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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10461768
• 关键词: Acids; Address; Affect; Biological; Boron; Chemistry; Complex; Consequentialism; Development; Disease; Esters; Evaluation; Grant; Health; Human; Lead; Methodology; Methods; Mission; Natural Products; Nature; Outcome; Pharmacologic Substance; Phenols; Positioning Attribute; Public Health; Quinones; Reaction; Reporting; Research; Route; United States National Institutes of Health; Variant; analog; bioactive natural products; chemical synthesis; functional group; innovation; novel; scaffold; success

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.

项目总结： 目前还缺乏一种健壮、高效、模块化的顺式-γ-羟基香芹酮合成方法 街区。这一基序的重要性因其存在于衍生的各种生物活性丙烷中而得到强调。 天然产品。这一差距的存在代表了一个重要的问题，因为在这个问题得到解决之前， 这些具有生物意义和结构意义的天然产物的合成将仅限于 将自己推向后续的功能化。这项提案中描述的研究试图引入新的 钯催化共轭加成化学高效合成顺式γ-的概念和反应活性 羟基香芹酮积木。这项拟议研究的基本原理是，高效地访问cis-γ- 羟基香芹酮构建块将使从Alotane衍生的天然产品更容易获得。 因此，更多地获得这些天然产品将有助于生物评估和理解 他们的有效机制。这将通过追求两个具体目标来实现：1)发展 用于合成顺式-γ-羟基香芹酮衍生物的健壮、可扩展和发散的路线，以及2)总的 在第一个目标下，在钯催化下引入新的方法和概念 将继续进行共轭加法。钯催化的对映选择性共轭加成反应的研究进展 乙烯基硼酸合成苯二酮单缩酮可用于顺式-γ-羟基香芹酮的高效合成 街区。该方法的引入也将达到顺式-γ-羟基香芹酮合成的范围之外 衍生物，因为反应的产物含有密集的合成手柄阵列，可以精确地 随心所欲地功能化。这种方法是创新的，因为使用喹诺酮单酮作为底物 共轭加成一直非常不发达，尽管产品具有合成的多功能性 形成了。在第二个目标下，顺式-γ-羟基香芹酮衍生物的高效从头合成将允许 合成一种以前从未合成过的天然产物，佛尔巴酮A，而第二个目的不是 依赖于第一个目标的成功，第一个目标的实现将允许更有效的 与其他已知替代路线比较时，合成所需的顺式-γ-羟基香芹酮衍生物。这个 所提出的研究具有重要意义，因为引入了更有效的方法来构建顺式γ- 羟基香芹酮积木将使具有生物活性的Alotane天然产品更容易获得。这 将有助于进一步对丙烷天然产物进行生物学评价，从而对人类健康产生积极影响。