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 acid s. The results of studies with different protecting groups for the alpha-hy droxy acids and coupling systems for depside bond formation are presented. The oligomers were prepared using a Wang-type linker with final TFA/CH2Cl2 cleavage. Depside linkage of the THP-protected acids (THP = tetrahydropyran yl) to the resin-bound chains was achieved with DIC/DMAP (DIC = diisopropyl carbodiimide, DMAP = 4-(dimethylamino)pyridine) and monitored by a color te st with 4-(p-nitrobenzyl)pyridine. THP deprotection was achieved with p-TsO H in CH2Cl2/MeOH and was monitored by GC. Following the established procedu re, 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 hydr oxy 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 val inomycin analogue 30 ([L-Val-D-Man-D-Val-L-Lac](3)) was entirely synthesize d 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-hydrox yester macrocycles.