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Efficient and Modular De Novo Synthesis of Hydroxycarvone Derivatives via Pd-Catalyzed Conjugate Addition: Application to theTotal Synthesis of Phorbasone A

Pd 催化共轭加成高效、模块化从头合成羟基香芹酮衍生物：在佛巴松 A 全合成中的应用

基本信息

批准号：
10461768
负责人：
Stephen Robert Sardini
金额：
$ 6.76万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

Project Summary: There is a lack of development of a robust, efficient, and modular synthesis of cis-γ-hydroxycarvone building blocks. The importance of this motif is highlighted by its presence in a variety of biologically active alotane derived natural products. The existence of this gap represents an important problem because until it is addressed, the synthesis of these biologically, and structurally interesting natural products will be confined to the amenability of carvone itself to subsequent functionalization. The studies described in this proposal seek to introduce new concepts and reactivity in the realm of Pd-catalyzed conjugate addition chemistry to efficiently synthesize cis-γ- hydroxycarvone building blocks. The rationale for the proposed research is that efficient access to cis-γ- hydroxycarvone building blocks will allow alotane derived natural products to be more accessible. Consequentially, increased access to these natural products will aid in biological evaluation, and understanding of the mechanism by which they are effective. This will be realized by pursuing two specific aims: 1) Development of a robust, scalable, and divergent route for the synthesis of cis-γ-hydroxycarvone derivatives, and 2) the total synthesis of phorbasone A. Under the first aim, introduction of new methods and concepts in Pd-catalyzed conjugate addition will be pursued. Development of a Pd-catalyzed enantioselective conjugate addition of vinylboronic acids to quinone monoketals will allow for the efficient synthesis of cis-γ-hydroxycarvone building blocks. Introduction of this method will also reach beyond the scope of the synthesis of cis-γ-hydroxycarvone derivatives, as the products of the reaction contain a dense array of synthetic handles that can be precisely functionalized at will. This approach is innovative, because the use of quninone monoketals as substrates for conjugate addition has been very underdeveloped, despite the synthetically versatile nature of the products formed. Under the second aim, an efficient de novo synthesis of cis-γ-hydroxycarvone derivatives will allow for the synthesis of a never before synthesized natural product, phorbasone A. While the second aim is not dependent on the success of the first aim, accomplishment of the first aim would allow for a more efficient synthesis of the requisite cis-γ-hydroxycarvone derivative when compared to other known alternative routes. The proposed research is significant, because introduction of more efficient methods to construct cis-γ- hydroxycarvone building blocks will allow biologically active alotane natural products to be more accessible. This will positively affect human health by aiding in further biological evaluation of alotane natural products.

项目摘要：目前还缺乏一种稳定、高效、模块化的顺式-γ-羟基香芹酮的合成方法个街区.该基序的重要性通过其存在于多种生物活性的阿洛坦衍生物中而突出。天然产品。这一差距的存在是一个重要的问题，因为除非得到解决，这些生物学上和结构上令人感兴趣的天然产物的合成将被限制在以下条件的适应性上：香芹酮本身进行后续功能化。本建议中所述的研究旨在引入新的概念和反应性领域的钯催化共轭加成化学，以有效地合成顺式-γ- 羟基香芹酮结构单元。所提出的研究的基本原理是，有效地获得顺式-γ- 羟基香芹酮结构单元将允许更容易地获得由阿龙烷衍生的天然产物。因此，增加对这些天然产物的获取将有助于生物学评价和理解。它们发挥作用的机制。这将通过追求两个具体目标来实现：1）发展一个强大的，可扩展的，和发散路线的合成顺式-γ-羟基香芹酮衍生物，和2）总佛巴松A合成在第一个目标下，引入新的方法和概念在钯催化将进行共轭加成。钯催化的对映选择性共轭加成反应的研究进展将乙烯基硼酸转化为醌单缩酮将允许顺式-γ-羟基香芹酮的有效合成，个街区.该方法的引入也将超越顺式-γ-羟基香芹酮的合成范围衍生物，因为反应的产物含有一系列密集的合成手柄，可以精确地任意功能化。这种方法是创新的，因为使用醌酮单缩酮作为底物，共轭加成反应一直很不发达，尽管产品的合成用途广泛形成了在第二个目标下，顺式-γ-羟基香芹酮衍生物的有效从头合成将允许合成了一种从未合成过的天然产物，佛巴酮A。第二个目标不是取决于第一个目标的成功，第一个目标的实现将允许更有效的当与其它已知的替代途径相比时，本发明提供了必需的顺式-γ-羟基香芹酮衍生物的合成。的提出的研究是有意义的，因为引入更有效的方法来构建顺式-γ- 羟基香芹酮结构单元将使生物活性的阿龙烷天然产品更容易获得。这将通过帮助进一步生物学评价阿洛坦天然产物而对人类健康产生积极影响。