14-Membered cyclodepsipeptides with alternating β-hydroxy and α-amino acids by cyclodimerization

The cyclodimerization (twinning) of β-hydroxy acid amides of type under ‘direct amide cyclization’ (DAC) conditions is described. Although other coupling methods also gave moderate results, best yields were obtained via DAC, reaching 88% for the cyclodimer . In all cases, when starting with racemic material, only the trans-substituted cyclodepsipeptides were isolated. Simple molecular modeling revealed that the formation of the cyclodimer is thermodynamically slightly more favorable than that of the cyclomonomer. The proposal that cyclodimer formation is preferred because of the presence of intramolecular H-bonds could not be confirmed by X-ray crystallography. The influence of substituents, both in the amino acid and in the hydroxy acid moieties, was also studied. It is shown, that cyclodimerization was successful only when the hydroxy acid moiety is α,α-disubstituted.