Photoredox Catalysis Applications to Bioactive Compounds

描述（由申请人提供）：本提案的总体主题是新的光氧化还原催化方法在制备生物活性化合物中的应用。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，它们还将以一种环保的方式使合成成为可能。可见光是一种无毒的“试剂”，不会产生化学废物，使用可见光的新方法是化学合成的有吸引力的策略。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，已成功地用于许多新的化学方法，这些化学方法将应用于合成具有生物活性的天然化合物。作为本提案的一部分制备的化合物将由NIH化学基因组学中心（NCGC）的Inglese实验室利用其高通量筛选能力评估其生物活性。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进。最初的目标文库将在波士顿大学准备，后续的支架开发，在适当的情况下，使用在首席研究员实验室准备的支架在NCGC进行修改。此外，Liu小组（科罗拉多大学）将评估开发的化合物对细胞周期调节的影响。拟议研究项目的目的是：1)合成双吲哚类生物碱天然产物gliocladin C、脱氧瘦素D、脱氧生物连接素A和plectosphaeroic acid A，实现异二聚体双（吡咯啉类）生物碱asperdimin和WIN 64745的合成，利用光氧化还原介导的立体控制自由基环化到吡咯上进行一系列吲哚嗪类生物碱的合成，利用光氧化还原催化的片段偶联策略实现放线树酸的合成。2)发展光氧化还原催化下胺类α-C-H功能化的新方法，并应用于生物碱天然产物crispine A、harmicine、tangutorine和undulifoline的合成。

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 α-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.