EFFICIENT SYNTHESIS OF BIOACTIVE GAMMA LACTAMS

描述：（主要研究者摘要）在我们的实验室中，我们有 发现了制备手性γ-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。这项计划中的研究将把目前的方法扩展到 包含氨基酸衍生物的各种体系，预期其 证明了这种方法的可行性、通用性和立体选择性。 方法论由于我们精心设计的模板预计将避免大多数 在以前已知的方法中发现的缺点，这项研究将给出 在手性吡咯烷酮合成中产生创新的合成方案。 由于吡咯烷和吡咯烷酮骨架在生物学上是普遍存在的， 活性天然产品，我们开发的技术将不仅提供 必要的技术，但也至关重要的中间体，这将是 立即有用各种手性γ-内酰胺将从天然产物制备。 氨基酸通过利用我们的环化程序，他们将被利用 用于合成各种天然产物，这些天然产物一直需要 大规模生产的有效合成路线。我们的合成目标包括 lactacystin、pramanicin、statine、rolipram、epolactaene和kainic acid。这些 化合物及其结构类似物作为手性药物具有很大的前景， 治疗多种疾病，如癌症、阿尔茨海默病、癫痫， 心血管疾病由于天然资源稀缺， 由于全合成的困难，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 合成成功后，我们高效的合成途径将为 解决这些化合物的有限可用性的道路。而且这些 γ-内酰胺合成的突出方法学将提供新的前景 发现结构相关的手性药物。我们认为这种新 技术将有助于推进有机合成，以及提高 生物学和药物化学等相关领域的进展， 在药物发现方面。

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.