, low natural abundance, and structural complexity of many bioactive natural products and their analogs, consequently, the discovery of simpler bioactive analogs and total synthesis are of high demand to facilitate the discovery of novel bioactive small molecules for the further bio-evaluations from natural product chemistry.

Shizukaols possess a common heptacyclic framework containing more than 10 contiguous stereocenters and potential biological activities. On basis of our preliminary investigations and relevant biogenetic hypothesis, we synthesized more suitable precusors, being at least biogenetically much closer to components for further transformation. Moreover, our preliminary investigation proved that the late stage conversion of the epoxy unit to the hydroxyl ketoester unit of shizukaols A and E, a common framework of the dimeric family members, is a more step-economic strategy for total syntheses. After great efforts and hard work of our coworkers, eventually, we have achieved the total syntheses of shizukaols A and E through mimicking the modified biogenetic pathway, including a modified biomimetic Diels-Alder reaction and biogenetic transformation of epoxy unit to the common hydroxyl ketoester species of the shizukaol family. This synthetic approach opens up practical avenues for the total syntheses of the intriguing Chloranthaceae family members, as well as the understanding of their relevant biological action in nature. A full story of this work can be found in:

Last but not least, we would like to express our sincere gratitude for Professor Henry N. C. Wong’s invaluable comments on this project and great contribution to the development of Organic Chemistry in China on the occasion of his retirement from the Chinese University of Hong Kong after a career over a span of 35 years.

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