Total synthesis of alpha-, beta- and gamma-naphthocyclinone

α-、β-和γ-萘环酮的全合成

• 批准号: 290521118
• 负责人: Dr. Mark Marcello Maturi
• 金额: --
• 依托单位: Department of Chemical Science and Engineering
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290521118?language=en
• 关键词: Total; synthesis; alpha; beta; gamma

The aim of this research project is the first total synthesis of alpha-, beta- and gamma-naphthocyclinone, three natural products from the naphthocyclinone family. All three compounds were isolated in 1974 as the colorful pigments from the mycelium of streptomyces arenae and are strong antibiotics against gram-positive bacteria. The biosynthetic pathway of naphthocyclinones was intensively investigated and it was thereby discovered that mother nature uses the monomeric pyranonaphthoquinone unit for dimerization in order to construct the naphthocyclinones.The retrosynthetic analysis envisions one common intermediate, which bears the complete carbon skeleton with its bicyclic core structure. This bicyclic core structure can be constructed via an aldol-addition by reductive cyclization, a method that was developed in the group of Suzuki. The precursor for the cyclisation could be furnished by an asymmetric rhodium-catalyzed C-C-cross coupling reaction of a western and an eastern fragment. Inspired by the biosynthesis of the naphthocyclinones, both fragments could be synthesized from one key intermediate that is a pyranonaphthalene compound.In view of the synthetic strategy, the naphthalene core of the key intermediate should be accessible by annulation of a benzoic acid ester derivative and a literature know chiral dihydropyron building block, which bears on of the stereogenic centers of the key intermediate. The pyrane ring of the key intermediate could be fully functionalized by a diastereoselective alkylation reaction of a lactol. After modulation of the key intermediate into the western and eastern fragment, the common intermediate, bearing the full carbon skeleton, could be synthesized by a cross coupling reaction and a reductive cyclisation. Following a sequence of a) oxidation to a para-naphthoquinone moiety, b) generation of a carboxylic acid functionality and c) removal of all phenol protecting groups should furnish the target compound beta-naphthocyclinone. Reversing the order of the first two steps of this sequence (first generation of the carboxylic acid functionality and then oxidation to a para-naphthoquinone moiety) should allow for a literature known lactonisation. Again removal of all phenol protecting groups should lead to gamma-naphthocyclinone. In analogy to the biosynthesis, an epoxidation followed by photochemical rearrangement should finalize the synthesis of alpha-naphthocyclinone. In pursue of this research, the racemic synthetic strategy for the key intermediate, as well as its modulation into the western and eastern fragment, has been successfully established and thus opening the path for the enantioselective totals synthesis of the target natural compounds.

该研究项目的目的是首次全合成萘环酮家族的三种天然产物α-，β-和γ-萘环酮。这三个化合物都是在1974年作为彩色色素从链霉菌的菌丝体中分离出来的，是对革兰氏阳性菌的强抗生素。通过对萘环素酮生物合成途径的深入研究，发现大自然利用吡喃萘醌单体进行二聚反应来构建萘环素酮，逆合成分析设想了一个共同的中间体，它具有完整的碳骨架和双环核心结构。该双环核心结构可以通过还原环化经由羟醛加成来构建，该方法是在Suzuki的组中开发的。环化反应的前体可以通过不对称铑催化的西部和东部片段的C-C交叉偶联反应来提供。受萘环酮生物合成的启发，这两个片段都可以从一个关键中间体吡喃萘化合物合成，考虑到合成策略，关键中间体的萘核应该通过苯甲酸酯衍生物和文献已知的手性二氢吡喃结构单元的环化来实现，该结构单元与关键中间体的立体异构中心有关。关键中间体的吡喃环可以通过内半缩醛的非对映选择性烷基化反应完全官能化。在将关键中间体调制成西部和东部片段之后，可以通过交叉偶联反应和还原环化来合成具有全碳骨架的共同中间体。在a）氧化成对萘醌部分，B）生成羧酸官能团和c）除去所有酚保护基的顺序之后，应提供目标化合物β-萘环酮。颠倒该顺序的前两个步骤的顺序（首先生成羧酸官能团，然后氧化成对萘醌部分）应允许文献已知的内酯化。再次去除所有酚保护基应导致γ-萘环酮。与生物合成类似，环氧化反应后进行光化学重排应完成α-萘环素酮的合成。在此基础上，成功地建立了关键中间体的外消旋合成策略，并将其拆分为西片段和东片段，从而为目标天然化合物的对映选择性全合成开辟了道路。