Asymmetric Alkylations - Synthetic Utility of Formamidines

有机合成计划资助了这项研究。迈耶斯博士将继续他卓有成效的开发合成光学活性材料的新方法。许多用于治疗疾病的分子都具有旋光性，这项工作有可能为它们的合成提供新的途径。用丁基锂金属化手性甲脒，然后与各种亲电试剂烷基化，得到与氮相邻的C-C键，具有很高的对映选择性。这一进程现已进入高级阶段，目前正在探索复杂的生物碱和其他含氮物质。未来的努力将集中在季碳衍生物上，并试图获得一些高对映体过量的螺异喹啉生物碱。还将寻求更有效和更容易获得的手性助剂，以提高季烷基化产品的ee %。除了四元碳立体中心外，不对称全合成将在具有生物学重要性的适当目标上进行尝试。其他研究将集中在这一过程的机理方面，利用Li-NMR、分子模型和同位素衍生物，努力阐明有机锂中间体的性质和反应性。最后，已经掌握的机械信息提供了一个线索，即作为获得这些旋光性胺的另一种方法，可以实现简单的决议。

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.