Total Synthesis of Bioactive Marine Natural Products

描述（由申请人提供）：我们研究计划的主要目标是开发使用复杂天然产物的新合成方法，以确定新的挑战。我们在全合成和由此获得天然产物方面的努力也将为生物有机化学领域的研究提供基础。新的合成方法将在制药和医学研究中得到进一步的应用，通过改进药物和生物活性物质的制备，为公众健康服务。本申请中追求的特定靶标是含有螺亚胺环的海洋毒素。这是一组不断扩大的复杂海洋天然产物，目前包括pinnatoxins，pteriatoxins，spirolides，spiro-prorocentrimine和gymnodimine。已确定独特的螺亚胺片段对其生物活性至关重要。其中一些天然产品与几起全球海鲜中毒事件有关。该合成方法具有通用性，可应用于海松毒素、螺内酯和裸甲亚胺的合成。目标结构中最具挑战性的部分是螺亚胺片段。我们开发了一种方法，使立体选择性爱尔兰克莱森重排的α-支链烯丙基酯。通常，在这些反应中观察到差的非对映选择性。采用我们的方法，两个非对映体可以访问与优秀的非对映体选择性。这是我们在合成螺亚胺片段中使用的主要方法。我们预计，我们在复杂天然产物的化学合成领域的努力将丰富合成方法的总体武库，促进药物化学和药物发现领域的研究。更具体地说，本文所述的海洋毒素与海产品中毒的公共卫生问题直接相关。人们注意到，在开发用于检测藻毒素的精确方法方面的一个主要问题是缺乏纯标准。因此，我们的合成目标将作为纯标准的海洋毒素检测探针的发展。有机合成的发展为药物发现和药物研究提供了方法，长期以来一直有益于人类健康。复杂天然产物的全合成是有机化学的一个主要分支，它定义了当前的最新技术水平，刺激了创新和发现，并确定了有待解决的新挑战。该研究将丰富复杂天然产物的全合成方法学。此外，我们将开发灵敏的免疫测定法，用于检测环境中的海洋毒素。这将有利于人类健康，防止某些类型的海产品中毒，这已成为一种全球现象。

DESCRIPTION (provided by applicant): The main objective of our research program is the development of new synthetic methods using complex natural products to identify new challenges. Our endeavors in total synthesis and resulting access to natural products will also provide the basis for research in the area of bioorganic chemistry. The new synthetic methods will find further utility in pharmaceutical and medicinal research, serving for the benefit of public health through improved preparation of drugs and bioactive substances. The specific targets pursued in this application are marine toxins containing a spiroimine ring. This is an expanding group of complex marine natural products that presently includes pinnatoxins, pteriatoxins, spirolides, spiro-prorocentrimine, and gymnodimine. The unique spiroimine fragment has been determined to be critical for their bioactivity. Some of these natural products have been implicated in several global seafood intoxication events. The proposed synthetic strategy is general and can be applied for the synthesis of pinnatoxins, spirolides, and gymnodimine. The most challenging part of the target structures is the spiroimine fragment. We developed a method that enables stereoselective Ireland-Claisen rearrangement of alpha-branched allylic esters. Typically, poor diastereoselectivity is observed in these reactions. Employing our method, both diastereomers can be accessed with excellent diastereoselectivity. This is the central method that we use in the synthesis of the spiroimine fragments. We anticipate that our efforts in the area of chemical synthesis of complex natural products will enrich the arsenal of synthetic methods in general, facilitating research in the fields of medicinal chemistry and drug discovery. More specific to this application, the marine toxins featured herein are directly related to the public health issue of seafood intoxication. It is noted that a major problem in the development of precise methods for detection of algal toxins is the lack of pure standards. Thus, the targets of our syntheses will serve as pure standards for the development of detection probes for marine toxins. PUBLIC HEALTH RELEVANCE Developments in organic synthesis have long benefited human health by providing methods for drug discovery and pharmaceutical research. The total synthesis of complex natural products is a major branch of organic chemistry that defines the current state-of-the-art, stimulates innovation and discovery, and identifies new challenges to be addressed. The research proposed in this application will enrich synthetic methodology through total synthesis of complex natural products. In addition, we will develop sensitive immunoassays for the detection of marine toxins in the environment. This will benefit human health by prevention of certain types of seafood intoxication, which has become a global phenomenon.