A General Methodology for Automated Solid-Phase Synthesis of Depsides and Depsipeptides. Preparation of a Valinomycin Analogue.

A general methodology is described that allows the solid-phase synthesis of depsides and depsipeptides from chiral alpha-hydroxy- and alpha-amino acids. The results of studies with different protecting groups for the alpha-hydroxy acids and coupling systems for depside bond formation are presented. The oligomers were prepared using a Wang-type linker with final TFA/CH(2)Cl(2) cleavage. Depside linkage of the THP-protected acids (THP = tetrahydropyranyl) to the resin-bound chains was achieved with DIC/DMAP (DIC = diisopropylcarbodiimide, DMAP = 4-(dimethylamino)pyridine) and monitored by a color test with 4-(p-nitrobenzyl)pyridine. THP deprotection was achieved with p-TsOH in CH(2)Cl(2)/MeOH and was monitored by GC. Following the established procedure, depsides made up from the same enantiomer (i.e., H-[L-Man](8)-OH, 25), by both enantiomers (i.e., H-[D-Man-L-Man](4)-OH, 26), or by different hydroxy acids in the same chain (i.e., H-[L-Lac-L-Hiv](3)-OH, 27) were prepared with an average yield of 95-97% per cycle. The linear precursor of the valinomycin analogue 30 ([L-Val-D-Man-D-Val-L-Lac](3)) was entirely synthesized on resin and cyclized in solution. Cyclization of the open-chain depsides is the final step in the preparation of a new class of chiral alpha-hydroxyester macrocycles.