Syntheses of Dap-3 Polymyxin Analogues via a Tris-Boc-Protected Polymyxin B Heptapeptide

A semi-synthesis of a polymyxin (PMB) analogue is described. Commercially available PMB is treated with di-tert-butyl dicarbonate (Boc₂O) to give globally protected PMB-Boc₅, and the reaction mixture is directly carried to the highly regioselective enzymatic hydrolysis to give the cyclic heptapeptide PMBH-Boc₃. After chromatographic isolation, the synthesis is completed by coupling with the tripeptide side chain, deprotection, and salt switch.