Tani Kousuke, Stoltz Brian M
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Boulevard, M/C 164-30, Pasadena, California 91125, USA.
Nature. 2006 Jun 8;441(7094):731-4. doi: 10.1038/nature04842.
The amide functional group is one of the most fundamental motifs found in chemistry and biology, and it has been studied extensively for the past century. Typical acyclic amides are planar. But the amide groups of bicyclic bridgehead lactams are highly twisted, and this distortion from planarity can dramatically affect the stability and reactivity of these amides; it also increases the basicity of the nitrogen so that it often behaves more like an amine than a typical planar amide. As a result, the structures and reactivity profiles of these 'anti-Bredt' amides differ significantly from those of planar amides. It is possible that this twisting phenomenon is not exclusive to cyclic systems-non-planarity may also be a critical biological design element that leads to amide ground-state destabilization and alters the reactivity, selectivity and mechanism of various protein and enzymatic processes (such as amide hydrolysis). The intriguing qualities of these twisted amides were first recognized in 1938 (ref. 11), wherein one of the simplest families was introduced--molecules containing the 1-azabicyclo[2.2.2]octan-2-one system. But the parent member of this group, 2-quinuclidone (molecule 1 in this paper), has not yet been unambiguously synthesized. Here, we report the chemical synthesis, isolation and full characterization of the HBF4 salt of 1. Critical to the success of the synthesis and isolation was the decision to generate 1 by a route other than classical amide bond formation. We anticipate that these results will provide a greater understanding of the properties of amide bonds.
酰胺官能团是化学和生物学中最基本的结构单元之一，在过去的一个世纪里受到了广泛的研究。典型的无环酰胺是平面的。但是双环桥头内酰胺的酰胺基团高度扭曲，这种与平面性的偏差会显著影响这些酰胺的稳定性和反应性；它还增加了氮的碱性，使得它的行为往往更像胺而不是典型的平面酰胺。因此，这些“反布瑞德特”酰胺的结构和反应活性与平面酰胺有很大不同。这种扭曲现象可能并非环状体系所特有——非平面性也可能是一个关键的生物学设计元素，导致酰胺基态不稳定，并改变各种蛋白质和酶促过程（如酰胺水解）的反应性、选择性和机制。这些扭曲酰胺的有趣特性最早在1938年被认识到（参考文献11），其中引入了最简单的一类分子——含有1-氮杂双环[2.2.2]辛烷-2-酮体系的分子。但是该类的母体成员，2-奎宁环酮（本文中的分子1）尚未被明确合成。在此，我们报告了1的HBF4盐的化学合成、分离及全面表征。合成和分离成功的关键在于决定通过经典酰胺键形成以外的途径生成1。我们预计这些结果将有助于更深入地理解酰胺键的性质。
