Angelw: a new synthetic route of natural product actinophyllic acid

Professor David Y - K Chen of Seoul National University in Korea and Professor Hidetoshi Tokuyama of Northeastern University in Japan jointly published a research report on the total synthesis of natural product actinophyllic acid on Angewandte Chemistry International Edition Plane symmetry is a common feature in chemical science, which attracts our imagination in its synthesis and function According to the definition, the compound with plane symmetry has two identical domains with mirror chemical reactivity, and the selective operation of one of the two identical domains produces a new asymmetric product with identity and reactivity This so-called symmetry process has a profound impact on organic synthesis, from the extensive preparation of simple components to highly refined molecular structure The success of the design strategy depends largely on the choice of chemical methods and the implementation time of the overall synthesis scheme In the context of goal oriented total synthesis, impressive feats have been achieved through the superb insight of practitioners Although the synthesis strategy based on asymmetry may be very beneficial, more importantly, symmetry represents a kind of generalized "thought process", on which the synthesis plan can be logically conceived When the target molecule does not have any pairing elements, asymmetric synthesis strategy is the best choice for target directed synthesis Actinophyllic acid (1) is easy to meet this standard, and has great value of scientific challenge because of its unique structure The main route of total synthesis of actinophyllic acid (source: angelwandte Chemie International Edition) is particularly attractive for its simplicity and availability; however, its three alkenyls must be modified in turn to achieve the purpose of solving symmetry In this case, the separated alkenes can be selectively dihydroxylated without affecting the conjugated dienes under the protection of the ketone of trione 2 Then the dihydroxylated carbon ring was oxidized and decomposed in compound 3, and the dihydroxylated carbon ring was oxidized again by the double reduction amination of intermediate dialdehyde Methoxybenzylamine 4 was converted to teoc carbamate 5 (teoccl) as a precaution, especially considering the possibility of using oxidation conversion or hydrophilic Lewis acid reagents on conjugated dienes The early exploration of the synthesis direction of compound 5 (source: angelwandte Chemie International Edition) dicyclodienylcarbamate 5 has been synthesized, and the next stage is the key symmetry event In view of the rich selection of specific conversion of olefins or conjugated dienes, and keeping in mind the structure of the target molecule, the symmetry method is initially considered, which will enable the installation of indole parts required by actinophyllic acid (1) In this respect, several aromatization schemes were experimented, but they were quickly eliminated due to the problems of reactivity and selectivity However, useful hydrogenation conditions have been found, which provide almost the same olefins 17 and 18 Next, the research team carefully analyzed the possibility of synthesis of intermediates 17, 20 and 21 into actinophyllic acid (1), especially when the necessary indole part was introduced In this analysis, they quickly realized that although several reasonable synthesis routes could be designed on the basis of intermediates 17, 20 and 21, the total number of synthesis steps may far exceed the number of envisaged steps Therefore, an asymmetric solution must be identified to ensure overall efficiency With continuous efforts, the research team finally found a very effective cycloaddition method on diene 5 In this case, isoxazoline 7 was obtained by regioselective [2 + 3] cycloaddition of compound 6 and diene 5 Compound 7 was further substituted and oxidized with methoxy group to get isoxazole 8 Summary of amino arylation reaction (source: Angewandte Chemie International Edition) at this time, after functionalization of two of the three olefins in triene 2, the remaining olefins in triene 8 will undergo arylation reaction to make the substrate undergo later desolvation Firstly, carbamate 8 was treated with TFA to protect its secondary amines, and the unstable dioxolane in the acid was intact The resulting amine TFA salt was directly aminoarylated After screening the reaction conditions, although the increase of catalyst load has a positive impact on the reaction yield, due to economic reasons, the research team chose a lower catalyst load and recovered the crude reaction mixture regularly Finally, compound 11 was obtained by removing the dioxaphentane from compound 10, and the target indole 12 was obtained by PdCl2 catalytic hydrogenation The final conversion of indole 12 to actinophyllic acid (1) is a slight modification by Overman and his colleagues, and the spectral properties are exactly the same as previously reported In a word, the full synthesis of a-ctinophyllic acid (1) based on asymmetry has been realized Through the judicious selection and carefully optimized reaction sequence, catalytic dihydroxylation, dipolar cycloaddition of nitrile oxide and intramolecular amino arylation are carried out successively to functionalize alkenes effectively, then reductive denitrification and later alkylation are carried out to complete the total synthesis Paper link: http://onlinelibrary.wiley.com/doi/10.1002/anie.201706312/abstract