EFFICIENT SYNTHESIS OF BIOACTIVE GAMMA LACTAMS

生物活性γ内酰胺的高效合成

• 批准号: 6828276
• 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/6828276
• 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：（主要研究者的摘要）在我们的实验室中，我们有 发现了一种有效的合成方案来制备手性γ-内酰胺 （吡咯烷酮）通过立体和区域选择性分子内 C-H 插入 酰胺的。这项预计的研究是将当前的方法扩展到 包含氨基酸衍生物的各种系统，预计 证明该方法的可行性、通用性和立体选择性 方法论。由于我们精心设计的模板有望避免大多数 先前已知方法中发现的缺点，本研究将给出 提出了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中普遍存在 活性天然产品，我们开发的技术不仅可以提供 必要的技术以及关键的中间体，这将是 立即有用。各种手性γ-内酰胺将从天然产物中制备 氨基酸通过我们的环化程序，并且它们将被利用 用于合成各种天然产物，这一直需要 用于大规模生产的高效合成路线。我们的合成目标包括 乳胞素、普拉马尼星、他汀、咯利普兰、依泊内酯和红藻氨酸。这些 化合物及其结构类似物作为手性药物具有广阔的前景 治愈癌症、阿尔茨海默病、癫痫等多种疾病 心血管疾病。由于自然资源的稀缺性和 全合成困难，生物学研究受到阻碍 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开辟新的道路 解决这些化合物的有限可用性的道路。而且，这些 γ-内酰胺合成的重要方法将提供新的视角 发现结构相关的手性药物。我们相信这个新 技术将有助于推进有机合成，并提高 生物学、药物化学等相关领域的进展，达到顶峰 在药物发现中。

项目成果

A novel synthetic route to chiral gamma-lactams from alpha-amino acids via Rh-catalyzed intramolecular C-H insertion.

通过 Rh 催化的分子内 C-H 插入从 α-氨基酸合成手性 γ-内酰胺的新路线。

• DOI: 10.1021/jo0259717
• 发表时间: 2002
• 期刊: The Journal of organic chemistry
• 作者: Yoon,CheolHwan;Flanigan,DavidL;Chong,Byong-Don;Jung,KyungWoon
• 通讯作者: Jung,KyungWoon

Glutathione, S-substituted glutathiones, and leukotriene C4 as substrates for peptidylglycine alpha-amidating monooxygenase.

谷胱甘肽、S-取代的谷胱甘肽和白三烯 C4 作为肽基甘氨酸 α-酰胺化单加氧酶的底物。

• DOI: 10.1016/s0003-9861(02)00730-0
• 发表时间: 2003
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Miller,LauraAaron;Baumgart,LauraE;Chew,GeoffreyH;deLong,MitchellA;Galloway,LamarC;Jung,KyungWoon;Merkler,KathleenA;Nagle,AdvaitS;Poore,DerekD;Yoon,CheolHwan;Merkler,DavidJ
• 通讯作者: Merkler,DavidJ