Total Synthesis of Hapalosin and Two Ring Expanded Analogs

The macrocyclic depsipeptide hapalosin was assembled from three subunits. Beginning with the condensation of a protected β-hydroxy acid 13 with the α-hydroxy ester 14, the hydroxy diester 16 was produced. This compound, in turn, was condensed with the γ-amino-β-hydroxy acid 17. Macrocyclization was performed on the fully deprotected amino acid 20. In a similar manner, a cyclization substrate 28 was prepared that contains valine instead of the α-hydroxy acid. In this case, however, the cyclization with the Shioiri reagent induced a Curtius rearrangement prior to the cyclization reaction. As a result the two ring expanded hapalosin analogs 29 and 30 were formed. The conformations of the three macrocycles were studied by 2D NMR spectroscopy and molecular dynamics simulation. It was found that in DMSO-d6 all of them prefer the s-trans-amide rotamer around the tertiary amide.