Exploratory Studies on a New Strategy for the Asymmetric Total Synthesis of the Arrow Poison-Frog Alkaloid Batrachotoxin: Asymmetric Synthesis of a Functionalized CD Ring

doi:10.6023/cjoc202007021

Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (11): 3858-3865.DOI: 10.6023/cjoc202007021 Previous Articles Next Articles

Special Issue: 创刊四十周年专辑

箭毒蛙生物碱Batrachotoxin的不对称全合成新策略初探——官能化的CD环的不对称合成

王小刚, 黄培强

厦门大学化学化工学院化学系福建省化学生物学重点实验室福建厦门 361005

收稿日期:2020-07-07 修回日期:2020-08-02 发布日期:2020-08-11
通讯作者: 黄培强 E-mail:pqhuang@xmu.edu.cn
基金资助:
国家重点研发计划（No.2017YFA0207302）、国家自然科学基金（No.21672176）和教育部长江学者和创新团队发展计划（PCSIRT）资助项目.

Exploratory Studies on a New Strategy for the Asymmetric Total Synthesis of the Arrow Poison-Frog Alkaloid Batrachotoxin: Asymmetric Synthesis of a Functionalized CD Ring

Wang Xiaogang, Huang Peiqiang

Fujian Provincial Key Laboratory of Chemical Biology, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005

Received:2020-07-07 Revised:2020-08-02 Published:2020-08-11
Supported by:
Project supported by the National Key R&D Program of China (No. 2017YFA0207302), the National Natural Science Foundation of China (No. 21672176), and the Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of the Ministry of Education.

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Abstract

Among the more than 800 alkaloids isolated from skins of arrow poison-frog, batrachotoxin had attracted the most widespread attention of scientists from several fields, due to its potent cardio and nerve toxicities and challenging structure. A new strategy, which is different from all the previous total syntheses (one racemic and two enantioselective), is disclosed. This strategy features the formation of the CDE skeleton and then the ABCDE core of batrachotoxin by a key Diels-Alder reaction between A ring and CDE framework. Because A ring segment is a known compound, the first key of synthesis resides in the construction of the CDE framework. Thus, in addition to the new synthetic strategy, the synthesis of a functionalized CD ring system is developed. The synthesis started from the preparation of 2-allylcyclopentane-1,3-dione and its Michael addition with hex-1-en-3-one. The Hajos-Wiechert-type reaction of the adduct was investigated under optimized conditions using L-phenylalanine as an organocatalyst and D-camphorsulfonic acid (D-CSA) as an additive, the desired Robinson annulation proceeded smoothly to give the desired cyclization product in 75% yield and 81% ee. The latter was converted into a functionalized CD skeleton that bears all elements for elaborating to CDE framework in seven steps.

Key words: batrachotoxin, Hajos-Wiechert reaction, alkaloids, synthetic strategy, asymmetric synthesis, Tsuji-Trost reaction, Michael addition, ozonolysis

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Wang Xiaogang, Huang Peiqiang. Exploratory Studies on a New Strategy for the Asymmetric Total Synthesis of the Arrow Poison-Frog Alkaloid Batrachotoxin: Asymmetric Synthesis of a Functionalized CD Ring[J]. Chinese Journal of Organic Chemistry, 2020, 40(11): 3858-3865.

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箭毒蛙生物碱Batrachotoxin的不对称全合成新策略初探——官能化的CD环的不对称合成

Exploratory Studies on a New Strategy for the Asymmetric Total Synthesis of the Arrow Poison-Frog Alkaloid Batrachotoxin: Asymmetric Synthesis of a Functionalized CD Ring

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