Synthetic Strategies Based on Epoxide Coupling Reactions

描述（由申请人提供）：该项目的总体目标是开发复杂分子合成的几种一般策略，使用具有改善人类健康潜力的天然产物来说明这些方法中每一种的特征。最近发现的催化环氧化物-炔还原偶联用于三种策略中的每一种，用于不同的目的：作为片段偶联，用于从共同的结构单元快速组装天然产物家族（具体目标1），作为大环化（具体目的2），并且对于立体限定的1的合成，3-二烯，用于跨环Diels-Alder反应，组装几种二萜类化合物的三环核心（具体目标3）。在具体目标1中，提出了两种互补的方法来合成四种天然产物，amphidinolides T2-T5和三种结构上与它们相关的分子。首先，双烯内酯T1和“伪T1”由四个简单的构建单元组装而成，并通过可能参与这些天然产物生物合成的三个反应转化为本研究中的其他六个靶点。另一种策略使用相同的构建块，并直接准备四个目标。具体目标2的目标是展示一种策略，其中催化大环化也安装了在许多有机分子家族中发现的关键官能团阵列。具体目标3描述了一种灵活的合成策略的cyatane型二萜类，包括erinacines，诱导神经生长因子的合成，和cyathins，allocyathins，和cyathatriols，具有抗菌和抗真菌活性的发展。该策略首先建立了两个cyathadiene天然产物，然后扩展到几个高度氧化的erinacines，cyathins，allocyathins和cyathatriols。

DESCRIPTION (provided by applicant): The overall goal of this project is the development of several general strategies of complex molecule synthesis, using natural products that have the potential to improve human health to illustrate the features of each of these approaches. A recently discovered catalytic epoxide-alkyne reductive coupling is used in each of the three strategies for a different purpose: as a fragment coupling for rapid assembly of a family of natural products from common building blocks (Specific Aim 1), as a macrocyclization (Specific Aim 2), and for the synthesis of stereodefined 1,3-dienes used in transannular Diels-Alder reactions that assemble the tricyclic core of several diterpenoids (Specific Aim 3). In Specific Aim 1, two complementary approaches are presented for the synthesis of four natural products, amphidinolides T2-T5 and three molecules structurally related to them. In the first, amphidinolides T1 and "pseudo-T1" are assembled from four simple building blocks and converted to the other six targets in this study by way of three reactions that may be involved in the biogenesis of these natural products. An alternative strategy uses the same building blocks and prepares four of the targets directly. The goal of Specific Aim 2 is the demonstration of a strategy in which a catalytic macrocyclization also installs a critical functional group array found in many families of organic molecules. Specific Aim 3 describes the development of a flexible synthetic strategy for the cyatane-type diterpenes, including the erinacines, which induce the synthesis of nerve growth factor, and the cyathins, allocyathins, and cyathatriols, which possess antibacterial and antifungal activity. The strategy is first established for two cyathadiene natural products and then extended to several highly oxygenated erinacines, cyathins, allocyathins, and cyathatriols.