New Methods and Strategies for the Synthesis of ETP Natural Products

ETP天然产物合成新方法和新策略

• 批准号: 8416968
• 负责人: Sarah Elizabeth Reisman
• 金额: $ 28.18万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416968
• 关键词: Anti-Bacterial Agents; Antibiotics; Antiviral Agents; Biological; Biological Factors; Biology; Cancer Center; Carbon; Chemistry; Cities; Collaborations; Collection; Communicable Diseases; Complex; DNA-Directed RNA Polymerase; Development; Disease; Exhibits; Family; Foundations; Future; Gliotoxin; Glycols; Goals; In Vitro; Indoles; Institutes; Kinetics; Methicillin; Methodological Studies; Methods; Organic Chemistry; Organometallic Chemistry; Preparation; Property; Reaction; Research; Staging; Staphylococcus aureus; Therapeutic Studies; Tin; Transition Elements; analog; aranotin; cancer therapy; chemical reaction; chemical synthesis; cycloaddition; inhibitor/antagonist; innovation; insight; monomer; prostate cancer cell; public health relevance; quinolone resistance; stereochemistry; verticillin A; viral RNA

DESCRIPTION (provided by applicant): Epidithiodiketopiperazine (ETP) natural products are a class of structurally complex fungal metabolites that exhibit biological properties including antiviral, antiproliferative, and antibacterial activities. The goal of the proposed research is to develop new synthetic methods and strategies for the synthesis of dihydrooxepine and pyrrolidinoindoline ETP natural products. The development of efficient chemical syntheses of ETP natural products is expected to facilitate the study of their biological properties, and demands innovative new methods to prepare dihydrooxepine and pyrrolidinoindoline core motifs. The proposed research comprises two projects, the first of which targets the natural products aranotin (2) and MPC1001B (5), and is expected to contribute new transition-metal catalyzed methods for the preparation of dihydrooxepines. In addition, the first comprehensive studies of ETP formation in the presence of a dihydrooxepine moiety will be carried out. The specific aims are: 1.1) to develop transition metal-catalyzed cycloisomerization reactions to prepare dihydrooxepines; 1.2) to complete a total synthesis of the antiviral natural project aranotin (2); 1.3) to complete a total synthesis of the antiproliferative natural product MPC1001B (5). The second project targets pyrrolidinoindoline ETPs such as 11-deoxybionectin A (8). To this end, a new enantioselective formal [3+2] cycloaddition to prepare pyrrolidinoindolines directly from indoles will be developed. The specific aims are: 2.1) to develop catalytic asymmetric formal [3+2] cycloaddition reactions to prepare pyrrolidinoindolines; 2.2) to study and elucidate the mechanism of catalytic asymmetric pyrrolidinoindoline formation; 2.3) to complete a total synthesis of 11-deoxybionectin A (8). Synthetic access to ETPs such as 2, 5, and 8, is expected to permit studies aimed at deepening our understanding of the underlying mechanisms of their biological properties. Through collaborations with the City of Hope Cancer Center and the Broad Institute of Harvard and MIT, these natural products and synthetic derivatives will be evaluated as biological probes and potential therapeutics for the study and treatment of cancer and infectious disease. It is anticipated that these studies will result in the development of new chemical reactions, further our fundamental understanding of organic and organometallic chemistry, and contribute valuable information on the chemistry and biology of two distinct families of ETP natural products.

描述（由申请人提供）：Epidithiodiketopiperazine （ETP）天然产物是一类结构复杂的真菌代谢物，具有抗病毒、抗增殖和抗菌活性等生物学特性。本研究的目的是为二氢奥西平和吡咯烷喹啉ETP天然产物的合成开发新的合成方法和策略。ETP天然产物的高效化学合成有望促进其生物学特性的研究，并需要创新的新方法来制备二氢奥西平和吡咯烷喹啉核心基序。拟开展的研究包括两个项目，第一个项目以天然产物aranotin(2)和MPC1001B(5)为目标，有望为过渡金属催化制备二氢氧平类药物提供新的方法。此外，将对二氢氧平片段存在下的ETP形成进行首次全面研究。具体目标是：1.1)建立过渡金属催化的环异构化反应，制备二氢氧平类药物；1.2)完成抗病毒天然项目紫菜素的全合成(2)；1.3)完成抗增殖天然产物MPC1001B的全合成(5)。第二个项目的目标是吡咯烷喹啉etp，如11-脱氧生物连接素A(8)。为此，将开发一种新的对映选择性正构[3+2]环加成法，直接从吲哚制备吡咯烷二吲哚。具体目的是：2.1)建立催化不对称形式[3+2]环加成反应制备吡咯烷二吲哚；2.2)研究和阐明催化生成不对称吡咯烷二吲哚啉的机理；2.3)完成11-脱氧生物连接素a的全合成(8)。对etp（如2、5和8）的合成途径有望允许旨在加深我们对其生物学特性的潜在机制的理解的研究。通过与希望之城癌症中心、哈佛大学博德研究所和麻省理工学院的合作，这些天然产物和合成衍生物将被评估为生物探针和潜在的治疗方法，用于研究和治疗癌症和传染病。预计这些研究将导致新的化学反应的发展，进一步加深我们对有机和有机金属化学的基本认识，并为两个不同的ETP天然产物家族的化学和生物学提供有价值的信息。