The design and general synthesis of enantiopure isoxazolidinone monomers as precursors for the preparation of enantiopure N-terminal hydroxylamine-β 3 -oligopeptides, which may be used as reaction partners with α-ketoacids in the decarboxylative amide ligation reaction, is described.
Two synthetic approaches to aza-surfactins are reported. In the first, our recently developed synthesis of unnatural 3-amino acids was used to prepare the requisite monomer, which was used in solid phase peptide synthesis, and followed by macrolactamization of a partially protected precursor. In the second, the corresponding 3-N-hydroxyaminoacid was used to prepare a fully unprotected cyclization precursor that was closed to give 3-epi-aza-surfactin by the first example of cyclization by the -ketoacid-hydroxylamine amide formation. Dedicated to Professor Albert Padwa on the occasion of his 75 th birthday INTRODUCTION Surfactin, the principle member of the lipopeptides, is a powerful antibiotic with a unique mechanism. 1 This growing class of natural products is produced by the genus Bacillus and has found application not only as antibiotics but also as antivirals, fibrin clot inhibitors, and other biological applications. 2 Their mode of action is thought to be membrane permeabilization by a detergent-like disruption of the lipid bilayer along with complexation and transport of ions through the membrane. The precise mechanism, however, remains unknown and several competing theories have been proposed. 3 Several different surfactin structures are known but they all share a common architecture: seven α-amino acids joined as a depsipeptide by macrolactonization with a β-hydroxy fatty acid. Structural studies with NMR techniques reveal a characteristic saddle-horse shape. 4 The long alkyl hydrocarbon chains and their cyclic cores endow these peptides with an amphipathic nature, which allow them to penetrate the membrane and disturb the target cells. Surfactin has attracted considerable attention for their potential medical applications. Improvements to the bioactivity, particularly to reduced toxicity, may be gained by modification of their cyclic peptide core. To date surfactin has been produced almost exclusively by
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