Method for the synthesis of cyclic depsipeptides

A method of synthesizing a depsipeptide of formula (IIa) from formula (IV) and formula (III):

• wherein PG2 is an amine protecting group and PG3 is a carboxylic acid protecting group, and
• by:
• deprotecting the amine group that is protected by PG2 in the formula (IV) in the presence of a base to obtain a deprotected amine group;
• deprotecting the carboxylic acid that is protected by the group PG3 in the formula (III) in the presence of an acid to obtain a deprotected carboxylic acid group;
• and
• condensing the deprotected amine group and the carboxylic acid group to obtain the depsipeptide of formula (IIa);
• and further synthesizing a cyclic depsipeptide of formula (I) from the depsipeptide of formula (IIa):
• wherein Y is an amine protecting group and X is a carboxylic acid protecting group;
• wherein
• R2 and R8, are independently hydrogen, straight-chain or branched C1-C8-alkyl, straight-chain or branched halogenated C1-C8 alkyl, hydroxy-C1-C6-alkyl, C1-C4-alkanoyloxy-C1-C6-alkyl, C1-C4-alkoxy-C1-C6-alkyl, aryl-C1-C4-alkyloxy-C1-C6-alkyl, mercapto-C1-C6-alkyl, C1-C4-alkylthio-C1-C6-alkyl, C1-C4-alkylsulphinyl-C1-C6-alkyl, C1-C4-alkylsulphonyl-C1-C6-alkyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, C1-C4-arylalkoxycarbonyl-C1-C6-alkyl, carbamoyl-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C4-alkylamino-C1-C6-alkyl, C1-C4-dialkylamino-C1-C6-alkyl, guanidino-C1-C6-alkyl, C1-C4-alkoxycarbonylamino-C1-C6-alkyl, 9-fluorenylmethoxycarbonyl(Fmoc)amino-C1-C6-alkyl, C2-C8-alkenyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, benzyl, substituted benzyl, phenyl, or phenyl-C1-C4-alkyl which may optionally be substituted by halogen;
• wherein x is 1, y is 1, R1, R4, R7 and R10 are each methyl, R6 and R12 are each methyl, R5 and R11 are each independently a straight-chain or branched C1-C4-alkyl or a straight-chain or branched halogenated C1-C4-alkyl, and R3 and R9 are each independently benzyl or substituted benzyl;
• wherein synthesizing a cyclic depsipeptide of formula (I) from the depsipeptide of formula (IIa) comprises:
• deprotecting the amine group that is protected by Y in the presence of an acid to obtain a deprotected amine group;
• deprotecting the carboxylic acid that is protected by X via hydrogenolysis to obtain a deprotected carboxylic acid group;
• and
• condensing the deprotected amine group and the deprotected carboxylic acid group by a coupling agent to obtain the cyclic depsipeptide of formula (I),
• wherein the coupling agent is BOP ((Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HBTU (2-(1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate) or Propylphosphonic anhydride (2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, PPACA).