Chapter 11 Total synthesis of lipid I and lipid II: Late-stage intermediates utilized in bacterial cell wall biosynthesis

Abstract

Cell wall biosynthesis inhibitors have dominated treatment regimens for the management of bacterial infections. Two of the most widely used classes of antibiotics—namely, β-lactams and glycopeptides—derive their antibacterial activity through the inhibition of key steps in the bacterial cell wall biosynthesis cascade. The emergence of bacterial resistance to these agents has begun to erode their once dependable clinical efficacy and has heightened the urgency for the identification and development of novel chemotherapeutic agents. Advances in biochemistry and bacterial genomics have facilitated the isolation and purification of the enzymes utilized in peptidoglycan biosynthesis. The isolation of the cell wall precursors from natural sources has proven difficult and is impractical for securing quantities necessary to enable detailed mechanistic study. A program has been directed toward the synthesis of lipid I and lipid II; late-stage intermediates utilized in peptidoglycan biosynthesis. Bacterial peptidoglycan consists of a network of β-[1,4]-linked carbohydrate polymers that are cross-linked through pendant pentapeptide chains. In the recognition of the difficulty in obtaining lipid intermediates in quantities to facilitate detailed mechanistic study of the peptidoglycan biosynthetic enzymes, an effort has been directed toward a chemical synthesis of both lipid I and lipid II. Several technical challenges had to be addressed to reach the target compounds. These challenges and their solutions are discussed this chapter.