EFFICIENT SYNTHESIS OF BIOACTIVE GAMMA LACTAMS

生物活性γ内酰胺的高效合成

• 批准号: 6226260
• 负责人: KYUNG W. JUNG
• 金额: $ 21.1万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-10 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6226260
• 关键词: acetamides; acetylcysteine; aminoacid analog; antineoplastics; biological products; biotechnology; chemical condensation; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; kainate; lactams; lactones; methylation; molecular asymmetry; pyrrolidines; rhodium; stereoisomer

DESCRIPTION: (Principal Investigator's Abstract) In our laboratories, we have discovered an efficient synthetic protocol to prepare a chiral gamma-lactam (pyrrolidinone) via a stereo- and regioselective intramolecular C-H insertion of an amide. This projected study is to extend the current methodology to various systems comprising amino acid derivatives, which are anticipated to demonstrate the feasibility, generality, and stereoselectivity of this methodology. Since our well designed templates are expected to avert most shortcomings found in the previously known methods, this research will give rise to an innovative synthetic protocol in chiral pyrrolidinone synthesis. Since pyrrolidine and pyrrolidinone skeletons are prevalent in biologically active natural products, our developed techniques will provide not only the necessary technologies but also crucial intermediates, which will be immediately useful. Various chiral gamma- lactams will be prepared from natural amino acids by utilizing our cyclization procedure, and they will be utilized for the synthesis of various natural products, which have constantly required efficient synthetic routes for mass production. Our synthetic targets encompass lactacystin, pramanicin, statine, rolipram, epolactaene, and kainic acid. These compounds and their structural analogs hold great promise as chiral drugs to cure numerous diseases such as cancer, Alzheimer's disease, epilepsy, and cardiovascular diseases. Due to their scarcity in natural sources and difficulties in total syntheses, biological studies have been hampered and further clinical trials are also far from being a reality. If the designed syntheses become successful, our efficient synthetic pathway will pave a new road to solve the limited availability of these compounds. Moreover, these salient methodologies in gamma-lactam synthesis will provide new perspectives in discovery of structurally related chiral drugs. We believe this new technology will help to advance organic synthesis, as well as to enhance the progress of related fields such as biology and medicinal chemistry, culminating in drug discovery.

描述：(首席研究员摘要)在我们的实验室里，我们有 发现了一种制备手性伽马内酰胺的有效合成方案 (吡咯烷酮)通过立体和区域选择性的分子内C-H插入 一种酰胺。这项计划的研究将把目前的方法扩展到 由氨基酸衍生物组成的各种系统，预计将 演示此方法的可行性、一般性和立体选择性 方法论。由于我们精心设计的模板有望避免大多数 在以前已知的方法中发现的缺陷，本研究将给出 提出了一种用于手性吡咯烷酮合成的创新合成方案。 由于吡咯烷和吡咯烷酮骨架在生物学上普遍存在 活性天然产物，我们开发的技术不仅将提供 必要的技术，但也是关键的中间体，这将是 立即派上用场。各种手性伽马-内酰胺类药物将由天然药物 氨基酸，利用我们的环化程序，它们将被利用 用于各种天然产物的合成，这需要不断地 大规模生产的高效合成路线。我们的合成目标包括 乳房菌素、普拉尼辛、他汀类、罗利普兰、依波拉坦和海人藻酸。这些 化合物及其结构类似物作为手性药物具有巨大的前景 治愈多种疾病，如癌症、阿尔茨海默氏症、癫痫和 心血管疾病。由于它们的自然资源稀缺， 在全合成、生物学研究方面的困难受到了阻碍 进一步的临床试验也远未成为现实。如果设计的 合成成功，我们的高效合成途径将铺平新的 解决这些化合物可获得性有限的道路。此外，这些 伽马-内酰胺合成的显著方法学将提供新的视角 在发现结构相关的手性药物方面。我们相信这一新的 技术将有助于推进有机合成，以及加强 生物和药物化学等相关领域的进展达到顶峰 在药物研发方面。