Total Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的全合成

基本信息

批准号：
8266483
负责人：
Armen Zakarian
金额：
$ 38.17万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-10 至 2013-07-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：我们研究计划的主要目的是使用复杂的天然产品来开发新的合成方法来确定新的挑战。我们在完全合成和最终获得天然产品的努力还将为研究生物有机化学领域的研究提供基础。新的合成方法将在药物和药用研究中找到进一步的效用，这可以通过改善药物和生物活性物质的准备来利用公共卫生。在本应用中追求的特定靶标是含有螺旋明环的海洋毒素。这是一组不断扩展的复杂海洋天然产品，目前包括斑脚毒素，翼龙，螺旋藻，螺旋藻，螺旋体 - 原饮食和体育症。独特的螺旋明碎片已被确定为其生物活性至关重要。其中一些天然产品与几个全球海鲜中毒事件有关。所提出的合成策略是一般的，可以用于合成pinnatoxins，螺母和裸霉素。目标结构中最具挑战性的部分是螺旋明碎片。我们开发了一种方法，该方法可以实现α分支的烯丙基酯的立体选择性爱尔兰 - 克莱森重排。通常，在这些反应中观察到不映射性差。采用我们的方法，可以使用出色的非对映选择性访问两个非映异构体。这是我们在螺旋胺片段合成中使用的中心方法。我们预计，我们在复杂天然产物的化学合成领域的努力将富含合成方法的库，从而促进药物化学和药物发现领域的研究。本文中的海洋毒素更为具体，与海鲜中毒的公共卫生问题直接相关。值得注意的是，开发用于检测藻类毒素的精确方法的主要问题是缺乏纯标准。因此，我们合成的靶标将作为开发海洋毒素检测探针的纯标准。长期以来，通过提供药物发现和药物研究的方法，有机合成的公共卫生相关性发展已使人类健康受益。复杂天然产品的总合成是有机化学的主要分支，它定义了当前的最新技术，刺激创新和发现，并确定要解决的新挑战。在本应用中提出的研究将通过完全合成复杂的天然产物来丰富合成方法。此外，我们将开发灵敏的免疫测定法，以检测环境中的海洋毒素。这将通过预防某些类型的海鲜醉酒来使人类健康受益，这已成为一种全球现象。