Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp III.: Synthetic study of rhodopeptins

Total syntheses of cl,clo (-Gly-L-Lys-L-Val-(R)-3-aminododecanoyl-) LV9nA and its diastereomer cyclo (-Gly-L-Lys-L-Val-(S)-3-aminododecanoyl-) LV9nB, congeners of rhodopeptin B5 on beta-amino acid moiety, were achieved. The beta-amino acid moiety was prepared as a racemate by the thermal Michael addition of an amine to alpha,beta-unsaturated eater. The racemic beta-amino acids were converted to their L-Valylamide derivatives and the obtained diastereomers were separated. Coupling of both diastereomers, L-val-beta-amino acids with Gly-L-Lys gave linear tetrapeptides, and tetrapeptides were cyclized by diphenylphosphoryl azide (DPPA) method between C-terminus of beta-amino acid and N-terminus of Gly to give cyclic tetrapeptides. The deprotected cyclic tetrapeptides, LV9nA and LV9nB, both exhibited almost the same antifungal activity as the naturally obtained rhodopeptins. Furthermore, comparison of the H-1 NMR spectra of two congeners and rhodopeptin B5 suggested that the stereochemistry of beta-amino acid moiety in natural rhodopeptin B5 has (R)-configuration.