The continuing challenge in the area of organic synthesis is to develop synthetic reactions that have generality, yet exhibit great selectivity. Dr. Molander has discovered a way to take an old reaction, the so-called Reformatsky reaction, and greatly increase its usefulness in the synthesis of complex natural products like the beta-lactam antibiotics. This project is in the Organic and Macromolecular Chemistry Program. This will develop novel entries into complex, enantiomerically pure organic substrates. The first aspect of the research will explore use of samarium diiodide-induced intramolecular Reformatsky reactions. Full development of this methodology will permit access to syn 1,3-diols by 1,3-asymmetric induction in a carbon-carbon bond-forming process. Facile generation of HMG-CoA reductase inhibitors is one of many important contributions that this advancement will permit. Application to nitrogen-containing substrates is also planned, and important new routes to pharmacologically important aminoglycoside and beta-lactam antibiotics will result from this aspect of the study. Chemistry based upon samarium diiodide reduction of vinyl oxiranes comprises the second aspect of the study. Allylic alcohols generated by this process will be incorporated into several natural products syntheses, including leukotriene B4. Another unique method for 1,3-asymmetric induction is planned, involving intramolecular Michael addition of samarium-based Reformatsky reagents to conjugated olefins. A novel cyclopropanation reagent, Sm/CH2I2, will be thoroughly studied to determine its unique role in organic synthesis, utilizing allylic alcohols as substrates in the first aspect of studies in this area. Stereocontrolled cyclizations onto chiral epoxides constitute another proposed approach to chiral carbocycles and heterocyclic substrates. Reactions utilizing alkynylborates and allylsilanes will be explored to provide access to organic molecules in which up to three contiguous stereocenters are controlled in a completely predictable fashion. Finally, the chemistry of epoxy anions will be explored. These unique nucleophiles may very well revolutionize the manner in which the versatile epoxide functional group is incorporated into organic molecules.
