Practical Strategies for Controlling Selectivity in Organic Reactions

描述(由申请人提供)：开发具有高度选择性和原子经济性的化学转化是一种基本需求。在一系列有机转变中，指导集团在控制区域和立体化学方面发挥了关键作用。然而，导向基团策略通常需要在有机底物中引入化学计量的合成不受欢迎的官能团(如膦)。该计划的长期目标是通过开发能够同时可逆地与金属催化剂和常见有机官能团(如醇、胺和羧酸)结合的配体来解决这一限制。通过使用配体作为支架，将催化剂和底物暂时连接在一起，引导基团控制选择性的能力将与催化的实用性相耦合。支架策略的价值在于，我们可以应用合成上有用的官能团与配体结合，然后定制配体，以在所需的转化中获得最佳性能。这一概念将应用于一系列底物的区域、非对映和对映选择性氢甲酰化反应。这一策略的成功应用将大大拓宽氢甲酰化反应可获得的化合物的范围，这是一种有效和实用的金属催化反应，并将提供获得生物相关杂环的途径。一旦这一概念通过应用于催化氢甲酰化而确立，我们将把这一概念应用于其他重要的过渡金属催化反应。 与公共卫生相关：2002年，单一对映体药物占全球药品销售额的40%。在过去的二十年里，全世界批准的对映体药物的数量稳步增加，而无手性药物的比例从所有批准的药物的43%下降到34%。这些趋势产生了对高效和选择性地制造单一立体异构体产品的方法的需求。建议的研究通过开发一种新的策略来控制有机转化中的立体选择性，直接解决了这一需求。

DESCRIPTION (provided by applicant): There is a fundamental need to develop chemical transformations that are highly selective and atom-economical. Directing groups have played a pivotal role in controlling regio- and stereochemistry in a range of organic transformations. However, often directing-group strategies require the introduction of stoichiometric quantities of synthetically undesirable functional groups (such as phosphines) into the organic substrates. The long-term goal of this program is to address this limitation by developing ligands that have the ability to simultaneously and reversibly bind to a metal catalyst and common organic functional groups (such as alcohols, amines, and carboxylic acids). By using a ligand as a scaffold to temporarily join the catalyst and substrate together, the power of directing groups to control selectivity will be coupled to the practicality of catalysis. The value of the scaffolding strategy is that we can apply a synthetically useful functional group to bind to the ligand, and then tailor the ligand for optimal performance in the desired transformation. This concept will be applied towards the regio-, diastereo-, and enantioselective hydroformylation of a range of substrates. Successful application of this strategy will significantly broaden the scope of compounds accessible from hydroformylation, an efficient and practical metal-catalyzed reaction, and will provide access to biologically relevant heterocycles. Once this concept is established through application to catalytic hydroformylation, we will apply this idea to other significant transition metal- catalyzed reactions. PUBLIC HEALTH RELEVANCE: In 2002, single enantiomer pharmaceuticals made up 40% of worldwide drug sales. Over the last twenty years the number of enantiopure drugs approved worldwide has steadily increased, while the percentage of achiral drugs decreased from 43 to 34% of all approved drugs. These trends have created a need for methods that efficiently and selectively make single stereoisomer products. The proposed studies directly address this need by developing a new strategy for controlling stereoselectivity in organic transformations.