FASTER CHEMICAL SYNTHESIS THROUGH MULTI-COMPONENT REACTIONS

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.