Total synthesis method of natural active product concentricolide and its analogue

Abstract

The invention relates to a total synthesis method of a natural active product concentricolide and its analogue. The total synthesis method is a universal, simple and effective racemic and asymmetric total synthesis method. The total synthesis method comprises that a 1,3-acetone dicarboxylate compound as a raw material and alkynal undergo a Michael-Aldol reaction to produce a phenyl compound of which the benzene ring contains a phenolic hydroxyl group; through a substitution reaction of the phenolic hydroxyl group and a halogenated carboxylate, and benzyl bit oxidation and reduction reactions, benzofuranone lactone is constructed; under the alkaline condition, through a Diekmann condensation reaction and a Krapho reaction, a benzofuran ring is constructed; and through a series of functional group conversion, racemic total synthesis of the natural active product concentricolide and its analogue is realized. The total synthesis method utilizes a chiral reagent to catalytically reduce a carbonyl group or a double bond thereby constructing a corresponding chiral center so that asymmetric total synthesis of the natural active product concentricolide and its analogue is realized.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for the total synthesis of natural active product carbonococcin and analogues thereof. Background technique [0002] The carbon skeleton structure of carbonococcin compounds is characterized by 6-hydro-1,7-dioxa[E]inden-8-one (6H-1,7-dioxa-as-indacen-8-one ), with adjacent benzofuran and benzofuranone lactone functional groups on the same benzene ring: these two types of functional groups have been the pharmacophore in many hot drugs (S.M.Eric, J.U.Rayomand, B.X. Zhang, et al, J. Am. Chem. Soc., 2004, 126(46), 15106–15119). [0003] In 2005, Qin Xiangdong and others from the Kunming Institute of Botany, Chinese Academy of Sciences first discovered the compound Concentricolide (X.D.Qing, Z.J.Dong, J.K.Liu, L.M.Yang, R.R.Wang, Y.T.Zheng, Y.Liu, Y.S.Wu , Q.T.Zheng, Concentricolide, an Anti-HIV Agent from the Ascomycete Daldinia concentrica, Helv.Chim.Acta., 20...

AI Technical Summary

Problems solved by technology

In 2009, the applicant once used the Diels-Alder reaction to complete the racemic total synthesis of Concentricolide, but the yield was extremely low and could not be prepared in large quantities (L.-Z.Fang, J.-K.Liu, First synthesis of racemic concentricolide, an anti-HIV-1 agent isolated from the fungus daldinia concentrica. Heterocycles, 2009, 78(8), 2107-2113.)

[0008] At the same time, Taiwan scholars also reported the total synthesis method of the compound in 2011 (C-W Chang, R-J Chein, The Absolute Configuration of Anti-HIV-1Agent(-)-Concentricolide: Total Synthesis of(+)-(R)- Concentricolide.J.Org.Chem., 2011, 76(10), 4154–4157), but the synthesis steps are lengthy, the synthesis conditions are harsh, and the raw materials and intermediates use more toxic and explosive organic substances, thus increasing the synthesis cost Difficulty in operation, difficult to apply to large-scale synthetic production

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