Asymmetric Alkylations - Synthetic Utility of Formamidines

不对称烷基化 - 甲脒的合成用途

• 批准号: 9000344
• 负责人: Albert Meyers
• 金额: $ 55.81万
• 依托单位: Colorado State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1995-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9000344&HistoricalAwards=false
• 关键词: Asymmetric; Alkylations; Synthetic; Utility; Formamidines

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.

有机合成计划为这项研究提供资金。迈耶斯博士将继续他卓有成效的合成光学活性材料的新方法的开发。许多用于治疗疾病的分子具有光学活性，这项工作有可能为它们的合成提供新的途径。用丁基锂对手性甲胺进行金属化，然后与不同的亲电体进行烷基化反应，得到与氮相邻的C-C键，对映体选择性很高。这一进程现已进入高级阶段，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剩的螺异喹啉生物碱。还将寻找更有效和更容易获得的手性助剂，以增加季烷基化产物的%ee‘s。除了四碳立体中心外，还将尝试在具有生物重要性的合适目标上进行不对称全合成。其他研究将集中在这一过程的机理方面，使用锂核磁共振，分子模拟，和同位素衍生物，努力澄清有机锂中间体的性质和反应性。最后，已经掌握的机械性信息提供了一个线索，即作为获得这些光学活性胺的另一种手段，可以实现简单的拆分。