Oxidative Coupling in Natural Product Synthesis

描述(申请人提供)：这项研究计划的统一主题是寻找创新的解决方案，以解决全合成中的复杂问题，使用氧化方法形成C-C键。在合成化学家的“工具箱”中，以直接和有效的方式建立不协调的官能团关系的合成工具严重缺乏。当考虑到能够适应不和谐键断开的广泛的天然产物时，开发形成这种键的新方法是有机化学中一个非常有吸引力的研究领域。虽然我们的实验室已经在氧化偶联领域取得了几项成功，但非常明显的是，人们对这一过程知之甚少。我们的主要目标是深入了解羰基烯醇酸盐选择性杂化所必需的要求，从而寻求填补合成化学中的一个空白。当战略地使用氧化C-C键形成时，在效率(缺乏保护基团、卤素、一次性官能团)、实用性(极其简洁的序列)、立体控制(经常观察到完全的非对映选择性)和氧化态的保守性(氧化态通过利用天然官能团在合成中线性增加)方面具有显著的优势。在全合成领域，将通过氧化C-C键的形成来完成以下工作：(1)全合成几个具有挑战性的Hapalindole和Ampluine家族成员，(2)全合成结构上有吸引力和高生物活性的韦氏吲哚类化合物，以及(3)与Benjamin Cravatt教授合作合成Stephacidins的简化类似物并确定它们的作用机理。这些项目也将成为有意进入药物发现领域的学生的一个极好的培训基地。在NCI以及罗伯特·亚伯拉罕、威廉·费尼奇和本·克拉瓦特教授的合作下，将认真进行对千金藤素、哈帕吲哚、鱼腥藤酮和歧义化合物的生物学评估，目的是研究甚至增强它们的生物活性。

DESCRIPTION (provided by applicant): The unifying theme of this research program is to find innovative solutions to complex problems in total synthesis using oxidative methods for C-C bond formation. Synthetic tools to forge dissonant functional group relationships in a direct and efficient fashion are sorely lacking in the synthetic chemist's "tool box". When the broad range of natural products that are amenable to dissonant bond disconnections is considered, the development of new methods to form such bonds is a highly attractive area of research in organic chemistry. While our lab has registered several successes in the arena of oxidative coupling, it is abundantly clear that very little is actually known about the process. Our main goal is to gain insight into the requirements necessary for selective heterocouplings of carbonyl enolates, thus seeking to fill a gap in synthetic chemistry. There are remarkable advantages to be gained in terms of efficiency (lack of protecting groups, halogens, disposable functional groups), practicality (extremely concise sequences), stereocontrol (complete diastereoselectivity often observed), and conservation of oxidation state (oxidation state increases linearly in a synthesis by using innate functionality) when oxidative C -C bond formation is employed strategically. In the total synthesis realm, the following will be accomplished using oxidative C-C bond formation: (1) total synthesis of several challenging members of the hapalindole and ambiguine family, (2) total synthesis of the structurally captivating and highly bioactive welwitindolinones, and (3) synthesis of simplified analogs of the stephacidins and determination of their mechanism of action in collaboration with Prof. Benjamin Cravatt. These projects will also serve as an excellent training ground for students who intend to enter the field of drug discovery. In collaboration with the NCI and Professors Robert Abraham, William Fenical, and Ben Cravatt the biological evaluation of the stephacidins, hapalindoles, fischerindoles, welwitindolinones, and ambiguines will be undertaken in earnest, with the goal of studying, and perhaps even enhancing their biological activity.