Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Acc Chem Res. 2009 Apr 21;42(4):530-41. doi: 10.1021/ar800182r.
IUPAC defines chemoselectivity as "the preferential reaction of a chemical reagent with one of two or more different functional groups", a definition that describes in rather understated terms the single greatest obstacle to complex molecule synthesis. Indeed, efforts to synthesize natural products often become case studies in the art and science of chemoselective control, a skill that nature has practiced deftly for billions of years but man has yet to master. Confrontation of one or perhaps a collection of functional groups that are either promiscuously reactive or stubbornly inert has the potential to unravel an entire strategic design. One could argue that the degree to which chemists can control chemoselectivity pales in comparison to the state of the art in stereocontrol. In this Account, we hope to illustrate how the combination of necessity and tenacity leads to the invention of chemoselective chemistry for the construction of complex molecules. In our laboratory, a premium is placed upon selecting targets that would be difficult or impossible to synthesize using traditional techniques. The successful total synthesis of such molecules demands a high degree of innovation, which in turn enables the discovery of new reactivity and principles for controlling chemoselectivity. In devising an approach to a difficult target, we choose bond disconnections that primarily maximize skeletal simplification, especially when the proposed chemistry is poorly precedented or completely unknown. By choosing such a strategy--rather than adapting an approach to fit known reactions--innovation and invention become the primary goal of the total synthesis. Delivery of the target molecule in a concise and convergent manner is the natural consequence of such endeavors, and invention becomes a prerequisite for success.
国际纯粹与应用化学联合会将化学选择性定义为“化学试剂优先与两个或多个不同官能团中的一个反应”，这个定义相当低调地描述了复杂分子合成的最大障碍。事实上，合成天然产物的努力往往成为化学选择性控制艺术和科学的案例研究，这是一种大自然已经熟练掌握了数十亿年但人类尚未掌握的技能。面对一个或多个反应性随意或顽固惰性的官能团，有可能破坏整个战略设计。有人可能会说，化学家控制化学选择性的程度与立体控制的最新技术相比相形见绌。在本报告中，我们希望说明必要性和坚韧不拔的结合如何导致用于构建复杂分子的化学选择性化学的发明。在我们的实验室中，优先选择使用传统技术难以或不可能合成的目标。成功地全合成这些分子需要高度的创新，这反过来又能够发现新的反应性和控制化学选择性的原则。在设计困难目标的方法时，我们选择的键断主要是最大限度地简化骨架，特别是当拟议的化学方法先例很少或完全未知时。通过选择这样的策略，而不是调整方法以适应已知的反应，创新和发明成为全合成的主要目标。以简洁和收敛的方式提供目标分子是这种努力的自然结果，而发明成为成功的先决条件。
