Photoredox Catalysis Applications to Bioactive Compounds

描述(由申请人提供)：本提案的主要主题是应用新的光氧化还原催化方法制备具有生物活性的化合物。由于广泛的官能团相容性和温和的反应条件，这些方法在各自的合成中提供了策略级的优势。重要的是，它们还将使合成能够以环保的方式进行。使用可见光的新方法是化学合成的诱人策略，可见光是一种不会产生化学废物的无毒“试剂”。由于大多数有机分子不能有效地吸收可见光，光敏催化剂因其光物理性质而被广泛研究，已成功地应用于许多新的化学方法，这些方法将应用于合成具有生物活性的天然化合物。作为这项建议的一部分准备的化合物将由美国国立卫生研究院化学基因组学中心(NCGC)的Inglese实验室利用其高通量筛选能力对其生物活性进行评估。从这些筛选活动中产生的线索将与NCGC的药物化学小组合作进行跟踪。最初的目标图书馆将在波士顿大学准备，在适当的情况下，后续脚手架开发将使用首席调查员实验室准备的脚手架，以便在NCGC进行修改。此外，刘小组(科罗拉多大学)将评估所开发的化合物对细胞周期调节的影响。1)合成双吲哚生物碱天然产物胶质粘附素C、脱氧瘦素D、脱氧生物连结素A和磷脂酸A，实现双(吡咯吲哚)杂二聚体生物碱asperdimin和Win 64745的合成，利用光氧化还原介导的立体可控自由基环化到吡咯上进行一系列吲哚利定生物碱的合成，以及采用光氧化还原催化片段偶联策略合成放线叶酸。2)开发了利用光氧化还原催化胺的？-C-H官能化的新方法，并将这些方法应用于生物碱天然产物克里斯平A、三尖杉酯碱、唐古托林和波度利福林的合成。 与公众健康相关：正在提出的光氧化还原催化的全新化学反应将使合成与癌症、感染和心血管疾病有关的生物活性天然产物成为可能。

DESCRIPTION (provided by applicant): The overarching theme of this proposal is the application of new photoredox catalysis methods to the preparation of biologically active compounds. These methodologies provide strategy-level advantages in their respective syntheses due to broad functional group compatibility and mild reaction conditions. Importantly they will also enable syntheses in an environmentally conscious fashion. New methods using visible light, a non-toxic 'reagent' that does not generate chemical waste, are attractive strategies for chemical synthesis. Since most organic molecules do not productively absorb visible light, photosensitive catalysts, widely studied for their photophysical properties, have been successfully employed for numerous new chemical methods which will be applied in the synthesis of biologically active natural compounds. The compounds prepared as part of this proposal will be evaluated for their biological activity by the Inglese Laboratory at the NIH Chemical Genomics Center (NCGC) using their high throughput screening capabilities. Leads which arise from these screening activities will be followed up in collaboration with the medicinal chemistry group at NCGC. The initial targeted libraries will be prepared at BU, with follow-up scaffold development, where appropriate, using scaffolds prepared in the Principal Investigator's lab for modification at NCGC. In addition, the Liu Group (University of Colorado) will evaluate the effect of the developed compounds on cell-cycle regulation. The aims of the proposed research projects are to: 1) Synthesize the bisindole alkaloid natural products gliocladin C, deoxyleptosin D, deoxybionectin A and plectosphaeroic acid A, achieve the synthesis of heterodimeric bis(pyrroloindoline) alkaloids asperdimin and WIN 64745, undertake the syntheses of a series of indolizidine alkaloids using photoredox- mediated, stereocontrolled radical cyclization onto pyrroles, and achieve the synthesis of actinophyllic acid using a photoredox-catalyzed fragment coupling strategy. 2) Develop new methods for the ?-C-H functionalization of amines using photoredox catalysis and appyl these methods to the syntheses of the alkaloid natural products crispine A, harmicine, tangutorine and undulifoline. PUBLIC HEALTH RELEVANCE: The fundamentally new chemical reactions in photoredox catalysis being proposed will enable the synthesis of biologically active natural products implicated in cancer, infection, and cardiovascular disease.