Synthesis of enolates by nucleophilic substitution

通过亲核取代合成烯醇化物

• 批准号: EP/W012626/1
• 负责人: Graham Pattison
• 金额: $ 51.7万
• 依托单位: University of Lincoln
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FW012626%2F1
• 关键词: Synthesis; enolates; nucleophilic; substitution

We need to be able to make new molecules to continue to advance technology that is available to society. The synthesis of new compounds underpins the discovery of new drugs, plastics, materials for displays and solar cells amongst a huge range of exciting applications. We need to be able to make these molecules in a way that is efficient as possible and minimises our impact on the environment. One factor that is extremely important for the efficiency of a synthesis is selectivity. A reaction must be as selective as possible so that it only generates our desired compound. A non-selective reaction will generate unwanted side-products that must be removed. This generates waste that must be removed, often using time-consuming procedures, and also must be disposed of in a way that minimises impact on the environment.One class of chemical compound that are especially useful in synthesis are ketones. These compounds show very versatile reactivity and are able to form a diverse range of new bonds. One key way that ketones react is as a type of intermediate known as an enolate. Enolates are one of our key intermediates for forming new carbon-carbon bonds, which make up the framework of all organic molecules. Enolates are normally made by removing a hydrogen ion attached to a carbon directly adjacent to a carbonyl group using a base. This leaves behind a negatively-charged intermediate which can react with an electrophile (positively charged species)This classical method for making an enolate can present several challenges with selectivity. The main one is that a ketone may have hydrogen atoms on either side of its carbonyl group, and either of these may be removed by a base. This leads to a mixture of enolates being formed and the final product will have a reduced yield as a result.Our strategy for making enolates circumvents this challenge by making enolates in a new way. Instead of making enolates by removing a hydrogen ion, we generate our enolate intermediate by substitution of an ester. To do this we react the ester with a nucleophile containing an atom (boron) that will make it act as if it is negatively charged. This then controls the site of partial negative charge in the enolate selectively, as only the side of the carbonyl group where the boron-containing group was introduced can react further. This prevents issues with selectivity and means that we can make a range of highly valuable ketones more efficiently and higher yielding than we could previously. This project aims to explore this new selective ketone synthesis fully to understand the types of systems that we can make using this method.

我们需要能够制造新的分子，以继续推进社会可用的技术。新化合物的合成为新药、塑料、显示器和太阳能电池材料的发现奠定了基础，这些材料有着广泛的令人兴奋的应用。我们需要能够以尽可能高效的方式制造这些分子，并将我们对环境的影响降至最低。对于合成效率极其重要的一个因素是选择性。反应必须尽可能具有选择性，以便只生成我们想要的化合物。非选择性反应将产生必须去除的不需要的副产物。这会产生必须去除的废物，通常需要耗时的程序，并且必须以最小化对环境影响的方式进行处理。酮是合成中特别有用的一类化合物。这些化合物显示出非常通用的反应性，并且能够形成各种各样的新键。酮反应的一个关键方式是作为一种称为烯醇化物的中间体。烯醇化物是形成新的碳-碳键的关键中间体之一，碳-碳键构成了所有有机分子的框架。烯醇化物通常通过使用碱除去连接到与羰基直接相邻的碳上的氢离子来制备。这留下了一个带负电荷的中间体，它可以与亲电体（带正电荷的物质）反应。主要的一个原因是酮在其羰基的任何一侧都可以有氢原子，并且这些氢原子中的任何一个都可以被碱除去。这导致形成烯醇化物的混合物，最终产品的产率将因此降低。我们的烯醇化物制备策略通过以新的方式制备烯醇化物来规避这一挑战。我们不是通过去除氢离子来制备烯醇化物，而是通过酯的取代来生成烯醇化物中间体。为了做到这一点，我们将酯与含有原子（硼）的亲核试剂反应，这将使它像带负电荷一样起作用。然后，这选择性地控制烯醇化物中部分负电荷的位点，因为只有引入含硼基团的羰基一侧可以进一步反应。这就避免了选择性的问题，意味着我们可以比以前更高效、更高产地生产一系列高价值的酮。该项目旨在充分探索这种新的选择性酮合成，以了解我们可以使用这种方法制造的系统类型。

项目成果

Assessing the rigidity of cubanes and bicyclo(1.1.1)pentanes as benzene bioisosteres

评估古巴烷和双环(1.1.1)戊烷作为苯生物等排体的刚性

• DOI: 10.1016/j.bmc.2024.117652
• 发表时间: 2024
• 期刊: Bioorganic & Medicinal Chemistry
• 影响因子: 3.5
• 作者: Pattison G