Total Synthesis and Comparative Evaluation of Luzopeptin A−C and Quinoxapeptin A−C

Full details of the total syntheses of luzopeptin A−C and quinoxapeptin A−C, C2-symmetric cyclic depsidecapeptides bearing two pendant heterocyclic chromophores, are disclosed and serve to establish the quinoxapeptin relative and absolute configuration. Key elements of the approach include the late-stage introduction of the chromophore and penultimate l-Htp acylation permitting the divergent synthesis of the luzopeptins, quinoxapeptins, and structural analogues from a common advanced intermediate. Symmetrical pentadepsipeptide coupling and macrocyclization of the 32-membered ring conducted at the single secondary amide site provided the common cyclic decadepsipeptide. The convergent preparation of the required pentadepsipeptide with installation of the labile ester in the final coupling was achieved under surprisingly effective racemization-free conditions. The quinoxapeptins were shown to bind to DNA by high-affinity bisintercalation analogous to sandramycin and the luzopeptins. Significant similarities ...