Oxidative Coupling in Natural Product Synthesis

描述（由申请人提供）：本研究项目的统一主题是利用氧化方法形成C-C键，为全合成中的复杂问题找到创新的解决方案。在合成化学家的“工具箱”中，以直接和有效的方式构建不和谐官能团关系的合成工具是非常缺乏的。当考虑到范围广泛的天然产物可适应不和谐键断开时，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。虽然我们的实验室在氧化偶联领域取得了一些成功，但很明显，对这个过程知之甚少。我们的主要目标是深入了解羰基烯醇酯选择性异偶联的必要条件，从而寻求填补合成化学的空白。当策略性地使用氧化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（通常观察到完全非对映选择性）和氧化态守恒（氧化态在使用固有功能的合成中线性增加）方面将获得显着的优势。在全合成领域，利用氧化C-C键形成将完成以下工作：(1)全合成hapalinole和ambiguine家族的几个具有挑战性的成员；(2)全合成结构吸引人且具有高生物活性的welwitindolinones；(3)与Benjamin Cravatt教授合作合成stephacidins的简化类似物并确定其作用机制。这些项目也将为有意进入药物发现领域的学生提供良好的训练基地。在NCI和Robert Abraham、William Fenical和Ben Cravatt教授的合作下，我们将认真地对stephacidins、hapalindoles、fishcherindoles、welwitindolinones和ambiguines进行生物学评估，目标是研究，甚至可能提高它们的生物活性。

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.