Molecules by Assembly-Line Synthesis: Conformational Control and Biological Activity Study

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Aggarwal's assembly-line synthesis represents a unique method that allows us to build a carbon chain by iterative homologation of boronic esters using chiral lithiated carbamates or esters as building blocks. The reaction shows high efficiency and complete stereocontrol in most cases, and its potential applicability has been further demonstrated with total syntheses of biologically active natural products. In this project, we propose to extend this methodology to the synthesis of conformationally designed molecules containing large substituents on side chains. We will investigate their three-dimensional structures by X-ray, advanced NMR and computational analysis, and determine the extent of conformational control remote from the main chain. This study will give us the knowledge of how to position molecular fragments with variable size in a precise position. In order to demonstrate the potential of this conformational control study, we will target helical structures with specific groups at specific places for optimum bonding to disrupt protein-protein interactions involved in cancer. We hope that the assembly-line synthesis along with conformational control study will enable us to rapidly build a series of biologically active compounds and facilitate new drug discovery.