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: 8118733
• 负责人: MICHAEL J KRISCHE
• 金额: $ 28.25万
• 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/8118733
• 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; 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）：我们报告了一类新的金属催化的C-C键形成 - 酒精的直接C-C偶联物质和？糖化合物。这些过程可以从酒精氧化水平中添加羰基，并提供了通常使用化学计量量的预测核粒子（例如，烯丙基酯试剂）制备的手性构件。但是，与经典的方法不同，我们报告的酒精C-C耦合过程规定了产生醛电力所需的离散氧化还原操作，它们避免产生摩尔量的金属副产品。在这里，我们提出了对“酒精不饱和C-C耦合”的首次系统研究，并证明了这种过程如何显着简化聚酮化合物天然产物的合成，后者是FDA批准的一类批准的治疗剂。 已建立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-NO2BZOH（10 mol％）CS2CO3（20 mol％）100 mol％10倍率。 THF（0.2 m），100 OC 51-83％的产率或200 mol％86-95％EE EE提出的催化对映选择性过程OH MLN（CAT。）不同的R2 R1不饱和R1手动配体ME或来自olefins r2 oh [ir（cod）CL] 2（2.5 mol％）OH％ACO（2.5 mol％）OH ACO（SSEGPH）（SSEGPH） - 4-CN-3-NO2BZOH（10 mol％）ME CS2CO3（20 mol％）100 mol％200 mol％THF（1.0 m），90 OC 61-73％产量86-97％EE 5：1-8：1-8：1dr OH R2 R2 R2 R1 R1 R1 R1 R1 R1 R1 R1 R1 R2 R2 R1 ME R2 R3 Me2 r3 Me2 r3 ry 2 ry 2 R3 R3 公共卫生相关性：超过60％的974个小分子在1981 - 2006年全球引入的药物中受到“天然产品”的启发。1在天然发生的化合物中，Polyketides在FDA批准的最销售销售的最销售的小分子中的20％中排名20％。手性并将作为单一象征实体销售。4在这里，我们提出了对“酒精不饱和C-C耦合”的首次系统研究，并证明了此类过程如何极大地简化了Polyketide天然产品的合成，这些产品是一类重要类FDA批准的治疗方法。 （1）“在过去25年中，天然产品是新药的来源”，纽曼，D。J。； Cragg，G。M. J. Nat。产品。 2007，70，461。（2）（a）“药物发现与开发中的天然产物”，Cragg，G。M。;纽曼，D。J。； Snader，K。M. J. Nat。产品。 1997，60，52-60。 （b）“最近基于天然产品的药物发现：制药行业的前瞻性”，Y.-Z. Shu。 J. Nat。产品。 1998，61，1053。（3）“手性药物”，Stinson，S.C。Chem。工程。 News 1998，76（9月21日），83。（4）“手性技术对制药行业的影响”，理查兹，A。 McCague，R。Chem。 1997年6月2日，422年。