FASTER CHEMICAL SYNTHESIS THROUGH MULTI-COMPONENT REACTIONS

功能性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。现代合成化学家有各种各样的方法可供他们使用，帮助他们组装任何选定的目标分子(TM)。传统上，有机分子是以一种循序渐进的方式制造的，通过执行一系列线性化学反应，在每一步中将两个反应成分结合在一起。通过这种方式，TM的复杂性建立在许多化学变化上。在过去的两个世纪里，这种方法对这个主题起到了很好的作用。尽管如此，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，充满了困难。这项提议的重点是探索使用多组分反应(MCR)，为问题提供本质上更有吸引力的解决方案。在理想的MCR中，所有的反应组件都以一种精心安排的方式在一个步骤中聚集在一起。由于合成TM所需的步骤较少，因此节省了大量的时间和成本。此外，MCR的应用通常使合成更加环保，因为需要的溶剂和试剂更少。事实上，MCR在一锅反应中产生高度功能化的分子，这意味着它们在组合和面向复杂性的合成中特别重要，这在药物发现过程中很常见。尽管MCR提供了优势和机会，但实用MCR的开发仍然是一个巨大的挑战。主要的障碍来自这样一个事实，即很难发明一个含有三个或更多组分的反应来产生一种(且只有一种)产品。尽管存在这些困难，但如何合理设计新的MCRs，以便快速合成各种分子，对学术界和工业界的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类新的基于高度应变的亚甲基氮杂环系统的MCR。这种MCR具有许多使其相当吸引人的属性：(A)操作简单；(B)产生两个新的分子间碳-碳键；(C)产生在合成中用途极其广泛的中间体--酮亚胺；(D)可以在溶液中或在固相中进行；(E)可以作为单一对映体用于制造分子。根据这一计划，我们计划开发这种MCR的新变种。具体地说，我们将研究是否可以通过开发涉及杂原子亲核试剂(例如叠氮、胺、醇、硫醇等)的变体来大大扩大这一反应的范围。这些研究应该会产生更高官能化(因此更有用)的分子。在第二步工作中，我们将研究这种MCR的用途，利用这种化学方法快速合成一系列具有重要医学意义的化合物。将被制造的分子的例子包括：α，α-二取代氨基酸、β-内酰胺、α-酰氨基酰胺、四氢-β-卡宾、四氢异喹啉和喹啉。

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.