ALCAMS · Application of Assembly Line Synthesis to The Construction of Biologically Active Molecules

This proposal seeks to develop a new strategy for chemical synthesis which we term “Assembly Line Synthesis”. Our plan is to develop new reactions and strategies which enable us to essentially grow a carbon chain with complete control over its shape (stereochemistry) and functionality (which groups are incorporated) in a single operation. Our unique methodology involves the reaction between a lithiated carbamate and a boronic ester to give the homologated product. This chemistry can be done in an iterative manner, without the need for purification between steps, enabling complex molecules to be created with complete control of both relative and absolute stereochemistry. To date we have done 7 homologations in one pot with full stereocontrol. Indeed, through choosing the approriate stereochemistry of substituents along a carbon chain, we have grown a molecule which adopts a linear conformation. We are interested in the further development of the homologation of boronic ester methodology and its application in the synthesis of chemically and biologically useful molecules.We now plan to apply this methodology to the synthesis of the hydroxyl phthioceranic acid, a potent antigen that stimulates the immune response towards tuberculosis. We expect to make this molecule in just 2-3 discrete operations, a far cry from the 30+ steps taken in the past. In collaboration with Prof. Wender at Stanford, we also plan to prepare improved transporters to carry lipophilic drug molecules (like the potent anti-cancer compound taxol) into cells. We will use our iterative methodology to create lipophilic carbon chains bearing polar guanidinium rich side arms with specific shape and improved transporter properties.