Versatile and Enantioselective Total Synthesis of Naturally Active Gnetulin

Significance 

The medical field is among the fields attracting great research interests amongst scholars. Because of this, we can boast of an improved health sector owing to advancements in healthcare technology. In the past few decades, natural polyphenols derived from resveratrol and isorhapontigenin have been intensively researched for medical applications owing to their intriguing skeleton and multifaced activities. Considering that the total synthesis of an array of resveratrol oligomers had been previously achieved, researchers have expected to replicate the same approach in the total synthesis of isorhapontigenin oligomers. In particular, gnetulin (an isorhapontigenin dimer) isolated from different plants have exhibited multifaced bioactivities. However, these natural products have not been widely explored despite their highly promising medical potential. Having been recently identified as prime targets for total synthesis, there is a great need to study the total asymmetric synthesis and structural activities of naturally active gnetulin products.

To this note, a joint effort by the Chinese Academy of Medical Sciences and Peking Union Medical College researchers: Changhui Shang, Yulong Kang, Qingyun Yang, Qibin Zhu, and Chunsuo Yao proposed a versatile and highly enantioselective total synthetic approach for gnetulin synthesis. This efficient approach was particularly used in the asymmetric synthesis and investigation of the naturally active oligostilbenes with or without methoxy groups at the aromatic rings. Their research work is currently published in the journal, Advanced Synthesis & Catalysis.

The authors targeted to resolve two main issues in the development of the new enantioselective approach: selection of suitable phenolic hydroxyl group and the selection of appropriate asymmetric catalysts for building two chiral centers. Commercially available materials were used as the starting materials. This strategy is expected to render natural products and natural product-like analogies accessible. Unlike previous work, it was worth noting that all the phenolic hydroxyl groups were protected by benzyl groups rather than methyl groups.

Reports showed successful synthesis of dimers from commercially available achiral materials in 13 steps. An overall yield of 7-9% was achieved with over 98% enantiomeric excess. This is among the highest yield ever to be reported in the literature. This was attributed to some of the key features of the method. They included but not limited to the stereo-controlled enantioselective conjugate reduction of 3-arylindenone catalyzed by methyloxazaborolidine and alpha-arylation of 3-aryl-1-indanones. As such, it was possible to access benzylic sulfide through esterification reaction between benzyl mercaptain and 2,3-diarylindanol.

In summary, the study for the first time reported the use of a versatile method for the enantioselective total synthesis of naturally active gnetulin. In a statement to Advances in Engineering, Dr. Chunsuo Yao noted that this approach offers a practical and efficient route that can be applied in applications such as the enantioselective synthesis of the optical antipodes of natural indane derivatives with or without methoxy groups at aromatic rings. It can as well be extended to synthesis of natural stilbene oligomers with biological activities.

Reference

Shang, C., Kang, Y., Yang, Q., Zhu, Q., & Yao, C. (2019). Versatile and Enantioselective Total Synthesis of Naturally Active Gnetulin. Advanced Synthesis & Catalysis, 361(16), 3768-3776.

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