Total Synthesis of Exiguolide Stereoisomers: Impact of Stereochemical Permutation on Reactivity, Conformation, and Biological Activity

(-)-Exiguolide is a marine macrolide natural product with potent anticancer activity. In this study, the total synthesis of exiguolide stereoisomers, (9<i>R</i>)-exiguolide, (9<i>R</i>,13<i>S</i>)-exiguolide, and (9<i>R</i>,13<i>S</i>,19<i>R</i>)-exiguolide, was achieved by capitalizing on our macrocyclization/transannular pyran cyclization strategy. The impact of the stereochemical permutation on the reactivity of advanced intermediates, the conformation of the macrocyclic skeleton, and the antiproliferative activity against human cancer cells were investigated in detail. The total synthesis of (9<i>R</i>,13<i>S</i>)-exiguolide and (9<i>R</i>,13<i>S</i>,19<i>R</i>)-exiguolide was completed in much the same way as that of the parent natural product using stereoisomeric building blocks. Nevertheless, the reactivity of the (9<i>R</i>,13<i>S</i>)- and (9<i>R</i>,13<i>S</i>,19<i>R</i>)-series of intermediates in macrocyclic ring-closing metathesis and transannular pyran-forming reactions was significantly different from that of naturally configured counterparts. The conformation of exiguolide stereoisomers, deduced by means of NMR spectroscopic analysis and DFT calculations, was clearly different from that of the parent natural product. Evaluation of the antiproliferative activity of exiguolide and its stereoisomers suggested the importance of the stereochemistry of the macrocyclic skeleton.