Thadani Avinash N, Stankovic Ana R, Rawal Viresh H
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5846-50. doi: 10.1073/pnas.0308545101. Epub 2004 Apr 6.
Like molecules of life (e.g., proteins and DNA), many pharmaceutical drugs are also asymmetric (chiral); they are not superimposable on their mirror images. One mirror image form (enantiomer) of a drug can have desirable activity, the other not. Consequently, the development of methods for the selective synthesis of one enantiomer is of great scientific and economic importance. We report here that a simple, commercially available chiral alcohol, alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), catalyzes the all-carbon Diels-Alder reactions of aminosiloxydienes and substituted acroleins to afford the products in good yields and high enantioselectivities (up to 92% enantiomeric excess). It is remarkable that the reactions are promoted by hydrogen bonding, the ubiquitous "glue" that helps to keep water molecules together and holds up the 3D structures of proteins. Hydrogen bond catalysis is little used in chemical synthesis, wherein most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. As it does for enzymes, hydrogen bonding not only organizes TADDOL into a well defined conformation, but, functioning as a Brønsted acid catalyst, it also activates the dienophile toward reaction with the diene. The gross structure of the TADDOL has been found to have a profound influence on both the rate and the enantioselectivity of the cycloadditions. These structure-function effects are rationalized by evaluating the conformation adopted by the TADDOLs in the crystal state. It is suggested that pi,pi-stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.
像生命分子（如蛋白质和DNA）一样，许多药物也是不对称的（手性的）；它们与其镜像不能重叠。药物的一种镜像形式（对映体）可能具有理想的活性，而另一种则不然。因此，开发选择性合成一种对映体的方法具有重大的科学和经济意义。我们在此报告，一种简单的、市售的手性醇，α，α，α'，α'-四芳基-1,3-二氧戊环-4,5-二甲醇（TADDOL），催化氨基硅氧基二烯与取代丙烯醛的全碳狄尔斯-阿尔德反应，以良好的产率和高对映选择性（高达92%对映体过量）得到产物。值得注意的是，这些反应是由氢键促进的，氢键是一种普遍存在的“胶水”，有助于使水分子聚集在一起并维持蛋白质的三维结构。氢键催化在化学合成中很少使用，在化学合成中，大多数反应是由与手性配体配位的路易斯酸性金属盐配合物促进的。就像对酶一样，氢键不仅将TADDOL组织成一种明确的构象，而且作为布朗斯特酸催化剂，它还能激活亲双烯体与双烯发生反应。已发现TADDOL的整体结构对环加成反应的速率和对映选择性都有深远影响。通过评估TADDOL在晶体状态下所采用的构象，对这些结构-功能效应进行了合理化解释。有人认为，π-π堆积在整个催化循环中，特别是对映选择性步骤中起着核心作用。
