The First Broad Examination of Michael Reactions in the Presence of a Diverse Array of Acidic Spectator Functional Groups: Enantioselective Synthesis

在多种酸性观众官能团存在下对迈克尔反应的首次广泛检验：对映选择性合成

• 批准号: 315258217
• 负责人: Professor Dr. Thomas Nugent
• 金额: --
• 依托单位: Department of Life Sciences and Chemistry
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315258217?language=en
• 关键词: First; Broad; Examination; Michael; Reactions

During synthetic route planning acidic functional groups are purposely circumvented by using protection/deprotection protocols; but these protocols do more to increase waste and lower overall yield than any other general ailment of synthesis. Here we suggest that this general problem can be reduced by showing that many common acidic functional groups (pKa= 0 to 14) can be spectators that require no protection during enantioselective Michael reactions. Our preliminary results go beyond high stereochemical achievement, for example several of the demonstrated reactions do not have racemic equivalents, e.g. when a carboxylic acid spectator group is present. Because of the advantages afforded by removing the need for acid based protecting groups, we are now able to suggest the shortest enantioselective syntheses known to date for Pristiq, a Pfizer drug for depression, and an important natural product, Mevalonic acid. From a global perspective, we hope that this research will inspire a push within the synthetic community to broaden synthetic route planning to include more unprotected acidic moieties to allow for more step-efficient synthesis. Here we show that this is possible.

在合成路线规划期间，通过使用保护/去保护方案有意规避酸性官能团；但这些方案比任何其他一般的合成问题更会增加浪费并降低总产率。在这里，我们建议通过证明许多常见的酸性官能团（pKa = 0至14）可以在对映选择性迈克尔反应过程中不需要保护来减少这个普遍问题。我们的初步结果超出了高立体化学成就，例如几个演示的反应没有外消旋等价物，例如当存在羧酸观众基团时。由于消除了对酸基保护基团的需求所带来的优势，我们现在能够建议迄今为止已知的最短的对映选择性合成 Pristiq（一种辉瑞治疗抑郁症的药物）和一种重要的天然产物甲羟戊酸。从全球角度来看，我们希望这项研究能够激发合成界内的推动力，扩大合成路线规划，包括更多未受保护的酸性部分，以实现更高效的合成。在这里我们证明这是可能的。