| Novel methodology and application of the intramolecular Diels-Alder (IMDA) reaction have been examined. The first project explored the IMDA reaction of acyclic (Z)-substituted-1,3-dienes—often considered to be poor substrates for this cyclization. It was found that under alkyl aluminum halide catalysis at temperatures below −20°C, efficient Diels-Alder cyclization of such susbstrates was possible, furnishing adducts in high endo selectivity and good to excellent yield. Substrates with aldehyde- and ketone-activated dienophiles were superior, while esters were not reactive. In sharp contrast, thermal Diels-Alder reaction of these substrates required high temperatures, resulted in low yields, and the endo selectivity precipitously dropped, in some cases favoring the exo product.; The second project aimed to synthesize superstolide A, a marine macrolide isolated from the New Caledonian sponge Neosiphonia superstes Sollas by D'Auria and coworkers in 1994. This compound is of synthetic interest due to its potent cytotoxic activity against several cancer cell lines. Some structural features of the compound present special challenges in its total synthesis, especially the substituted cis-octahydronaphthalene unit as well as a 16-membered lactone. The intramolecular Diels-Alder reaction was considered to be well suited for the construction of the cis-octahydronaphthalene nucleus. Synthesis of a highly functionalized pentaenylic Diels-Alder substrate was accomplished by successive Wittig olefination and Suzuki cross coupling reactions to incorporate a dienylic linchpin fragment. An intramolecular Diels-Alder reaction in 2,2,2-trifluoroethanol at 75°C proved to be successful and selective (≥6:1 diastereoselectivity). The adduct was elaborated to a silyl-protected seco acid intermediate, potentially leaving only five steps for completion of the total synthesis of superstolide A. |
