EFFICIENT SYNTHESIS OF BIOACTIVE GAMMA LACTAMS

点击翻译按钮获取中文摘要

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.