CHEMICAL SCIENCE

Shenzhen Bay Laboratory has achieved a new breakthrough in the three-dimensional divergence of natural products


On May 2, 2022, a team of academicians Xiaoming Feng and Yangbin Liu of Shenzhen Bay Laboratory published an article in the journal Chem titled “Stereodivergent Total Synthesis of Rocaglaol Initiated by Synergistic Dual-Metal-Catalyzed Asymmetric Allylation of Benzofuran-3( 2H)-one” new study.

The research group developed a bimetallic asymmetric stereodispersible benzofuran-3(2H)ketopropyl alkylation strategy, realized the stereodispersive total synthesis of eight chiral rocaglaol, and conducted a preliminary investigation of the stereochemical structure-activity relationship. The corresponding authors of the paper are Feng Xiaoming and Liu Yangbin; the first author is Xu Yang.

Chirality is one of the essential attributes of nature, and there are chiral phenomena in the macroscopic to microscopic worlds. Chirality often has a great influence on the activity of drug molecules, and it is of great scientific significance and practical value to obtain all stereoisomers of chiral molecules by asymmetric synthesis methods, and then to carry out a complete study on the relationship between chiral isomers and physiological activity. However, traditional methods often use different starting materials and differentiated synthesis routes, and there are problems such as difficult development and difficult preparation of some chiral isomers. Stereodiscentral synthesis is a collective asymmetric synthesis of multiple diastereomers of multichiral central molecules using chiral catalysts to accurately and controllably achieve multiple diastereomers of multichiral central molecules under unified raw materials, synthesis routes and reaction conditions. In recent years, this strategy has developed rapidly, providing an important guarantee for the synthesis of multiple chiral isomers with important physiologically active natural products and the study of pharmacodynamic relationships.

Recently, the Team of Feng Xiaoming/Liu Yangbin of Shenzhen Bay Laboratory used benzofuran-3(2H)ketone and allyl alcohol carbonate as substrates to achieve asymmetric allyl alkylation reaction through chiral bimetallic synergistic catalytic strategy, which can conveniently prepare all four stereoisomers of the product with high yield and high selectivity. In addition, the stereodiscopic divergent total synthesis of eight isomers of natural product rocaglaol and its anticancer activity were completed.

Figure 1: Stereodispersive asymmetric total synthesis of rocaglaol

The authors used the chiral diazoxide-nickel complex (von catalyst) developed by the research group as a catalyst to selectively control the stereomorphism of the nucleophilic reagent benzofuran-3 (2H) ketone, and at the same time used the chiral phosphine-iridium complex catalyst to add oxidation with methyl cinnamyl carbonate to obtain electrophilic allyl iridium species, and then the two underwent allyl alkylation reaction. By changing the absolute configuration of the two chiral catalysts, all four stereoisomers of the product were prepared with excellent yield and selectivity.

Figure 2: Bimetallic co-catalysis for stereodispolar synthesis

(R,S)-8The intermediate aldehyde was obtained by borohydrogenation – oxidation and subsequent DMP oxidation, and the C1-bit differential isomer of Roxomiranol was obtained at a total yield of 46% by using samarium diiode-mediated pinacol coupling reaction10。 After that, the C1-position hydroxyl group is redoxed and re-reduced, and the hydroxyl configuration of the C1-position is reversed, and the natural product Roxmillanol is finally realized1Asymmetrical total synthesis. Using the above unified route and method, the authors for the first time concisely and efficiently completed the other six stereoisomers of Rocmillanol11-16Chiral fully synthetic.

Figure 3: Asymmetrical synthesis of eight stereoisomers of Lockemilanol

Preliminary anti-cancer activity tests have shown that eight stereoisomers of Roxmilanol have inhibitory effects on Ramos (human B lymphoma cells), MV4-11 (human acute monocyte leukemia cells) and MOLM-13 (human acute myeloid leukemia cells). But there are significant differences in the anti-cancer activity of different stereoisomers: such as roximilanol1, significant anticancer activity, IC50 = 7-11 nM; and enantiomers of Roxmillanol12The anti-cancer activity was significantly reduced, with IC50 > 1000 nM. The comparison found that changing the stereo configuration of chiral centers in different positions had different degrees of influence on their anti-tumor activity, roughly showing the trend of C3 > C3a, C8b > C1, and other activity differences are being studied.

Figure 4: Study of the structure-activity relationship between anti-cancer activity

The research work has been funded by the National Natural Science Foundation of China (22188101, 22001177), the Shenzhen Bay Laboratory Start-up Fund (S201100003) and the Shenzhen Bay Laboratory Major Project (S211101001-1), and has applied for patent protection (CN202111202605.5). (Source: Science Network)

Related paper information:https://doi.org/10.1016/j.chempr.2022.04.006



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