Total Synthesis\nof Exiguolide Stereoisomers: Impact\nof Stereochemical Permutation on Reactivity, Conformation, and Biological\nActivity

(−)-Exiguolide is a marine\nmacrolide natural product\nwith\npotent anticancer activity. In this study, the total synthesis of\nexiguolide 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\nby capitalizing on our macrocyclization/transannular pyran cyclization\nstrategy. The impact of the stereochemical permutation on the reactivity\nof advanced intermediates, the conformation of the macrocyclic skeleton,\nand the antiproliferative activity against human cancer cells were\ninvestigated 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\nthe same way as that of the parent natural product using stereoisomeric\nbuilding 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\nmetathesis and transannular pyran-forming reactions was significantly\ndifferent from that of naturally configured counterparts. The conformation\nof exiguolide stereoisomers, deduced by means of NMR spectroscopic\nanalysis and DFT calculations, was clearly different from that of\nthe parent natural product. Evaluation of the antiproliferative activity\nof exiguolide and its stereoisomers suggested the importance of the\nstereochemistry of the macrocyclic skeleton.