Cycloadditions and cycloreversions of pyrazinones: preparation of diverse medicin

描述（由申请人提供）：对进行不对称转化的新化学反应的研究是一项有价值的练习。研究不对称合成的好处在很大程度上是实用的：新方法的发展导致高效和资源丰富的生产有价值的复杂分子。当这项研究工作指向生物活性分子的制备时，这项运动就与生物医学科学密切相关，并能直接影响人类健康。本提案描述了一个统一的研究计划，用于制备三种重要的具有药用优势的结构基序：[2.2.2]-重氮三环、2-吡啶酮和表聚硫代二氧哌嗪（ETP）生物碱。目前已知有70多种不同的真菌代谢物（包括brevianamides、notoamides和stephacidins）具有共同的[2.2.2]-重氮双环核心。该天然产物家族具有多种生物活性，包括抗寄生虫、抗肿瘤、神经保护、钙调素抑制和杀虫特性。2-吡啶酮是一种普遍存在的功能，在药物开发和医学中得到了广泛的应用。喜树碱是最著名的含有2-吡酮的天然产物之一，是治疗结直肠癌的重要化疗药物。喜树碱的合成研究已经产生了半合成衍生物（伊立替康和拓扑替康），它们的毒性降低，并在临床中取代了天然产物。ETP生物碱表现出多种令人印象深刻的生物活性（最显著的是肿瘤选择性，亚纳摩尔细胞毒性），具有良好的治疗潜力。目前制备聚硫桥的方法需要强酸性或碱性条件。我们建议通过与双原子硫的形式环加成直接进入ETP核心（在中性反应条件下）。本提案中描述的研究计划将使新方法能够从常见中间体2,5-二酮哌嗪偶氮二烯（吡嗪酮）前体制备[2.2.2]-重氮三环，2-吡啶酮和ETP结构。此外，我们正在追求多米诺骨牌或“一锅”反应方法来制备这些结构，这种努力对我们作为研究人员的时间来说是经济的，但也具有资源和成本效益，并且有最大的机会精简研究已知的生物活性分子和新的化学空间。我们的研究工作也将广泛有助于对未开发反应的反应性和选择性的基本化学理解。威廉玛丽学院不提供化学博士学位（只有学士/硕士学位）；因此，我的研究小组由本科生研究人员（和一名硕士候选人）组成。我目前的研究项目为基于发现的学习创造了一个严格的环境，并在一对一的研究体验中加强了教学和培训。拟议中的研究将在这种情况下继续进行。美国国立卫生研究院的支持将使每年有4名本科生和一名硕士候选人参与该奖项的研究。

DESCRIPTION (provided by applicant): The investigation of new chemical reactions that perform asymmetric transformations is a valuable exercise. The benefits of research in asymmetric synthesis are largely practical: the development of new methods leads to efficient and resourceful production of complex molecules of value. When this research effort is directed to the preparation of bioactive molecules, the exercise becomes acutely relevant to biomedical sciences and can directly impact human health. This proposal describes a unified research plan for the preparation of three important medicinally privileged structural motifs: [2.2.2]-diazabicyclic, 2-pyridone, and epipolythiodioxopiperazine (ETP) alkaloids. More than 70 distinct fungal metabolites (including the brevianamides, notoamides, and stephacidins) are now known to share in common the [2.2.2]-diazabicyclic core. Diverse biological activities including antihelmintic, antitumor, neuroprotective, calmodulin (CaM)-inhibition and insecticidal properties are observed across this natural product family. 2-pyridones are a ubiquitous functionality that has found widespread application in drug development and medicine. Camptothecin, one of the most well known natural products containing a 2-pyridone, is an important chemotherapeutic agent in the toolbox for the treatment of colorectal cancer. Synthetic research on camptothecin has delivered semi-synthetic derivatives (irinotecan and topotecan), which exhibit reduced toxicity and have replaced the natural product in the clinic. ETP alkaloids show varied and impressive bioactivities (most notably tumor selective, subnanomolar cytotoxicity) and have promising therapeutic potential. Current methods to prepare the polysulfide bridge require strongly acidic or basic conditions. We propose the direct entry to the ETP core (under neutral reaction conditions) by formal cycloaddition with diatomic sulfur. The research plan described in this proposal will enable new methods to prepare [2.2.2]- diazabicyclic, 2-pyridone, and ETP structures from a common intermediate, a 2,5-diketopiperazine azadiene (pyrazinone) precursor. Additionally, we are pursuing domino or "one- pot" reaction methodology for the preparation of these structures, an effort that is economical with regard to our time as researchers, but also resource and cost efficient and has the greatest opportunity to streamline research into both known bioactive molecules and new chemical space. Our research efforts will also contribute broadly to fundamental chemical understanding of the reactivity and selectivity of underexplored reactions. The College of William & Mary does not offer a doctoral degree in chemistry (BS/MS only); accordingly, my research group is composed of undergraduate researchers (and one MS candidate). My current research program creates a rigorous environment for discovery-based learning and enforces teaching and training in the one-on-one research experience. The proposed research would continue within this climate. Support from the NIH would enable the research of 4 undergraduates and one Master's candidate for each year of the award.