Unlocking Access to Cyclopropanones as Divergent Reactive Intermediates in Synthesis

解锁环丙酮作为合成中不同反应中间体的途径

• 批准号: 10620218
• 负责人: Vincent Lindsay
• 金额: $ 36.14万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620218
• 关键词: Amines; Chemicals; Chemistry; Curiosities; Data; Development; Electronics; Funding; Harvest; Hydrazines; Hydrazones; Ketones; Kinetics; Knowledge acquisition; Methods; Natural Products; Nature; Organic Synthesis; Pharmaceutical Preparations; Pharmacologic Substance; Process; Production; Reaction; Reagent; Route; Technology; Transition Elements; Work; analog; base; bioimaging; carbene; crystallinity; cyclic compound; novel; nucleophilic addition; scaffold

ABSTRACT Strained cyclic compounds are often used as key intermediates in the synthesis of bio-active drugs and natural products through strain-releasing reactions such as ring-expansion and ring-opening processes. While small ring ketones such as cyclobutanones have found widespread applicability in these transformations, the analogous use of cyclopropanone derivatives as substrates has seriously lagged behind, as these compounds have long been considered unsustainable synthetic intermediates due to their extreme strain and kinetic instability. This work proposes the use of 1-sulfonylcyclopropanols as a general class of stable cyclopropanone surrogates in organic synthesis, unlocking access to myriad previously inaccessible synthetic disconnections via strain-releasing reactions. These include (1) rearrangements initiated by the addition of nucleophiles, (2) transition metal-catalyzed C–C activation and deconstruction strategies, and (3) application of cyclopropanone derivatives as 1,1-cyclopropyl linchpins. We have already developed an efficient enantioselective route to these compounds and have obtained significant preliminary data in each of these types of reactions, leading to a variety of chiral synthons difficult to access by other methods. Both the electronic and steric nature of the sulfonyl moiety in these surrogates, which is acting here as a base-labile protecting group and conferring crystallinity to these compounds, is found to have a crucial impact on their rate of equilibration to cyclopropanone, highlighting their tunable reactivity and the potential for their widespread applicability as synthetic intermediates. During the funding period and using the mechanistic knowledge acquired, this technology leading to enantioenriched 1-sulfonylcyclopropanols will be extended to the formation of 1- sulfonylcyclopropylamine and hydrazines as modular precursors of chiral cyclopropanimines and hydrazones, respectively, and will allow novel access to chiral amine-containing scaffolds as well as strained chiral carbene equivalents. We firmly believe that the stability, ease of synthesis and modular character of these reagents will serve as a general solution to harvest the untapped versatility of cyclopropanones and its analogues as highly reactive building blocks in synthesis. Thus, this work will significantly expand the scope of disconnections available to chemists in the realm of strained ring activation and functionalization, evolving these severely strained derivatives from chemical curiosities to versatile synthetic intermediates, greatly contributing to streamline the production of biologically relevant organic molecules.

摘要 张力环化合物常被用作合成生物活性药物的关键中间体 和天然产物通过诸如扩环和开环的应变释放反应 流程.虽然小环酮如环丁酮已经发现广泛的应用性， 这些转化，环丙酮衍生物作为底物的类似用途， 由于这些化合物长期以来被认为是不可持续的合成中间体， 由于它们的极端应变和动力学不稳定性。这项工作提出了使用1-磺酰基环丙醇 作为有机合成中稳定的环丙酮替代物的一般类别， 以前无法通过应变释放反应合成断开。其中包括（1） 通过亲核试剂的加成引发重排，（2）过渡金属催化的C-C活化 （3）环丙酮衍生物作为1，1-环丙基 关键人物我们已经开发了一种有效的对映选择性路线，这些化合物， 在这些类型的反应中获得了重要的初步数据，导致了各种手性 其他方法难以接近的障碍物。磺酰基部分的电子和空间性质 在这些替代物中，它在这里充当碱不稳定的保护基团并赋予结晶性， 发现这些化合物对它们与环丙酮的平衡速率具有决定性的影响， 突出了它们的可调反应性和它们作为合成的广泛适用性的潜力， 中间体的在资助期间，利用获得的机械知识， 导致对映体富集的1-磺酰基环丙醇将扩展到形成1- 磺酰基环丙胺和肼作为手性环丙亚胺的模块前体， 腙，分别，并将允许新的访问手性含胺的支架，以及 应变手性卡宾等价物。我们坚信，稳定性，易于合成和模块化 这些试剂的特性将作为一种通用的解决方案，以收获未开发的多功能性， 环丙酮及其类似物在合成中作为高反应性结构单元。因此，这项工作将 显着扩大范围的断开提供给化学家在领域的紧张环 活化和功能化，使这些严重紧张的衍生物从化学好奇心发展到 多功能合成中间体，极大地促进了生物相关药物的生产 有机分子

项目成果

Expedient synthesis of spiro[3.3]heptan-1-ones via strain-relocating semipinacol rearrangements.

• DOI: 10.1016/j.tet.2023.133296
• 发表时间: 2023-02
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: M. Jung;Jane E. Muir;V. Lindsay

Divergent Synthesis of β-Fluoroamides via Silver-Catalyzed Oxidative Deconstruction of Cyclopropanone Hemiaminals.

通过环丙酮半缩醛的银催化氧化解构β-氟酰胺的发散合成。

• DOI: 10.1021/acs.orglett.3c01992
• 发表时间: 2023
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Jang,Yujin;Deng,Weixia;Sprague,IvanS;Lindsay,VincentNG
• 通讯作者: Lindsay,VincentNG

Synthesis of Highly Congested Tertiary Alcohols via the [3,3] Radical Deconstruction of Breslow Intermediates.

• DOI: 10.1021/acs.orglett.2c01627
• 发表时间: 2022-06-17
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Rivera, Roger Machin;Burton, Nikolas R.;Call, Luke D.;Tomat, Marshall A.;Lindsay, Vincent N. G.
• 通讯作者: Lindsay, Vincent N. G.

One-Pot Synthesis of Strain-Release Reagents from Methyl Sulfones.

• DOI: 10.1021/jacs.2c00923
• 发表时间: 2022-03-23
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Jung, Myunggi;Lindsay, Vincent N. G.
• 通讯作者: Lindsay, Vincent N. G.