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: 8259146
• 负责人: MICHAEL J KRISCHE
• 金额: $ 28.18万
• 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/8259146
• 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、新型的金属催化C-C键形成——醇和α-不饱和化合物的直接C-C偶联。这些过程能够从醇氧化水平进行羰基加成，并提供手性结构单元，这些手性结构单元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。然而，与经典方法不同，我们报道的醇C-C偶联过程规避了生成醛亲电子试剂所需的离散氧化还原操作，并且它们避免了摩尔量的金属副产物的生成。在这里，我们提出了对“醇不饱和C-C偶联”的首次系统研究，并展示了此类过程如何极大地简化聚酮天然产物的合成，聚酮天然产物是FDA批准的一类重要的治疗剂。 已建立的催化对映选择性工艺 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摩尔% 10 当量THF (0.2 M), 100 oC 51-83% 产率或 200 mol% 86-95% ee 建议的催化对映选择性过程 OH MLn (cat.) 多种 R2 R1 不饱和化合物 R1 手性配体 Me 或来自烯烃的改性剂 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 R2 R1 R1 R1 R2 R1 Me R2 R3 R3 Me 来自 二烯 来自 烯炔 来自 炔烃 来自 烯炔 R2 R2 R2 R2 R3 R3 公共健康相关性：1981 年至 2006 年期间，全球推出的 974 种小分子药物中，超过 60% 受到“天然产品”的启发。1 在天然化合物中，聚酮化合物占 FDA 批准的最畅销小分子药物的 20% .2 因此，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%是手性的，将作为单一对映异构体实体上市。4在这里，我们提出了对“醇-不饱和C-C偶联”的首次系统研究，并展示了此类过程如何极大地简化聚酮天然产物的合成，聚酮天然产物是 FDA 的一类重要产品- 批准的治疗剂。 (1) “过去 25 年天然产物作为新药的来源”，Newman, D. J.；克拉格 (G. M. J. Nat)产品。 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.；斯纳德 (K. M. J. Nat)产品。 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.纳特。产品。 1998, 61, 1053。(3)“手性药物”，Stinson, S. C. Chem。工程师。 News 1998, 76（9 月 21 日）, 83。 (4)“手性技术对制药行业的影响”，Richards, A.； 麦卡格，R.化学。印度，1997 年，6 月 2 日，422。