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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的应变的环状化合物通常用作合成生物活性药物的关键中间体和天然产物通过释放应变的反应，例如环膨胀和开环的反应过程。小环酮（例如环丁酮）发现了宽度的适用性这些转变，环丙酮衍生物作为底物的类似使用已认真滞后，因为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。这项工作提出使用1-磺基氯丙醇作为有机综合中稳定环丙酮的一般类以前通过应变释放反应无法访问的合成断开连接。这些包括（1）通过添加核粉状剂引发的重排，（2）过渡金属催化的C – C激活和解构策略，以及（3）将环丙酮衍生物应用于1,1-环丙基 Linchpins。我们已经为这些化合物开发了有效的对映选择性途径，并具有在每种类型的反应中获得了明显的初步数据，导致了多种手性合成子很难通过其他方法访问。磺酰基部分的电子和空间性质在这些替代物中，在这里充当基本的保护群体，并会议结晶度这些化合物被发现对它们对环丙酮的平衡速率具有至关重要的影响，突出显示其可调反应性和宽度适用性的潜力中间人。在资助期并使用获得的机械知识，这项技术导致映射1-磺酰基丙醇将扩展到1-的形成亚磺酮丙烷胺和氢嗪作为手性环丙胺的模块化前体分别为氢气区域，将允许新颖的访问手性胺的脚手架以及紧张的手性碳纤维当量。我们首先认为稳定性，易于合成和模块化这些试剂的特征将作为收获未开发多功能性的一般解决方案环丙酮及其类似物是合成中高反应性的构建块。那，这项工作将在紧张环领域，明显扩大了化学家可用的断开范围激活和功能化，使这些严重扭曲的衍生物从化学好奇心发展为多功能合成中间体，极大地促进了简化生物学相关的生产有机分子。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
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.