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）：我们报告了一种广泛的新型金属催化C-C键形成-醇和？的直接C-C偶联。不饱和化合物这些方法能够从醇氧化水平进行羰基加成，并提供通常使用化学计量的预金属化亲核试剂（例如烯丙基金属试剂）制备的手性结构单元。然而，与经典方法不同，我们报告的醇C-C偶联过程规避了生成醛亲电体所需的离散氧化还原操作，并且它们避免了生成摩尔量的金属副产物。在这里，我们提出了第一个系统的调查“醇不饱和的C-C耦合”，并演示了如何这样的过程大大简化了聚酮化合物的天然产物，这是一类重要的FDA批准的治疗药物的合成。 确定的催化对映选择性过程OH [Ir（cod）Cl] 2（2.5 mol%）OH AcO（R）-Cl，MeO-BIPHEP（5 mol%）R R m-NO2 BzOH（10 mol%）Cs2 CO 3（20 mol%）100 mol% 10 equiv. THF（0.2 M），100 oC 51-83%产率或200 mol% 86-95% ee 不同的R2 R1不饱和R1手性配体Me或来自烯烃的改性剂R2 OH [Ir（cod）Cl]2（2.5摩尔%）OH AcO（S）-SEGPHOS（5摩尔%）R R Me 4-CN-3-NO2 BzOH（10摩尔%）Me Cs2 CO 3（20摩尔%）100摩尔% 200摩尔% THF（1.0 M），90 oC 61-73%产率86-97% ee 5：1-8：1dr OH R2 OH OH OH R2 R1 R1 R1 R2 R1 Me R2 R3 R3 Me来自二烯来自丙二烯来自炔来自烯R2 R2 R2 R2 R3 R3 公共卫生相关性：从1981年到2006年，在全球范围内作为药物引入的974种小分子中，超过60%是受到“天然产物”的启发。1在天然存在的化合物中，聚酮化合物在FDA批准的最畅销的小分子药物中占20%。2因此，超过50%的世界上最畅销的药物是单一对映体，据估计，目前正在开发的所有药物中有80%是手性药物，并将作为单一对映体实体上市。我们提出了第一个系统的研究“醇-不饱和碳-碳耦合”并展示此类工艺如何极大地简化聚酮天然产物的合成，聚酮天然产物是FDA批准的一类重要治疗药物。(1)“过去25年天然产物作为新药来源”，纽曼，D。J.道：克拉格湾M. J. Nat. Prod. 2007，70，461。(2)（a）“药物发现和开发中的天然产物”，Cragg，G. M.;纽曼，D. J.道：Snader，K. M. J. Nat. Prod. 1997，60，52-60. (b)“最近基于天然产物的药物发现：制药行业的前景”，Shu，Y.- Z. J. Nat. Prod. 1998，61，1053. (3)“Chiral Drugs，”Stinson，S. C. Chem. Eng. News 1998，76（Sept.（注21），第83页。(4)“手性技术对制药工业的影响”，理查兹，A.; 麦卡格河1997年6月2日，第422页。