The Organic Synthesis Program is funding this research. Dr. Meyers will continue his very fruitful development of new methods for synthesizing optically active materials. Many of the molecules used in treating diseases are optically active and this work has the potential to provide new routes for their synthesis. Metalation of chiral formamidines using butyllithiums, followed by alkylation with various electrophiles, gives C-C bonds adjacent to nitrogen in very high enantioselectivity. This process has now entered the advanced stage whereby complex alkaloids and other nitrogen-containing substances are being explored. Future efforts will center on quaternary carbon derivatives and attempts to reach a number of spiroisoquinoline alkaloids in high enantiomeric excess. A search for more efficient and readily available chiral auxiliaries will also be undertaken to increase the % ee's of the quaternary alkylated products. In addition to the quaternary carbon stereocenters, asymmetric total syntheses will be attempted at suitable targets of biological importance. Other studies will focus on mechanistic aspects of this process using Li-NMR, molecular modeling, and isotopic derivatives in an effort to clarify the nature and reactivity of the organolithium intermediates. Finally, mechanistic information, already in hand, has provided a clue that facile resolutions may be accomplished as an alternative means of reaching these optically active amines.
