Polyketides via C-C Coupling of Alcohols: Green Chemistry.

通过醇的 C-C 偶联的聚酮化合物：绿色化学。

• 批准号: 8461879
• 负责人: MICHAEL J KRISCHE
• 金额: $ 7.04万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461879
• 关键词: Alcohols; Aldehydes; Alkenes; Alkynes; Biological Factors; Chemistry; Cods; Coupling; Development; Drug Industry; FDA approved; Family; Felis catus; Generations; Glycols; Hydrogen; Investigation; Ligands; Marketing; Metals; Methods; Morus; Oxidation-Reduction; Pharmaceutical Preparations; Process; Reagent; Reporting; Route; Source; Study Section; Technology; Therapeutic Agents; base; bryostatin; bryostatin 2; catalyst; diene; drug development; drug discovery; enantiomer; meetings; news; oxidation; propadiene; prospective; public health relevance; small molecule

DESCRIPTION (provided by applicant): We report a broad, new class of metal-catalyzed C-C bond formations - the direct C-C coupling of alcohols and ?-unsaturated compounds. These processes enable carbonyl addition from the alcohol oxidation level and provide access to chiral building blocks that are typically prepared using stoichiometric quantities of pre-metallated nucleophiles (e.g. allylmetal reagents). However, unlike classical approaches, the alcohol C-C coupling processes we report circumvent discrete redox manipulations required for generation of aldehyde electrophiles, and they avoid the generation of molar quantities of metallic byproducts. Here, we propose the first systematic investigations into "alcohol-unsaturated C-C coupling" and demonstrate how such processes dramatically simplify the synthesis of polyketide natural products, which are an important class of FDA-approved therapeutic agents. Established Catalytic Enantioselective Processes OH [Ir (cod) Cl] 2 (2.5 mol%) OH AcO (R)-Cl,MeO-BIPHEP (5 mol%) R R m-NO2BzOH (10 mol%) Cs2CO3 (20 mol%) 100 mol% 10 equiv. THF (0.2 M), 100 oC 51-83% Yield or 200 mol% 86-95% ee Proposed Catalytic Enantioselective Processes OH MLn (cat.) Diverse R2 R1 Unsaturates R1 Chiral Ligand Me or Modifier From Olefins R2 OH [Ir(cod)Cl]2 (2.5 mol%) OH AcO (S)-SEGPHOS (5 mol%) R R Me 4-CN-3-NO2BzOH (10 mol%) Me Cs2CO3 (20 mol%) 100 mol% 200 mol% THF (1.0 M), 90 oC 61-73% Yield 86-97% ee 5:1-8:1dr OH R2 OH OH OH R2 R1 R1 R1 R2 R1 Me R2 R3 R3 Me From Dienes From Allenes From Alkynes From Enynes R2 R2 R2 R2 R3 R3 PUBLIC HEALTH RELEVANCE: Over 60% of the 974 small molecules introduced as drugs worldwide from 1981-2006 were inspired by "Natural Products".1 Among naturally occurring compounds, polyketides rank among 20% of the top-selling FDA-approved small molecule drugs.2 Accordingly, 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.4 Here, we propose the first systematic investigations into "alcohol- unsaturated C-C coupling" and demonstrate how such processes dramatically simplify the synthesis of polyketide natural products, which are an important class of FDA-approved therapeutic agents. (1) "Natural Products as Sources of New Drugs over the Last 25 Years," Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461. (2) (a) "Natural Products in Drug Discovery and Development," Cragg, G. M.; Newman, D. J.; Snader, K. M. J. Nat. Prod. 1997, 60, 52-60. (b) "Recent Natural Products Based Drug Discovery: A Pharmaceutical Industry Prospective," Shu, Y.-Z. J. Nat. Prod. 1998, 61, 1053. (3) "Chiral Drugs," Stinson, S. C. Chem. Eng. News 1998, 76 (Sept. 21), 83. (4) "The Impact of Chiral Technology on the Pharmaceutical Industry," Richards, A.; McCague, R. Chem. Ind. 1997, June 2, 422.

描述（由申请人提供）：我们报告了一类广泛的，新的金属催化的C-C键形成-醇和？不饱和化合物。这些工艺使羰基从醇氧化水平加成，并提供了通常使用化学计量量的预金属亲核试剂（例如烯丙基金属试剂）制备的手性构建块的途径。然而，与经典方法不同，我们报道的醇C-C偶联过程避免了生成醛亲电试剂所需的离散氧化还原操作，并且避免了摩尔量金属副产物的产生。在这里，我们首次提出了对“醇-不饱和C-C偶联”的系统研究，并展示了这种过程如何极大地简化了聚酮类天然产物的合成，聚酮类天然产物是一类重要的fda批准的治疗剂。已建立的催化对体选择性过程OH [Ir (cod) Cl] 2 (2.5 mol%) OH AcO (R)-Cl,MeO-BIPHEP (5 mol%) R R M - no2bzoh (10 mol%) Cs2CO3 (20 mol%) 100 mol% 10等量THF (0.2 M)， 100 oC 51-83%产率或200 mol% 86-95% ee不同R2 R1不饱和R1手性配体或改性剂从烯烃R2 OH [Ir(cod)Cl]2 (2.5 mol%) OH AcO (S)-SEGPHOS (5 mol%) R R Me 4-CN-3-NO2BzOH (10 mol%) Me Cs2CO3 (20 mol%) 100 mol% 200 mol% THF (1.0 M)， 90 oC 61-73%产率86-97% ee 5:1-8:1dr OH R2 OH OH OH OH OH OH R2 R1 R1 R2 R1 R2 R3 R3 Me从二烯从烯烯从炔烯从炔烯