The natural product, uvaricin, was the first member of a now expanding family of bistetrahydrofuran-containing compounds to have its gross structure reported. Nothing was known prior to the initiation of this project about any of the stereochemical features of these materials. Various members of this family show extremely promising biological properties ranging from potent antitumor to pesticidal to antimicrobial activities. There is speculation that the binding of metal ions by these natural polyethers may play an important role in governing their biological behaviour. If so, then stereochemical issues will be of utmost importance. A series of oligomeric, stereoregular, 2,5-linked tetrahydrofurans will be prepared. The relative complexation constants of these stereoisomeric materials with various mono- and divalent metal ions will be measured in order to determine the magnitude of the dependence of binding on stereochemistry. The relative stereochemistry of all six of the stereogenic centers in the bis-THF portion of uvaricin (as well as asimicin and several other very new members of the natural family) is now known from the work performed during the first three years of the study. The stage is now set for further synthetic work which should solve the remaining stereochemical issue while simultaneously providing an interesting and complementary analog of uvaricin for biological screening. A great incentive to prepare simpler, symmetrical analogs of some of the extremely active natural compounds of this family in an effort to locate the active pharmacophore now exists and this will be undertaken. Symmetry concepts have played an important role in guiding the relevant chemical synthesis in this area. In the context of an ongoing synthesis of teurilene, a structurally related natural polyether, a new concept -- the synthesis of achiral molecules through the use of asymmetric synthesis -- which may have considerably more generality than might at first glance be apparent has been discovered. This idea will be further exploited in the course of completion of the teurilene synthesis as well as a synthesis of differide, a racemic natural dilactone.
