Syntheses of hapalosin analogs by solid-phase assembly of acyclic precursors

Abstract

The paper details the synthesis of hapalosin analogs 4 (cyclic depsipeptides) using solid-phase chemistry. Key building blocks were the Fmoc-protected γ-amino-β-hydroxy acid 11 and the THP-protected syn-β-hydroxy acids 18. The amino acid 11 was fashioned from the amine 6 which was obtained by an ADH-route. The protected amino acids 18 were prepared by Evans aldol reactions. Esterification of 18 with the Wang resin started the solid-phase assembly of the depsipeptides 25 containing all the building blocks. A final solution-phase deprotection of the amino group followed by macrolactamization completed the synthesis of the analogs 4. In one instance (compound 4aaa) the conformation was studied using ROESY NMR spectroscopy and MD simulation. This revealed an almost complete (93:7) preference for the s-cis-rotamer.