Asymmetric Synthesis of Bioactive Natural Products Using Nazarov Cyclization

利用纳扎罗夫环化不对称合成生物活性天然产物

• 批准号: 8371415
• 负责人: Alison J Frontier
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371415
• 关键词: Acids; Acquired Immunodeficiency Syndrome; Antiviral Agents; Asthma; Atherosclerosis; Behavior; Biological; Biological Factors; Carbazoles; Carbon; Carbonates; Catalysis; Cations; Chemicals; Chemistry; Complex; Cyclization; Cyclopentane; Development; Disease; Evaluation Studies; Generations; Goals; Grant; Health; Heart Diseases; Hela Cells; Hepatitis C; Human; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Ketones; Lipoxygenase; Lipoxygenase Inhibitors; Malignant Neoplasms; Methods; Mutate; Outcome; Oxazolidinones; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Protocols documentation; Psoriasis; Public Health; Reaction; Research; Research Project Grants; Series; Severe Acute Respiratory Syndrome; Soybeans; Specificity; Structure; Structure-Activity Relationship; Study models; Sulfoxide; System; Therapeutic; Thinking; Variant; Virus; Virus Diseases; analog; cancer therapy; carbazole; chemical synthesis; cytotoxic; design; diene; diketone; enantiomer; improved; interest; novel; novel strategies; programs; small molecule; stereochemistry; tetrapetalone A

DESCRIPTION (provided by applicant): In order to enable the study of bioactive natural products with complex structures, chemists need to be able to synthesize them and any unnatural analogs of interest. However, there are many molecules with dense arrays of chiral centers that are still difficult to prepare with high efficiency and selectivity. Synthetic chemist are constantly searching for versatile, effective new methods for the creation of vicinal chiral centers and quaternary centers, especially in an enantiopure form. The development of efficient, stereoselective carbon-carbon bond-forming methods will enable chemists to more effectively prepare biologically interesting target molecules, and enable more detailed study of these compounds for applications as chemical therapies. The common theme throughout the aims of the research program is the Nazarov electrocyclization, which delivers cyclopentane rings containing adjacent stereocenters and/or quaternary carbon centers. The aims of the grant seek to develop new variations of the cyclization for application to enantioselective synthesis, execute the cyclization in the demanding syntheses of bioactive target molecules that would be difficult to prepare using other strategies. Novel cyclization strategies will also be developed during the synthetic aims, as well as two desymmetrization sequences to obtain either a single enantiomer (from a prochiral precursor) or a single diastereoisomer (from the thermodynamically controlled cyclization of a chiral precursor). Specifically, we intend to study 1) the conjugate addition-initiated Nazarov electrocyclization, 2) enantioselective synthesis of tetrapetalone A and 3) enantioselective total synthesis of tubingensins A and B via a novel interrupted Nazarov cyclization. The public health challenges associated with AIDS, hepatitis C, and the recent emergence of dangerous new viruses like SARS and H1N1 influenza demand a drug pipeline full of compounds able to battle these rapidly mutating diseases. Natural products represent a valuable pool of potential antivirals, if chemical studies can be performed to understand and improve activity and potency. Human lipoxygenases (HLOs) are implicated in a number of disease processes, including cancer, heart disease, asthma, atherosclerosis and psoriasis. Identification of new HLO inhibitors with specificity and complementary modes of action is essential for continued progress in the treatment of these diseases. The aims of this grant focus on the synthesis of a soybean lipoxygenase inhibitor, which is a good model for the study of HLO (tetrapetalone A) and two new small molecule agents with antiviral activity (tubingensins A and B). Successful synthesis will make these natural products available by chemical synthesis, paving the way for a thorough biological evaluation and study of structure/activity relationships. Ultimately, goals include the identification of new antiviral agents and a better understanding of the behavior of lipoxygenase inhibitors. PUBLIC HEALTH RELEVANCE: Many bioactive natural products have complex structures that are difficult to prepare with high efficiency and selectivity. The new chemical methods that will be developed over the course of this project will strongly augment the synthetic toolbox available for the preparation of valuable compounds with pharmaceutical potential. Furthermore, achieving the advanced synthetic aims of the program research will allow us to build rare molecules with promising, but poorly understood biological activity for further assessment as agents for the treatment of cancer, inflammatory diseases and viral infections.

描述（由申请人提供）：为了使具有复杂结构的生物活性天然产品的研究，化学家需要能够合成它们以及任何不自然的感兴趣的类似物。但是，有许多具有密集的手性中心阵列的分子，这些分子仍然很难以高效率和选择性制备。合成化学家一直在寻找用于创建毗邻手性中心和第四纪中心的多功能，有效的新方法，尤其是以对映射形式。有效，立体选择性碳键合的方法的发展将使化学家能够更有效地准备生物学有趣的靶标分子，并能够对这些化合物作为化学疗法的这些化合物进行更详细的研究。研究计划的整个目标的共同主题是纳扎罗夫电环化，它提供了含有相邻立体中心和/或第四纪碳中心的环戊烷环。赠款的目的旨在开发用于对映选择综合的应用程序的新变化，执行 生物活性靶标分子的苛刻合成中的环化很难使用其他策略进行准备。在合成目标期间还将制定新的环化策略，以及两个对称序列，以获得单个对映异构体（来自术前体前体）或单个映射异构体（来自手术前体的热力学控制的环化学）。具体而言，我们打算研究1）共轭添加引发的纳扎罗夫电环化化，2）四脑酮A和3）通过新型的中断的拿撒康环化的对照素选择管蛋白A和B的对映选择性合成。与艾滋病，丙型肝炎以及最近出现的危险新病毒（如SARS和H1N1流感）相关的公共卫生挑战，要求使用能够与这些快速突变疾病作斗争的化合物的药物管道。如果可以进行化学研究以了解和提高活动和效力，则天然产品代表了潜在的抗病毒药物的宝贵池。人脂氧酶（HLOS）与许多疾病过程有关，包括癌症，心脏病，哮喘，动脉粥样硬化和牛皮癣。以特异性和互补的作用方式鉴定新的HLO抑制剂对于这些疾病治疗的持续进展至关重要。该赠款的目的集中在大豆脂氧合酶抑制剂的合成上，这是研究HLO（四脑A）和两种具有抗病毒活性（Tubingensin a和b）的新小分子剂的良好模型。成功的合成将使这些天然产物通过化学合成，为彻底的生物学评估和研究结构/活动关系铺平道路。最终，目标包括鉴定新的抗病毒剂，以及更好地了解脂氧合酶抑制剂的行为。 公共卫生相关性：许多生物活性天然产品具有复杂的结构，这些结构很难以高效率和选择性来制备。在该项目过程中将开发的新化学方法将强烈增加可用于制备具有药物潜力的有价值化合物的合成工具箱。此外，实现该计划研究的先进合成目标将使我们能够建立具有有希望的但知之甚少的生物学活性的稀有分子，以作为治疗癌症，炎症性疾病和病毒感染的药物的进一步评估。