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130.The Journey of Schinortriterpenoid Total Syntheses

Zhen Yang*

Acc. Chem. Res., 2019, 52 (2), 480–491

Plants in the Schisandraceae family are important components of the traditional Chinese herbal medicines and are often used to treat various illnesses. Therefore, these Schisandraceae plants are valuable sources for the discovery of new chemical entities for novel therapeutic development. Considerable progress has been made in the identification of bioactive and structurally novel triterpenoids from the Schisandraceae family in the past two decades. In particular, Sun and co-workers have successfully isolated over 100 nortriterpenoids from the Schisandraceae family. Some of these nortriterpenoids have strong inhibitory activities toward hepatitis, tumors, and HIV-1. However, the natural scarcity of these nortriterpenoids in the Schisandraceae plants has hampered their isolation and further biomedical development, and their biosynthesis has not been fully elucidated. It is therefore important and urgent to develop efficient and streamlined total syntheses of these medicinally important nortriterpenoids. Such syntheses will provide sufficient materials for detailed biological studies as well as new synthetic analogues and probe molecules to improve their biological functions and elucidate their mode of actions. However, because of their structural novelty and complexity, the total syntheses of these nortriterpenoid natural products present a significant challenge for synthetic chemists, despite the progress made in organic synthesis, particularly total synthesis, in the 20th century and since the beginning of the 21st century. New synthetic methodologies and strategies therefore need to be invented and developed to facilitate the total syntheses of these nortriterpenoid natural products. With this in mind, our group has spent the last 15 years, ever since the isolation of micrandilactone A (1) by Sun and co-workers in 2003 (Sun et al. Org. Lett. 2003, 5, 1023−1026), working on synthetic studies with a view to developing methods and strategies for the total syntheses of schinortriterpenoids. Enabling methods such as a thiourea/Pd-catalyzed alkocycarbonylative annulation and a thiourea/Co-catalyzed Pauson–Khand reaction have been developed under these circumstances to form the key ring systems and stereocenters of these complex target molecules. These methodological advances have led us to the first total syntheses of schindilactone A (2), lancifodilactone G acetate (6a), 19-dehydroxyarisandilactone A (9), and propindilactone G (10) with diverse structural features via a branching-oriented strategy. The chemistry developed during our total synthesis campaign has not only helped us to deal with various challenges encountered in the syntheses of the four target molecules, but has also opened up new avenues for synthesizing other naturally occurring schinortriterpenoids and their derivatives, which will likely result in molecules with improved biological functions and tool compounds to enable elucidation of their mechanism of actions or potential cellular targets. This Account highlights the chemistry evolution of our schinortriterpenoid syntheses.

129.Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation

Wei Chen, Renyu Guo, Zhen Yang*, and Jianxian Gong*

J. Org. Chem., 2018, 83 (24), pp 15524–15532

The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key α-naphthol intermediate and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps.

128.Total Syntheses of Crinipellins Enabled by Cobalt‐Mediated and Palladium‐Catalyzed Intramolecular Pauson–Khand Reactions

Zhihui Huang, Dr. Jun Huang, Yongzheng Qu, Weibin Zhang, Prof. Dr. Jianxian Gong*, Prof. Dr. Zhen Yang*

Angew. Chem. Int. Ed. 2018, 57(28), 8744 –8748

• Highlighted in Synfacts, 2018, 14, 788.

Efficient total syntheses of the naturally occurring, potent antibiotic compounds (−)‐crinipellin A and (−)‐crinipellin B are described. The key advanced intermediate, a fully functionalized tetraquinane core, was constructed by a novel thiourea/palladium‐catalyzed Pauson–Khand reaction. This intermediate can serve as a common intermediate for the collective total synthesis of other members of the crinipellin family.

127.Diversity-Oriented Synthesis of Natural Products via Gold-Catalyzed Cascade Reactions

Yueqing Gu, Ceheng Tan, Jianxian Gong*, Zhen Yang*

Synlett 2018, 29(12): 1552-1571

This account describes our group’s latest research in the field of diversity-oriented synthesis of natural products via gold-catalyzed cascade reactions. We present two general strategies based on gold-catalyzed cycloisomerization: a gold-catalyzed cascade reaction of 1,7-diynes and a pinacol-terminated gold-catalyzed cascade reaction. We highlight our development of synthetic methods for the construction of biologically active natural products by using these two strategies.

126.Asymmetric Total Syntheses of Insulicolide A, 14-O-Acetylinsulicolide A, 6β,9α-Dihydroxy-14-p-nitrobenzoylcinnamolide, and 7α,14-Dihydroxy-6β-p-nitrobenzoylconfertifolin

Yang Lai, Nan Zhang, Yi Zhang, Jia-Hua Chen*, and Zhen Yang*

Org. Lett., 2018, 20 (14), 4298–4301

Asymmetric total syntheses of insulicolide A, 14-O-acetylinsulicolide A, 6β,9α-dihydroxy-14-p-nitrobenzoyl cinnamolide, and 7α,14-dihydroxy-6β-p-nitrobenzoylconfertifolin have been achieved for the first time. The key steps in the synthesis include: (1) an iridium-catalyzed enantioselective polyene cyclization to construct the drimane core bearing two all-carbon quaternary chiral centers at C4 and C10 and (2) a cascade ozonolysis of the phenol ring to form the lactone fragment of the target molecules.