Catalytic C-C Bond Forming Hydrogenations

催化 C-C 键形成氢化

• 批准号: 8222427
• 负责人: MICHAEL J KRISCHE
• 金额: $ 1.91万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8222427
• 关键词: 1-Propanol; 3-hydroxybutanal; Accounting; Acetylene; Acylation; Alcohols; Aldehydes; Alkenes; Alkylation; Alkynes; Amines; Anhydrides; Butadiene; Carbon Monoxide; Catalysis; Cods; Coupling; Development; Drug Industry; Ethylenes; Family; Felis catus; Funding; Generations; Goals; Health; Hydrogen; Hydrogen Bonding; Hydrogenation; Imines; Iridium; Ketones; Laboratories; Ligands; Marketing; Mediating; Metals; Methodology; Methods; Oxidation-Reduction; Parents; Pharmaceutical Preparations; Process; Propanols; Propionates; Reaction; Reagent; Reducing Agents; Reporting; Research; Resolution; Rhodium; Sales; Scheme; Screening procedure; Staging; Technology; base; carbonyl compound; catalyst; design; drug development; drug market; enantiomer; news; oxidation; prenylation; propadiene

DESCRIPTION (provided by applicant): Enantioselective hydrogenation accounts for over half the chiral drugs produced industrially, withstanding physical or enzymatic resolution. Whereas conventional hydrogenation involves C-H bond formation, our research breaks dogma by establishing hydrogenation as a method for C-C bond formation. In the prior funding period, we demonstrated that hydrogenation could be used to couple diverse p-unsaturated reactants to carbonyl compounds and imines, constituting a byproduct-free alternative to stoichiometrically preformed organometallics in a range of classical C=X (X = O, NR) addition processes. In the proposed funding period, we seek to continue these first systematic efforts to exploit catalytic hydrogenation in C-C couplings beyond hydroformylation. PUBLIC HEALTH RELEVANCE: Over 50% of the world's top-selling drugs are single enantiomers and it is estimated that 80% of all drugs currently entering development are chiral and will be marketed as single-enantiomer entities. In 1994, the chiral drug market grossed over "45.2 billion US dollars worldwide, which corresponds to an increase of 27% in a single year!" In 1999, the chiral drug market topped 100 billion US dollars in sales. In 2002, world-wide sales of single enantiomer drugs reached more than 159 billion US dollars. Notably, enantioselective hydrogenation accounts for over half the chiral drugs produced industrially, withstanding physical or enzymatic resolution. The enormous impact of hydrogenation vis-¿-vis chiral drugs portends an equally powerful approach to reductive C-C bond formations mediated by hydrogen. However, since the discovery of alkene hydroformylation and the parent Fischer-Tropsch reaction, processes restricted to the use of carbon monoxide, the field of hydrogenative coupling has lain fallow. In this proposal, we report the first systematic efforts to exploit hydrogenation in C-C couplings beyond hydroformylation. Our efforts have led to the development of a broad new family "hydrogenative C-C couplings" - byproduct-free alternatives to stoichiometrically preformed organometallics in an ever-increasing range classical C=X (X = O, NR) addition processes.

描述（由申请人提供）：对映选择性氢化占工业生产的手性药物的一半以上，经受住物理或酶促拆分。传统的氢化涉及 C-H 键的形成，而我们的研究打破了教条，将氢化确立为 C-C 键形成的方法。在之前的资助期间，我们证明了氢化可用于将不同的对不饱和反应物与羰基化合物和亚胺偶联，在一系列经典的 C=X (X = O, NR) 加成过程中构成化学计量预形成的有机金属化合物的无副产物替代品。在拟议的资助期内，我们寻求继续这些首次系统性的努力，以在加氢甲酰化之外探索 C-C 偶联中的催化氢化。 公共卫生相关性：全球最畅销药物中超过 50% 是单一对映体，据估计，目前进入开发的所有药物中 80% 是手性药物，并将作为单一对映体实体上市。 1994年，手性药物市场总额“全球超过452亿美元，相当于一年增长了27%！” 1999年，手性药物市场销售额突破1000亿美元。 2002年，全球单一对映体药物销售额达到1590亿美元以上。值得注意的是，在物理或酶促拆分的情况下，对映选择性氢化占工业生产的手性药物的一半以上。氢化相对于手性药物的巨大影响预示着一种同样强大的方法来还原氢介导的 C-C 键形成。然而，自从发现烯烃加氢甲酰化和母体费托反应（仅限使用一氧化碳的工艺）以来，氢化偶联领域一直处于闲置状态。在本提案中，我们报告了首次在加氢甲酰化之外系统地利用 C-C 偶联中的氢化作用。我们的努力导致了一个广泛的新系列“氢化 C-C 偶联”的开发 - 在不断增加的经典 C=X (X = O, NR) 加成过程中，化学计量预形成的有机金属的无副产品替代品。