Efficient Asymmetric Synthesis by Dynamic Resolution of Organolithiums

The research outlined in this proposal is in the area of organic chemistry and in particular, the study of chiral organolithium species. When the lithium atom is attached to a carbon containing different substituents then two mirror image forms exist. These can interconvert by breaking the carbon-lithium bond and re-forming it on the opposite face of the molecule. In the presence of a different fixed single mirror image molecule that acts as a ligand to the lithium atom, then two molecules (diastereomeric complexes) are formed. These can have different stability and reactivity and this method can allow the resolution of the two mirror images of the organolithium. The mixture is then quenched and the selectivity in the final product arises from the preferential reaction of one of the mirror image forms of the organolithium. We have shown that this process is applicable to 5-membered rings (2-lithiopyrrolidines) and very high selectivities were achieved. A distinct advantage of this chemistry over other methods in asymmetric synthesis is that a dynamic process occurs, in which the two complexes can interconvert and hence high yields of the products are possible (unlike a conventional kinetic resolution). The aim of this research is to build on this powerful chemistry and apply it to other organolithium species. The first priority is to apply the chemistry to the preparation of enantiomerically enriched 6-membered rings (such as piperidines, piperazines and tetrahydroisoquinolines). These are important ring systems in many alkaloids and other biologically active molecules. Our chemistry will allow an efficient and selective method to access these products starting from simple organolithium species by carrying out a dynamic resolution in the presence of a chiral ligand. The method by which the dynamic resolution occurs and the best ligand, substituent on the nitrogen atom, solvent, temperature and time for resolution will be investigated. The research will also study the rate of interconversion of the mirror images as this will lead to useful information to effect the dynamic process. In addition, we will apply the chemistry to the preparation of some simple alkaloid natural products.The chemistry will then be extended to other compounds and in particular to acyclic compounds. This will lead to a general efficient asymmetric synthesis of chiral amines and alcohols. As above, we need to determine the extent of selectivity, the mode of resolution and rate of interconversion of the organolithiums and the absolute configuration of the products. This information will provide valuable insights into the role of a number of factors including the substrate structure, the substituents, solvent, temperature and additives on the chemical and configurational stability of organolithium species, plus of course their ability to act as substrates for effective dynamic resolution.