阅读说明：本技术 一种抗疟疾药物watsonianones A的合成方法 (Synthetic method of anti-malarial drug watsoniones A ) 是由 谭海波 杨松光 张晓� 吴贵云 刘洪新 于 2019-10-09 设计创作，主要内容包括：本发明公开了一种抗疟疾药物watsonianones A的合成方法。它是将syncarpic acid与异戊醛通过脯氨酸催化的Knoevenagel反应获得前体化合物4,再将化合物4与syncarpic acid发生脯氨酸催化的Michael加成反应,得到产物watsonianone A。本发明成功地完成了watsonianone A(1)的首次全合成,并为该类化合物的快速合成提供了简明的合成策略,并为快速获得该生物活性分子和结构衍生物提供了前提保障。(The invention discloses a synthetic method of an antimalarial drug watsoniones A. Obtaining a precursor compound 4 by carrying out a Knoevenagel reaction catalyzed by proline on syncaric acid and isovaleraldehyde, and carrying out a Michael addition reaction catalyzed by proline on the compound 4 and the syncaric acid to obtain a watsonianone A product. The invention successfully completes the first total synthesis of watsonianone A (1), provides a simple synthesis strategy for the rapid synthesis of the compounds, and provides a precondition guarantee for rapidly obtaining the bioactive molecules and structural derivatives.)

1. A synthetic method of a compound Watsonianone A is characterized in that a precursor compound 4 is obtained by leading syncarpic acid and isovaleraldehyde to be subjected to Knoevenagel reaction catalyzed by proline, and then the compound 4 and the syncarpic acid are subjected to Michael addition reaction catalyzed by proline to obtain a product Watsonianone A;

the structure of syncaric acid is shown as follows:

the structure of the compound 4 is shown as the following formula:

2. a method for synthesizing a compound Watsonianone A is characterized in that excess syncarpic acid is mixed with isovaleraldehyde and catalyzed by proline to obtain the product Watsonianone A;

the structure of syncaric acid is shown as follows:

3. the method of claim 2, wherein the excess is 2-10 equivalents of syncaric acid to isovaleraldehyde.

4. A process according to claim 1 or 2, characterized in that the syncaric acid is prepared by:

subjecting the phloroglucinol to hydroxyl oxidation and selective carbon methylation with monohalogenated methane under an alkaline environment to obtain a compound 6, and carrying out thermally-promoted reverse Friedel Crafts acylation reaction on the compound 6 to obtain a compound syncarpic acid;

the structural formula of the compound 6 is shown as follows:

5. the method of claim 4, wherein the monohalomethane is methyl iodide.

Technical Field

The invention belongs to the field of synthetic pharmaceutical chemistry, and particularly relates to a preparation method of watsoniones A and analogues thereof.

Background

The complex, novel and diversified structure and broad-spectrum and remarkable biological activity of phloroglucinol compounds have attracted wide attention of synthetic and pharmaceutical chemists in recent years. Watsonianone A (1) (see: Watsonianone A-C, anti-plasmodium beta-diketones from the Australian tree, Corymbia watsoniana Org. biomol. chem.,2013,11,453-458) is a novel complex phloroglucinol compound isolated and found from Myrtaceae Myrtle Orymbia watsoniana, and evaluation of antimalarial activity shows that it has very good antimalarial activity, particularly Dd2 and sensitive 3D7 Plasmodiumfalciparum which are resistant to chloroquinoline, and IC of the compound₅₀The value was as low as 5.3 umol/mL. In addition, watsonianone A (1) has antimalarial activity which is more normal than human cytotoxicity and has selectivity factors up to 100 times, so that the watsonianone A has a bright pharmaceutical application prospect and is considered as an important lead compound for developing novel anti-cancer drugs. Although this compound has a very novel structure and outstanding biological activity, and then the content of the compound in the nature is very rare and is difficult to obtain in large quantities by separation, no relevant report of chemical total synthesis exists at present. Thus, this patent is the first synthetic report of the antimalarial compound watsonianone a (1).

The invention content is as follows:

the invention aims to provide a chemical synthesis preparation method of a Watsonianone A (1) compound with remarkable antimalarial effect.

The patent firstly proposes a biomimetic synthesis way (shown as a formula 2) of watsonianone A (1) by analyzing the structural characteristics of the watsonianone A. Based on the biomimetic synthesis assumption, an efficient synthesis strategy is successfully designed and realized and is used for the rapid construction of the watsonianone A (1) framework and the concise synthesis of structural analogs. The synthesis strategy comprises two main key reactions, namely Knoevenagel condensation and Michael addition reactions catalyzed by small organic molecules. In the foregoing synthetic analysis, watsonianone a (1) can be back-pushed to the key α, β -unsaturated intermediate 4 via small organic molecule catalyzed Michael addition, and key intermediate 4 can be rapidly obtained from precursor compounds 2 and 3 via small organic molecule catalyzed Knoevenagel condensation. In addition, Knoevenagel condensation and Michael addition reactions catalyzed by small organic molecules can be catalyzed by proline as a catalyst; therefore, the watsonianone A (1) can be rapidly synthesized in one step through a biomimetic tandem reaction of Knoevenagel condensation/Michael addition reaction catalyzed by proline. Based on the synthesis assumption, the patent develops the full synthesis exploration of watsonianone A (1), successfully realizes the biomimetic full synthesis of the watsonianone A (1) for the first time, and provides a high-efficiency, reliable and economic preparation method for conveniently obtaining a large amount of watsonianone A (1) and analogues thereof for subsequent structure-activity relationship, pharmaceutical development and production.

The invention realizes the first full synthesis of watsonianoneA (1) by using a concise and clear synthesis strategy. In the whole synthesis process, the phloroglucinol 5 is used as a starting material, is commercially available and low in price, the reaction condition is mild, the operation is simple, and the synthesis route is convenient for the rapid and large-scale preparation of the compound. First, the key precursor syncarpicid 2 was obtained by selective carbon methylation followed by a thermally-promoted reverse Friedel Crafts acylation.

Subsequently, syncarpic acid 2 was condensed with excess isovaleraldehyde 3 by a proline catalysed Knoevenagel reaction to directly install the isoprene chain to obtain the common precursor compound 4 in yields of more than 90% for this synthetic step. Finally, syncapic acid 2 undergoes a proline catalyzed Michael addition reaction with the key co-precursor compound 4, eventually leading to a further conversion in high yield to the target product watsonianone a (1).

In addition, the present subject was also searched for different catalytic condensation conditions, aiming to realize direct condensation of syncaric acid 2 and isovaleraldehyde 3 by a one-step reaction, and further to convert into watsonianone a (1). It is satisfactory that watsonianone a (1), a natural product expected by the present invention, is successfully obtained in an excellent yield of 93% by a pre-designed Knoevenagel condensation/Michael addition tandem reaction when a slight excess of syncarpic acid 2 and isovaleraldehyde 3 is used as reaction conditions.

Synthetic route to formula 3-Watsonianone A

The synthesis method of the compound Watsonianone A comprises the steps of carrying out a Knoevenagel reaction on syncaric acid and isovaleraldehyde under the catalysis of proline to obtain a precursor compound 4, and carrying out a Michael addition reaction on the compound 4 and the syncaric acid under the catalysis of the proline to obtain a product Watsonianone A;

the structure of syncaric acid is shown as follows:

the structure of the compound 4 is shown as the following formula:

the invention provides a synthesis method of a second compound Watsonianone A, which is characterized in that excessive syncapicacid and isovaleraldehyde are catalyzed by proline to obtain a product Watsonianone A;

the structure of syncaric acid is shown as follows:

the excess means that the amount of syncaric acid is 2 to 10 times equivalent to that of isovaleraldehyde.

Preferably, the syncaric acid is prepared by the following method:

under alkaline environment, the acetylphloroglucinol and monohalogenated methane are subjected to hydroxyl oxidation and selective carbon methylation reaction to obtain a compound 6, and the compound 6 is subjected to thermal-promoted reverse Friedel Crafts acylation reaction to obtain a compound syncarpicacid;

the structural formula of the compound 6 is shown as follows:

the monohalogenated methane is methyl iodide.

The invention successfully completes the first total synthesis of watsonianone A (1), provides a simple synthesis strategy for the rapid synthesis of the compounds, and provides a precondition guarantee for rapidly obtaining the bioactive molecules and structural derivatives.

The specific implementation mode is as follows:

the following examples are further illustrative of the present invention and are not intended to be limiting thereof.