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

在合成路线规划过程中，通过使用保护/去保护协议来有意避开酸性官能团；但是这些协议比任何其他合成的一般病症更容易增加浪费和降低总产率。在这里，我们建议，通过证明许多常见的酸性官能团(pKa=0到14)可以作为旁观者，在不对称Michael反应中不需要保护，可以减少这一普遍问题。我们的初步结果超越了很高的立体化学成就，例如，当存在羧酸旁观者基团时，几个已证明的反应没有外消旋等价物。由于消除了对酸性保护基团的需要所带来的优势，我们现在能够为Pristiq(辉瑞的一种治疗抑郁症的药物)和一种重要的天然产物甲伐他酸建议迄今最短的对映选择性合成。从全球的角度来看，我们希望这项研究将激励合成界内部推动扩大合成路线规划，以包括更多无保护的酸性部分，从而实现更高效的合成。在这里，我们展示了这是可能的。

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.