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

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--醇和不饱和化合物的直接C-C偶联。这些过程实现了醇氧化水平上的羰基加成，并提供了获得手性构建块的途径，这些构建块通常是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。然而，与经典方法不同的是，我们报告的醇C-C耦合过程避免了产生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，我们提出了第一个关于“酒精-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FDA批准的一类重要的治疗药物。建立了催化对映体选择性反应过程：OH[Ir(Cod)Cl]2(2.5mol%)OHACO(R)-Cl，MeO-BIPHEP(5mol%)Rm-NO2BzOH(10mol%)Cs2CO3(20mol%)100mol%10当量。四氢呋喃(0.2M)，100oC 51-83%的产率或200mol%86-95%ee建议的催化对映体选择性过程OH mln(CAT.)不同的R2 R1不饱和R1手性配体Me或来自烯烃的修饰剂R2 OH[Ir(Cod)Cl]2(2.5mol%)OH ACO(S)-SEGPHOS(5mol%)Rme4-CN-3-NO2BzOH(10mol%)Me Cs2CO3(20mol%)100mol%200mol%THF(1.0M)，90 OC 61-73%产率86-97%ee 5：1-8：1DR OH R2 R2 R2 R1 Me R2 R3 R3 Me 与公共健康相关：1981-2006年间，全球推出的974种小分子药物中，超过60%的灵感来自“天然产物”。1在天然化合物中，多酮类药物在FDA批准的最畅销小分子药物中排名20%。2因此，世界上最畅销的药物中，超过50%是单一对映体，据估计，目前正在开发的所有药物中有80%是手性的，并将作为单一对映体实体上市。4在这里，我们提议对“醇-不饱和C-C偶联”进行首次系统研究，并展示这种过程如何极大地简化聚酮类天然产物的合成，它们是FDA批准的一类重要的治疗药物。(1)《作为过去25年新药来源的天然产品》，Newman，D.J.；Cragg，G.M.J.Nat。戳。2007年，70,461。(2)(A)“药物发现和开发中的天然产品”，Cragg，G.M.；Newman，D.J.；Snader，K.M.J.Nat。戳。1997，60，52-60。(B)“基于天然产物的新药发现：制药业的前景”，Shu Y.-Z.J.Nat。戳。1998年，61,1053。(3)“手性药物”，斯廷森，S.C.化学。英语。新闻1998，76(9月21)，83。(4)《手性技术对制药业的影响》，理查兹，A.；麦凯格，R.Chem。印地安人。1997年6月2日，422.

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.