Total Synthesis of Plusbacin A3 Using a Diastereoseletive Joullie-Ugi Three Component Reaction

In this manuscript, our synthetic study and antibacterial investigation of plusbacin A(3) (1), which is an antibacterial depsipeptide, and its dideoxy derivative are described. To establish an efficient total synthesis of 1, a solvent-dependent diastereodivergent Joullie-Ugi three-component reaction (JU-3CR) was optimized to construct trans-3-hydroxyl prolines [Pro(3-OH)]. Firstly, the effect of solvent on diastereoselectivity of the JU-3CR was investigated by an a-substituted five membered cyclic imine as a substrate. The cis and trans isomers were selectively generated in toluene and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), respectively. The Hammett analysis of the JU-3CR suggests the presence of two reaction mechanisms in the JU-3CR. With the diastreoselective JU-3CR in hand, we applied the reaction to the synthesis of plusbacin A(3). Two strategies were investigated toward the total synthesis of 1. In the first synthetic strategy, the key steps were the trans-selective JU-3CR and a late stage macrolactonization. The JU-3CR provided the desired trans products, and the coupling of the fragments to prepare the precursor to the cyclization proceeded smoothly. However, all the attempts toward the macrolactonization were unsuccessful to provide the desired cyclic peptide. Then, the second synthetic strategy that included an esterification in an initial stage was investigated. Two Pro(3-OH) residues were constructed by the JU3CR with a convertible isocyanide strategy. Subsequent peptide coupling and macrolactamization successfully afforded plusbacin A(3). Investigating the antibacterial activity of 1 compared with that of its dideoxy analogue revealed that the threo-beta-hydroxyaspartic acid residues are essential for antibacterial activity. Notably, there was a low potential for the development of resistance in S. aureus against plusbacin A(3).