New Methods and Strategies for the Synthesis of ETP Natural Products

描述（由申请人提供）：表二硫代二酮哌嗪（ETP）天然产物是一类结构复杂的真菌代谢产物，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氧杂卓和吡咯烷吲哚啉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的发展有望促进其生物学性质的研究，并需要创新的新方法来制备二氢氧杂卓和吡咯烷吲哚啉核心基序。 拟议的研究包括两个项目，其中第一个项目针对天然产物aranotin（2）和MPC 1001 B（5），预计将为制备二氢氧杂卓提供新的过渡金属催化方法。此外，第一个全面的研究ETP形成的存在下的二氢氧杂卓部分将进行。具体目标是：1.1）开展过渡金属催化环异构化反应制备二氢氧杂环庚三烯; 1.2）完成抗病毒天然产物aranotin（2）的全合成; 1.3）完成抗增殖天然产物MPC 1001 B（5）的全合成。第二个项目针对吡咯烷吲哚啉ETP，如11-脱氧生物连接素A（8）。为此，将发展一种新的对映选择性的甲醛[3+2]环加成反应，直接从吲哚制备吡咯烷吲哚啉。具体目标是：2.1）开展催化不对称缩甲醛[3+2]环加成反应制备吡咯烷吲哚啉; 2.2）研究并阐明催化不对称吡咯烷吲哚啉形成的机理; 2.3）完成11-脱氧生物连接素A（8）的全合成。合成获得ETP，如2，5和8，预计将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City of Hope癌症中心以及哈佛和麻省理工学院的Broad研究所的合作，这些天然产物和合成衍生物将被评估为研究和治疗癌症和传染病的生物探针和潜在治疗剂。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理解，并为ETP天然产物的两个不同家族的化学和生物学提供有价值的信息。

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.