Westlake University's latest article: "Combination Boxing" Helps Efficient Synthesis of Natural Product daphenylline

Recently, Haihua Lu's team from the School of Science of Westlake University published a research paper entitled " Concise Enantioselective Total Synthesis of Daphenylline Enabled by an Intramolecular Oxidative Dearomatization" in the Journal of the American Chemical Society .
By developing a novel intramolecular oxidative dearomatization reaction, combined with multiple methods such as long-range carboxylic acid-directed Mukaiyama -Michael addition and tandem reductive amination - aminolysis reactions, the complex natural product phoenix alkaloid D was realized.
The most concise and efficient asymmetric synthesis of aphenylline so far .
Researcher Lu Haihua of West Lake University is the corresponding author of this work, and Zhejiang University - West Lake University joint doctoral students Cao Mengyue and Dr.
Ma Binjie are the co-first authors of the paper .

Image credit: J.

The genus Rhizoma is an evergreen shrub, which is widely distributed in China, has ornamental value, and has a certain medicinal value in traditional Chinese medicine in China

Figure 1.
Typical natural alkaloids

Among them, daphenylline ( 3 ) was isolated from Daphniphyllum longeracemosum in China by Hao Xiaojiang's team from Kunming Institute of Botany, Chinese Academy of Sciences .
It is the first member of the alkaloid family with a unique 1,2,3,4 -tetrasubstituted benzene ring structure, but the natural isolation yield is low, only 0.
000073% .
Structurally, daphenylline ( 3 ) also has an aza [3.
3.
1] bridged ring and a 6-5-7-5 -ring system .
How to construct its unique skeleton has become the key and difficult point in the synthesis of this natural alkaloid, and has attracted many organic synthetic chemists at home and abroad, including famous synthetic chemists in China, Professor She Xuegong (Lanzhou University), and researcher Li Ang (Chinese Academy of Sciences Shanghai Institute of Organic Chemistry), Professor Zhai Hongbin (Peking University Shenzhen Graduate School), Researcher Qiu Fayang (Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences), etc.
In 2013 , Li Ang's team used a novel photo-induced olefin isomerization /6π electrocyclization / aromatization tandem reaction to achieve the first total synthesis of daphenylline .
Subsequently, another 5 cases of total synthesis studies were reported one after another.






.
Different from the previous synthesis, Lu Haihua's team constructed a key seven-membered carbocyclic ring and a quaternary carbon-containing continuous chiral center by studying the intramolecular dearomatization reaction of naphthol derivative 13 , and then combined the long-range carboxylic acid-directed Mukaiyama-Michael Addition reaction ( MMR ) and tandem reductive amination / ammonolysis, complete the asymmetric synthesis of daphenylline ( 3 ) concisely and efficiently (Fig.
2 ) .

Figure 2.
Synthesis strategy of Lu Haihua's team

First, starting from the large-scale preparation of naphthindanone 15 , they obtained the diene compound 14 with high efficiency through a simple two-step transformation
.
Although the asymmetric hydrogenation of such exocyclic olefins has been reported to be challenging, they found that, after ligand screening and other corresponding optimizations, Rh(NBD) ₂ BF ₄ /Tol-BINAP as catalyst and trifluoroethanol When used as solvent, high enantioselective hydrogenation of diolefin 14 can be achieved to build the key starting carbon chiral center to give intermediate 16 ( 90% ee ) .
This intermediate is demethylated by boron tribromide to obtain the designed oxidative dearomatization ring-closing precursor naphthol ester 13 .
Through the study of its oxidative dearomatization cyclization, it was found that only when iodine was used as the oxidant, the compound could construct the key seven-membered ring and the continuous carbon chiral center containing quaternary carbon in high yield, and the target product 12 was obtained .
Next, they achieved a highly diastereoselective construction of a chiral center at the C ₂ position ( dr = 13:1 ) using the long-range carboxylic acid-directed Mukaiyama-Michael reaction ( MMR ) ; The yield of lactone compound 20 was obtained .
Finally, they use Fukuyama



The key tricarbonyl compound 21 was obtained by reduction method , which completed the construction of nitrogen-containing ring and cage structure through tandem reductive amination / ammonolysis reaction, and finally realized the efficient synthesis of daphenylline .

Figure 3.
Synthesis of (-)-daphenylline

In summary, Lu Haihua's team started from the readily available naphthindanone, through a novel intramolecular oxidative dearomatization reaction, combined with long-range carboxylic acid-directed Mukaiyama-Michael addition and tandem reductive amination - aminolysis reaction, etc.
, A concise and efficient asymmetric synthesis of the complex natural product daphenylline was achieved .

This work has been strongly supported by the General Program of the National Natural Science Foundation of China, the National Overseas High-level Talents (Youth Program), the Key Program of the Natural Science Foundation of Zhejiang Province , the China Postdoctoral Science Foundation , and West Lake University
.

Link to the original paper:

https://pubs.

Introduction to the Natural Product Synthesis Team

The main research interests of Lu Haihua's natural product synthesis team at West Lake University include: 1 ) Taking natural products as the guide, developing efficient, asymmetric diversity-oriented synthesis, and then conducting research on the creation of natural product drugs; 2 ) Through method and strategy innovation, the realization of Efficient synthesis of complex natural products

Homepage of the research group: http://chem-lu.