Thiyl Radicals and Isocyanides: A New Approach Towards Biologically Active Heterocycles

硫基自由基和异氰化物：研究生物活性杂环化合物的新方法

• 批准号: EP/J01544X/1
• 负责人: Stephen Hilton
• 金额: $ 12.77万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FJ01544X%2F1
• 关键词: Thiyl; Radicals; Isocyanides; New; Approach

The pharmaceutical industry is under intense pressure to improve the supply of new therapeutics whilst at the same time, reducing both cost and transition-time from discovery to application. This problem is hard to resolve without the development of new synthetic methodology or new technology and the proposed research will address both aspects of this.Most medicines and agrochemicals are based on heterocycles and as a result, the search for new efficient methodology for their syntheses that avoids the use of protecting groups is essential. One key neglected class of reaction that is an obvious solution to this problem is radical chemistry, which uses mild conditions without the need for protecting groups. However, radical chemistry has received little attention from the pharmaceutical industry because the majority of reactions involve the use of organotin derivatives and are often carried out at high dilution. Whilst this is acceptable for the gram amounts required for medicinal chemistry, this is clearly impractical when moving to the kilogram quantities required in process chemistry. Synthetic routes are often redesigned and radical chemistry removed to minimise the purification steps required to remove the toxic by-products. To address this challenge, flow chemistry technology has emerged as a viable means for performing many types of chemical transformations as reactions can be run over time or in parallel, to produce either gram or kilogram quantities. Therefore, the transition from medicinal to process laboratories has become less cost-intensive and flow-chemistry has attracted considerable attention from the pharmaceutical industry. Unfortunately, despite its potential, radical chemistry has not undergone the same transition in the pharmaceutical industry due to its reliance on organotin compounds. In preliminary studies, we have demonstrated that a non-toxic sulfur radical/ isocyanide based cyclisation of tricyclic heterocycles is viable and that it is a credible replacement for organotin derivatives. In the proposed research, we will explore the scope of this process to synthesise a range of key biologically active heterocycles, including anti-cancer compounds currently undergoing clinical trials. In conjunction with this, we will apply our chemistry to flow reactor technology to demonstrate that radical chemistry can be revisited as a method to produce larger scale quantities of material for the pharmaceutical industry.

制药行业面临着巨大的压力，需要改善新疗法的供应，同时减少从发现到应用的成本和过渡时间。如果没有新的合成方法或新技术的发展，这个问题很难解决，拟议的研究将解决这两个方面。大多数药物和农用化学品都是以杂环化合物为基础的，因此，必须寻找新的有效的合成方法，避免使用保护基团。一个被忽视的反应类别是自由基化学，它是解决这个问题的一个明显的方法，它使用温和的条件而不需要保护基团。然而，自由基化学很少受到制药工业的关注，因为大多数反应涉及使用有机锡衍生物，并且通常在高稀释度下进行。虽然这对于药物化学所需的克量是可以接受的，但当转移到过程化学所需的千克量时，这显然是不切实际的。通常重新设计合成路线，去除自由基化学，以尽量减少去除有毒副产物所需的净化步骤。为了应对这一挑战，流动化学技术已经成为一种可行的方法，可以进行多种类型的化学转化，因为反应可以长时间进行，也可以并行进行，可以产生克或公斤的数量。因此，从药物实验室到过程实验室的转变已经变得不那么成本密集，流动化学已经引起了制药工业的相当大的关注。不幸的是，尽管具有潜力，但由于对有机锡化合物的依赖，自由基化学在制药工业中并没有经历同样的转变。在初步研究中，我们已经证明了基于硫自由基/异氰化物的无毒三环杂环化是可行的，并且它是有机锡衍生物的可靠替代品。在拟议的研究中，我们将探索这一过程的范围，以合成一系列关键的生物活性杂环化合物，包括目前正在进行临床试验的抗癌化合物。与此同时，我们将把我们的化学应用于流动反应器技术，以证明自由基化学可以作为一种为制药工业生产更大规模材料的方法。

项目成果

A Radical-Mediated Approach to the Total Synthesis of Fluorinated Marinoquinoline A and Related Tricyclic and Tetracyclic Congeners

• DOI: 10.1055/s-0034-1378614
• 发表时间: 2015-01-01
• 期刊: SYNLETT
• 影响因子: 2
• 作者: Patel, Bhaven;Hilton, Stephen T.
• 通讯作者: Hilton, Stephen T.

ChemInform Abstract: A Radical-Mediated Approach to the Total Synthesis of Fluorinated Marinoquinoline A and Related Tricyclic and Tetracyclic Congeners.

ChemInform 摘要：一种自由基介导的氟化马林喹啉 A 及相关三环和四环同系物全合成方法。

• DOI: 10.1002/chin.201522219
• 发表时间: 2015
• 期刊: ChemInform
• 作者: Patel B

Three-Dimensional Printing of a Scalable Molecular Model and Orbital Kit for Organic Chemistry Teaching and Learning

• DOI: 10.1021/acs.jchemed.6b00953
• 发表时间: 2017-09-01
• 期刊: JOURNAL OF CHEMICAL EDUCATION
• 影响因子: 3
• 作者: Penny, Matthew R.;Cao, Zi Jing;Hilton, Stephen T.
• 通讯作者: Hilton, Stephen T.

Tuneable radical cyclisations: a tin-free approach towards tricyclic and spirocyclic heterocycles via a common precursor

• DOI: 10.1039/c4ra02420f
• 发表时间: 2014-04
• 期刊: RSC Advances
• 影响因子: 3.9
• 作者: B. Patel;G. Saviolaki;C. Ayats;M. A. E. Garcia;T. Kapadia;S. Hilton