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On October 24, 2022, Jia Yanxing's team from the State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmacy, Peking University, was published in the internationally renowned journal Journal of the American Chemical Society The latest research results in the field of total synthesis of natural products, "Total Synthesis of (?).
- Principinol C" (natural product (? - Total synthesis of Principinol C).
Natural products have always been an important source of drug discovery, but due to the low natural content of many natural products, difficult isolation and extraction and other factors limit their subsequent activity research, how to achieve a large number of active natural products synthesis has always been an important scientific problem
to be solved.
In recent years, with the increasing attention of scientists to the field of total synthesis of natural products, the total synthesis of many natural products has been realized
.
The intramolecular Pauson-Khand reaction has been widely used in the construction of cyclopentenone structures of natural products, and the general 5/5 and 6/5 bicyclic backbones can be efficiently synthesized from the corresponding alkyne compounds, but 7/5 by the corresponding enyne compounds The bicyclic framework has not yet been used in
the total synthesis of natural products.
Natural products of Xylopodium have good biological activities, such as cardiotoxicity, neurotoxicity, analgesia, sedation and inhibition of protein tyrosine phosphatase 1B caused by sodium ion channel regulation, which have always been the focus
of synthetic chemists.
Among them, natural products (? Principinol C is a diterpene compound isolated by Hou Aijun's team at Fudan University in 2014 from aerial plants in southern Tibet, China, and its biological activity has not been extensively studied
due to insufficient isolation yield.
This natural product has a unique and novel 5/7/6/5 four-ring backbone, which also includes a [3.
2.
1] bridge ring skeleton and 8 consecutive chiral centers, four chiral hydroxyl groups and a carbonyl group, which is extremely challenging
to synthesize.
After ingenious design, Jia Yanxing's team started from the team's existing bridge ring compound fragment 1 and completed the construction of the correct configuration hydroxyl group at the C-14 position through the Cascade reduction/aldol/retro-aldol reaction
。 After selectively guiding epoxidation to obtain compound 4, the authors boldly selected the retention of epoxy groups through steric hindrance regulation, and retained epoxy functional groups by conditional screening in a total of 10 linear steps
.
After several steps of highly stereoselective reaction, the side chain was extended, and the 7,5 bicyclic backbone was constructed with the first intramolecular Pauson-Khand reaction of the alkyne as the key reaction, and the natural product ( ? - Construction of the core skeleton of Principinol C"5/7/6/5
.
After late oxidation state adjustment and removal of protective groups, the first asymmetric total synthesis
of this natural product 7 was realized.
The total yield of this synthetic route is 1.
8%, which is much higher than the total synthetic yield of similar natural products before, and the synthesis step is shorter, only 16 steps from the known bridge ring compound, and the team finally obtained a chiral natural product of 20mg.
Lay the foundation for
further research on its biological activity.
At the same time, it also provides an efficient loop construction method for the skeleton construction of similar natural products, and the diversified synthesis of such natural products is also carried out
by the team.
Dr.
Tianhao Ma and Dr.
Hao Cheng of Peking University are co-first authors
of the paper.
This work was supported by the National Natural Science Foundation of China and the Peking University-Baidu Foundation
.
Link to paper: https://doi.
org/10.
1021/jacs.
2c08694
The authors are: Tianhao Ma, Hao Cheng, Mallesham Pitchakuntla, Weihao Ma, and Yanxing Jia
【Introduction to Jia Yanxing】
Jia Yanxing is a distinguished professor of liberal arts at Peking University and a recipient of
the National Science Foundation for Outstanding Young Scholars.
He has long been committed to the research
of total synthesis and medicinal chemistry of complex natural products.
He has published more than 70 papers in international high-level journals as the corresponding author; Granted 4 patents
.
He was awarded the 2008 Chinese Pharmaceutical Association-Servier Youth Medicinal Chemistry Award, and was selected into the New Century Excellent Talent Support Program of the Ministry of Education in 2009, 2010 and 2013 He won the Asian Core Program Academic Report Award twice, the "Outstanding Young Professor Award" of the Sino-US Association of Professors of Chemistry and Chemical Biology in 2011, and 2019 He won the 4th Chinese Pharmaceutical Association-Yiling Biomedical Innovation Award, Bayer Scholar Award and 2021 WuXi AppTec Life Chemistry Research Award
.
Contributed by State Key Laboratory of Natural Medicines and Biomimetic Drugs
