The primary theme of this proposal is the development of samarium(II) iodide (SmI2) as a selective reductive coupling agent for organic synthesis. The proposal has been organized to reflect three current interests: development of individual reactions that can be promoted by SmI2; sequential processes for the efficient construction of complex molecules from simple substrates; and application of the methods developed to the synthesis of biologically relevant molecules. Ketyl-allene coupling reactions will be explored because few examples of this reaction exist in the literature and the availability of chiral, nonracemic substrates has the potential to provide a useful entry to highly functionalized, enantiomerically enriched cycloalkanols. A comprehensive examination of substrates that can undergo cyclization to form seven-, eight-, and perhaps even nine-membered rings will be undertaken. Finally, an examination of the generation of epoxy acyl- and aziridinyl acyl radicals (or the corresponding anions) by SmI2 and their use in organic transformations will be undertaken. A series of cascade processes has been targeted for study that would provide a useful and interesting transformation leading from relatively simple substrates to reasonably complex products. Thus a variety of simple reductive coupling/fragmentation processes are proposed that would lead to the construction of medium-membered carbocycles and heterocycles. Two enantioselective total syntheses are proposed that will utilize a SmI2-promoted reaction as a key step. The first is an efficient synthesis of the biologically active antihypertensive agent variecolin. The second is a synthesis of a tetracyclic sesterterpenoid that inhibits glycosylphosphatidylinositol (GPI)- anchoring at nanomolar concentrations. The study of the mechanism of action of GPI-anchoring inhibitors may lead to therapies for parasitic protozoan infections.