Enantioselective Diels-Alder reactions catalyzed by hydrogen bonding
Enantioselective Diels-Alder reactions catalyzed by hydrogen bonding
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DOI：
10.1073/pnas.0308545101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Rawal, VH
中科院分区：
文献类型：
--
作者：
Thadani, AN;Stankovic, AR;Rawal, VH
就像生命的分子（例如，蛋白质和DNA），许多药物也是不对称的（手性）;它们不能在它们的镜像上重叠。药物的一种镜像形式（对映异构体）可能具有所需的活性，另一种则没有。因此，开发选择性合成一种对映体的方法具有重要的科学和经济意义。本文报道了一种简单的手性醇α，α，α ′，α ′-四芳基-1，3-二氧戊环-4，5-二甲醇（TADDOL）催化氨基二烯和取代丙烯醛的全碳Diels-Alder反应，以良好的收率和高的对映选择性（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，氢键是一种无处不在的“胶水”，有助于将水分子保持在一起，并保持蛋白质的3D结构。氢键催化在化学合成中很少使用，其中大多数反应通过与手性配体配位的刘易斯酸性金属盐的络合物来促进。与酶一样，氢键不仅将TADDOL组织成明确定义的构象，而且作为布朗斯台德酸催化剂，它还活化亲二烯体与二烯反应。TADDOL的总结构已被发现有一个深刻的影响的速率和对映选择性的环加成。这些结构-功能效应通过评估晶体状态下TADDOLs所采用的构象来合理化。有人建议，π，π-堆积在整个催化循环中起着核心作用，特别是，对映选择性步骤。
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 Bronsted 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.