Chemical Synthesis of Chiral Bioactive Molecules

 描述(申请人提供)：该研究计划的主要目标是开发新的化学反应和合成策略，用于手性生物活性小分子的制备和研究。在过去的十年里，制药行业的研究人员已经开始认识到候选药物结构复杂性的好处，在进行临床测试和FDA批准的过程中，复杂性更高的分子表现出更高的成功率。为了能够制备更复杂的生物活性分子，必须开发合成工具--新的化学反应--以及用于组装具有手性中心和多环骨架的分子的合成逻辑。拟议的研究计划将寻求通过两个一般领域的化学研究来满足这一需求。第一个研究领域将集中在开发新的镍催化的对映选择性还原交叉偶联反应。这些反应容忍一系列官能团，在温和的条件下发生，并使用廉价的、富含稀土的金属作为催化剂和化学计量比的还原剂。最重要的是，它们不需要使用预先生成的有机金属试剂。一系列新的不对称还原交叉偶联反应的初步结果为本研究的可行性提供了有力的证据。第二个研究领域将集中在合成硫代二酮基哌嗪和生物碱二萜类复杂的多环天然产物。这项研究的预期结果有两个：它将为制备复杂的多环分子提供新的反应和策略，并将提供获得与药物相关的天然产品及其衍生物的途径，这些产品可能在药物发现工作中作为先导化合物。这项研究将由PI、五名化学研究生和三名博士后研究员组成的团队进行。作为该项目的一部分，研究生和博士后研究人员将接受有机化学理论、方法和策略方面的严格培训。这项研究的成功实施将为人类疾病的研究和治疗提供新的工具，使小分子的合成成为可能。

 DESCRIPTION (provided by applicant): The overarching goal of this research program is to develop new chemical reactions and synthetic strategies for the preparation and study of chiral bioactive small molecules. Over the past decade, researchers in the pharmaceutical industry have begun to recognize the benefit of structural complexity in drug candidates, wherein molecules with greater complexity exhibit higher success rates as the proceed through the process of clinical testing and FDA approval. In order to enable the preparation of bioactive molecules with increased complexity, it is imperative to develop both the synthetic tools - new chemical reactions - and the synthetic logic for assembling molecules with chiral centers and polycyclic frameworks. The proposed research program will seek to address this need through chemical research in two general areas. The first research area will focus on the development of new Nickel-catalyzed enantioselective reductive cross-coupling reactions. These reactions tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as catalysts and stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. Preliminary results obtained for a series of new asymmetric reductive cross-coupling reactions provide compelling evidence for the feasibility of this research. The second research area will focus on the synthesis of complex, polycyclic natural products of the epidithiodiketopiperazine and alkaloid diterpenoid families. The expected outcomes of this research are two-fold: it will provide new reactions and strategies for preparing complex polycyclic molecules, and it will provide access to medicinally relevant natural products and their derivatives, which could serve as lead compounds in drug discovery efforts. This research will be carried out by a team composed of the PI, five chemistry graduate students and three postdoctoral researchers. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.