Catalytic C-C Bond Forming Hydrogenations

催化 C-C 键形成氢化

• 批准号: 8269204
• 负责人: MICHAEL J KRISCHE
• 金额: $ 5.07万
• 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/8269204
• 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）：工业上生产的手性药物中，对映选择性氢化占一半以上，可经受物理或酶的溶解。传统的氢化反应涉及碳-氢键的形成，而我们的研究打破了常规，建立了氢化反应作为碳-碳键形成的方法。在之前的资助期内，我们证明了加氢可以用于将各种p-不饱和反应物偶联到羰基化合物和亚胺，在一系列经典的C=X （X = O， NR）加成过程中构成无副产物的化学计量预成型有机金属的替代品。在提议的资助期内，我们寻求继续这些第一个系统的努力，以利用催化氢化C-C偶联超越氢甲酰化。公共卫生相关性：世界上最畅销的药物中有50%以上是单对映体，据估计，目前正在开发的所有药物中有80%是手性的，并将作为单对映体实体上市。1994年，全球手性药物市场总额超过452亿美元，相当于一年增长27% ！1999年，手性药物市场销售额突破1000亿美元。2002年，全球单对映体药物销售额超过1590亿美元。值得注意的是，在工业生产的手性药物中，对映选择性氢化反应占了一半以上，尽管存在物理或酶的溶解。氢化对手性药物的巨大影响预示着氢介导的还原性C-C键形成的同样强大的方法。然而，自从发现烯烃氢甲酰化反应和母体费托反应（仅限于使用一氧化碳的过程）以来，氢化偶联的研究领域就停滞不前了。在这一建议中，我们报告了第一个系统的努力，利用氢甲酰化以外的C-C偶联的氢化。我们的努力导致了一个广泛的新家族“氢化C-C偶联”的发展-在不断增加的范围内，化学计量预成型有机金属的无副产物替代品经典C=X （X = O， NR）加成工艺。