An original strategy was developed for the synthesis of valuable unsaturated macrocyclic lactones, macrodiolides, containing a 1Z,5Z-diene moiety in 57-79% yields and >98% stereoselectivity by hafnium triflate Hf(OTf)4-catalyzed intermolecular esterification of aliphatic α,ω-dicarboxylic acids with α,ω-alka-nZ,(n+4)Z-dienediols (1,12-dodeca-4Z,8Z-dienediol, 1,14-tetradeca-5Z,9Z-dienediol, 1,18-octadeca-7Z,11Z-dienediol). The diols were obtained by homo-cyclomagnesiation of tetrahydropyran ethers of oxygenated 1,2-dienes with EtMgBr in the presence of Mg metal and Cp2TiCl2 catalyst (10 mol. %). The resulting macrodiolides exhibit high cytotoxic activity in vitro against Jurkat, K562, U937, Hek293 and HeLa tumor cell lines.
The problem of stereoselective methods for the synthesis of macrocyclic compounds containing 1Z, 5Z-diene grouping in their structure was analyzed, using 1,2-dienes (Cemilev reaction) using alkyl halide derivatives of Mg (RMgX) by Ti- action at a key stage of the synthesis, containing complex catalysts. The resulting macro-carbocycles are of interest as new synthetic biologically active precursors for the creation of modern drugs for the treatment of cancer.