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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.

项目概要：缺乏稳健、高效和模块化的顺式-γ-羟基香芹酮合成方法的开发块。该基序的重要性因其存在于多种具有生物活性的阿罗烷衍生物质中而凸显。天然产品。这种差距的存在是一个重要问题，因为在解决这个问题之前，这些生物学上和结构上有趣的天然产物的合成将仅限于以下方面：香芹酮本身用于随后的功能化。本提案中描述的研究旨在引入新的 Pd 催化共轭加成化学领域的概念和反应性，有效合成顺式-γ- 羟基香芹酮结构单元。拟议研究的基本原理是有效获得 cis-γ- 羟基香芹酮结构单元将使阿罗烷衍生的天然产品更容易获得。因此，增加对这些天然产品的获取将有助于生物学评估和理解其有效机制。这将通过追求两个具体目标来实现：1）发展一种用于合成顺式-γ-羟基香芹酮衍生物的稳健、可扩展且发散的路线，以及2) 佛巴酮A的合成。在第一个目标下，引入Pd催化的新方法和新概念将进行共轭加成。钯催化对映选择性共轭加成反应的开发乙烯基硼酸到醌单缩酮将允许有效合成顺式-γ-羟基香芹酮建筑块。该方法的引入也将超出顺式-γ-羟基香芹酮的合成范围衍生物，因为反应产物含有密集的合成手柄，可以精确地随意功能化。这种方法是创新的，因为使用醌单缩酮作为底物尽管产品具有合成多功能性，但缀合物加成尚未得到充分开发形成。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一种以前从未合成过的天然产物佛巴酮 A。虽然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提高效率与其他已知的替代路线相比，合成了必需的顺式-γ-羟基香芹酮衍生物。这所提出的研究意义重大，因为引入了更有效的方法来构建 cis-γ- 羟基香芹酮结构单元将使具有生物活性的阿罗烷天然产品更容易获得。这将通过帮助对阿洛坦天然产品进行进一步的生物学评价，对人类健康产生积极影响。