Late functionalization of natural products by super electrophilic silane ions

Natural products refer to all kinds of compounds produced by organisms that can help organisms survive and develop in the natural competitive environment These compounds are produced by biosynthesis and have biological activity, which can help species resist invasion of foreign enemies and pathogens Sometimes, these natural products can be directly used as active drugs, such as penicillin and paclitaxel In addition, people can improve their activity by synthesis Some people think that the internal role of natural products in their ecosystem can promote the development of bioavailability and biological potential Therefore, people should actively explore new structures When these structures are expressed in molecular diversity, the biological activity can be maximized Diversity is a complex concept It can be determined that chemical diversity is associated with high selectivity and low confusion in protein expression The diversity of commercial compounds is too low, and the complexity of the library obtained by structural synthesis is medium, while that of natural products is the highest The late stage functionalization (LSF) strategy attempts to use natural products to fill the diversity space around it (Figure 1a), and hopes that these variants can maintain particularity, and provide important information such as structure activity relationships (SARS), optimal activity, bioavailability, etc Figure 1 A) LSF expands the diversity space of natural products; b) piers mechanism source of borane isomerization to realize C-O reduction: the application of nature chemistry LSF strategy accelerates the development of relevant synthesis means However, the complexity of natural products makes directed synthesis challenging, because the cross reactivity of functional groups hinders the realization of chemical selectivity The catalytic conversion in LSF usually modifies a single site precisely, but the method of using catalysts or reagents to modify multiple different sites on natural products at the same time is rare Finding this method can enhance the application of LSF in the realization of structural diversity It seems that silane ion is not a good choice to promote the selective transformation of complex molecules because of its strong electrophilic and oxyphilic properties Unlike the separable carbon positive ions, the Lewis acidity of silane ions is very strong, and they can hardly exist alone except Lewis acid-base pairs One of the gentlest ways to produce silane ions is the combination of fluoararyborane Lewis acid B (C6F5) 3 (BCF) and silane The instantaneous polarization of Si-H bond produces borane / silane addition product I, which makes silicon electrophilic and easy to be attacked by Lewis base (piers mechanism, FIG 1b) The ionization of silane makes it useful in reducing silylation The application of BCF in reduction reaction shows that LSF with chemical selectivity can be realized in complex target Recently, Professor Michel R Gagn é and his team from the Department of chemistry, University of North Carolina, Chapel Hill, published an article in nature chemistry, reporting that the directional functionalization of complex molecules can be realized by operating silane ion and its equilibrium anion In the paper, the team said that the chemical selectivity of functionalization of natural products will be diverse and controllable by using R 3Si + and H properly, so as to provide a new chemical modification tool for finding new bioactive molecules Fig 2 Functional sources of complex natural products catalyzed by fluoroarylborane: the author of nature chemistry selected three fluoroarylborane Lewis acids (Fig 2a) and silanes with different intensities to activate and modify different natural products (1, 3 and 5) Gibberellin 1 was treated with a catalytic equivalent BCF and an excess of silane to give a product 2 of C-O reduction and allyl shift of lactone (93%, FIG 2b) Dihydroartemisinin 3 reacts at unit point to produce hemiacetal reduction product 4 (92%, FIG 2C) It can be seen that the reactions of 2 and 3 avoid non selective excitation and over reduction, and the results are exciting Next, the more complex natamycin 5 was selectively modified by adding Lewis base PPH 3 to stabilize the silane intermediate It can be seen from Fig 2D that different combinations of fluoroarylborane and silane can produce different products 7 - 10 under different reaction conditions In order to explore the influence of reaction variables on the products, the authors used 1H NMR, 13C NMR and 19F NMR spectra to monitor the reaction It is found that the relative activity of different functional groups can be controlled by single equivalent addition The reaction first undergoes the dehydrogenation and silanization of carboxylic acid to generate the corresponding silane ester intermediate (as shown in II in Fig 2D) If the reaction is quenched at this time, a new carboxylic acid will be obtained However, the second equivalent silane reacts with alkenyl ester, and the third equivalent leads to the elimination of internal semiacetals It can be seen that the control of reaction time is very important for condition optimization In addition, although the author has not done too much research on the temperature, it can be seen from the comparison of the products 8 (25 ℃) and 9 (- 10 ℃) that the temperature has an impact on the chemical selectivity of the reaction Another important reagent in the reaction, Lewis base PPH 3, can form Lewis base pair with BCF and play the role of silane ion carrier The addition product of Lewis is very difficult to dissolve, and it can dissolve quickly after adding silane to form bcf-h - / me 2 ETSI PPH 3 + ion pair Fig 3 Source of chemically selective amide reduction catalyzed by fluoroarylborane: Based on the successful application of the above three catalysts, the author also studied (3-hexyl) (C6F5) 2B (3-hex-b) The results showed that 3-hex-b was too active to react directly with natamycin 5, but PPH 3 could inhibit the reaction completely So the author changed the substrate to acetamide derivative 11 of natamycin, and obtained the product 12 of N-acetyl selective reduction to N-ethyl by relatively mild reaction (Fig 3a) This catalytic type of amide reduction has never been observed before It is significant that other more active functional groups in the substrate are preserved The author further carried out this reaction with natamycin derivative 13 containing two amide bonds, and also obtained product 12 (Fig 3a) A similar selective amide reduction reaction was also verified in the reaction of strychnine 15 (Fig 3b) Figure 4 Application source of fluoroarylborane method in the modification of 10-deacyloxyberryl gibberellin III: nature chemistry finally, in order to test the feasibility of fluoroarylborane method in expanding the new structure space around natural products, the author conducted LSF study on the precursor of taxol, 10-deacyloxyberryl gibberellin III (17, 19 and 22) (Figure 4) Under the action of different BCF and silanes, the author observed a variety of novel changes A new structure 18 can be obtained by BCF alone catalyzing 17 2,4,6-bcf can catalyze 19 alone to get 20 and 21 When silane and oxheterocyclobutane are added into the reaction to open the ring, and acetate is reduced at the same time, after going through the intermediate dioxarbene ion III, a single diastereomer 23 can be obtained Conclusion: Michel R Gagn é's team has developed a new chemical selective conversion method for complex bioactive compounds Through the interaction of silane ion and reducing anion, a series of novel natural product derivatives can be obtained The application of BCF / borane method will broaden the diversity of natural products and provide more choices for drug screening We have reason to believe that this method will become a powerful tool for improving the structure of natural products and drugs.