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

The paper details the synthesis of hapalosin analogs 4 (cyclic depsipeptide s) using solid-phase chemistry. Key building blocks were the Fmoc-protected gamma -amino-beta -hydroxy acid 11 and the THP-protected syn-beta -hydroxy acids 18. The amino acid 11 was fashioned from the amine 6 which was obtai ned by an ADH-route. The protected amino acids 18 were prepared by Evans al dol reactions. Esterification of 18 with the Wang resin started the solid-p hase assembly of the depsipeptides 25 containing all the building blocks. A final solution-phase deprotection of the amino group followed by macrolact amization completed the synthesis of the analogs 4. In one instance (compou nd 4aaa) the conformation was studied using ROESY NMR spectroscopy and MD s imulation. This revealed an almost complete (93:7) preference for the s-cis -rotamer. (C) 2001 Elsevier Science Ltd. All rights reserved.