FASTER CHEMICAL SYNTHESIS THROUGH MULTI-COMPONENT REACTIONS

通过多组分反应加快化学合成速度

• 批准号: EP/D035384/1
• 负责人: Mike Shipman
• 金额: $ 30.38万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FD035384%2F1
• 关键词: FASTER; CHEMICAL; SYNTHESIS; THROUGH; MULTI

The chemical synthesis of functional organic molecules continues to underpin many key advances in human medicine, crop protection, biotechnology, and material science. Modern synthetic chemists have a vast array of methods at their disposal to assist them in the assembly of any chosen target molecule (TM). Traditionally, organic molecules are made in a stepwise fashion, by executing a linear sequence of chemical reactions, which forge the union of two reaction components in each step. In this way, the complexity of the TM is built up over a number of chemical transformations. This approach has served the subject very well over the last two centuries. That said, the synthesis of even moderately complex TMs remains a costly and labour-intensive undertaking that is fraught with difficulties. This proposal focuses on exploring the use of multi-component reactions (MCRs) that offer an intrinsically more attractive solution to the problem. In an idealised MCR, all the reaction components come together in an orchestrated way in a single step. As the resultant synthesis of the TM requires fewer steps, significant time and cost savings accrue. In addition, the application of MCRs often makes the synthesis more environmentally benign as fewer solvents and reagents are required. The fact that MCRs generate highly functionalised molecules in one-pot reactions means that they are especially important in combinatorial and complexity-oriented synthesis, common in the drug discovery process. Despite the advantages and opportunities that MCRs offer, the development of practical MCRs remains a significant challenge. The principal obstacle stems from the fact that it is much harder to invent a reaction with three or more components that produces one (and only one) product. In spite of such difficulties, the rational design of new MCRs, for the rapid synthesis of all kinds of molecules, represents a timely and important challenge for academic and industrial researchers alike. Our research group has discovered a new class of MCR based upon the highly strained methyleneaziridine ring system. This MCR has a number of attributes which make it rather attractive: (a) it is operationally simple to perform; (b) generates two new intermolecular carbon-carbon bonds; (c) produces ketimines which are extremely versatile intermediates in synthesis; (d) can be performed in solution or on solid phase; (e) can be used to make molecules as single enantiomers. Under this programme, we plan to develop new variants of this MCR. Specifically, we will examine if the scope of this reaction can be substantially broadened by the development of variants involving heteroatom based nucleophiles (e.g. azide, amines, alcohols, thiols etc). More highly functionalised (and hence more useful) molecules should emerge from these studies. In a second strand of work, we will examine the use of this MCR for the rapid synthesis of a wide range of medicinally important classes of compound using this chemistry. Examples of the molecules to be made include: alpha,alpha-disubstituted amino acids, beta-lactams, alpha-acylaminoamides, tetrahydro-beta-carbolines, tetrahydroisoquinolines, and quinolines.

功能有机分子的化学合成继续支撑着人类医学、作物保护、生物技术和材料科学的许多关键进展。现代合成化学家拥有大量方法可以帮助他们组装任何选定的目标分子 (TM)。传统上，有机分子是通过执行线性化学反应序列以逐步方式制造的，在每个步骤中形成两个反应组分的结合。通过这种方式，TM 的复杂性是通过许多化学转化而建立起来的。在过去的两个世纪里，这种方法很好地服务了这个主题。也就是说，即使是中等复杂的TM的合成仍然是一项成本高昂、劳动密集型的工作，而且充满困难。该提案的重点是探索多组分反应（MCR）的使用，为该问题提供本质上更具吸引力的解决方案。在理想化的 MCR 中，所有反应组分在一个步骤中以精心策划的方式聚集在一起。由于 TM 的合成需要更少的步骤，因此可以节省大量时间和成本。此外，MCR 的应用通常使合成更加环保，因为需要更少的溶剂和试剂。 MCR 在一锅反应中生成高度功能化的分子这一事实意味着它们在药物发现过程中常见的组合和面向复杂性的合成中尤其重要。尽管 MCR 提供了优势和机遇，但实用 MCR 的开发仍然是一个重大挑战。主要障碍源于这样一个事实：发明一种由三种或更多组分产生一种（且仅一种）产物的反应要困难得多。尽管存在这些困难，合理设计新的 MCR 以快速合成各种分子，对学术和工业研究人员来说都是一个及时而重要的挑战。我们的研究小组发现了一种基于高张力亚甲基氮丙啶环系统的新型 MCR。该 MCR 具有许多使其相当有吸引力的属性： (a) 操作执行简单； (b)产生两个新的分子间碳-碳键； (c) 生产酮亚胺，酮亚胺是合成中极其通用的中间体； (d)可以在溶液中或在固相上进行； (e) 可用于制备单一对映体的分子。根据该计划，我们计划开发该 MCR 的新变体。具体来说，我们将检查是否可以通过开发涉及基于杂原子的亲核试剂（例如叠氮化物、胺、醇、硫醇等）的变体来大幅拓宽该反应的范围。这些研究应该会出现更多功能化（因此更有用）的分子。在第二部分工作中，我们将研究这种 MCR 的用途，利用这种化学方法快速合成各种具有重要药用价值的化合物。待制备的分子的实例包括：α，α-二取代氨基酸、β-内酰胺、α-酰基氨基酰胺、四氢-β-咔啉、四氢异喹啉和喹啉。