Synthesis of Macrocyclic Lactones via Ring Transformation of 4-(w-Hydroxyalkyl)-1,3-oxazol-5(4H)-ones

Abstract

The synthesis of alpha-benzamido-alpha-benzyl lactones 23 of various ring size was achieved either via ‘direct amide cyclization’ by treatment of 2-benzamido-2-benzyl-omega-hydroxy-N,N-dimethylalkanamides 21 in toluene at 90 – 110° with HCl gas or by ‘ring transformation’ of 4-benzyl-4-(omega-hydroxyalkyl)-2-phenyl-1,3-oxazol-5(4H)-ones under the same conditions. The precursors were obtained by C-alkylations of 4-benzyl-2-phenyl-1,3-oxazol-5(4H)-one (15) with THP- or TBDMS-protected omega-hydroxyalkyl iodides. Ring opening of the THP-protected oxazolones by treatment with Me2NH followed by deprotection of the OH group gave the diamides 21, whereas deprotection of the TBDMS series of oxazolones 25 with TBAF followed by treatment with HCl gas led to the corresponding lactones 23 in a one-pot reaction.