Synthetic and Mechanistic Studies on Preparatively Significant Reactions

预备性显着反应的合成与机理研究

• 批准号: 10387451
• 负责人: Scott Eric Denmark
• 金额: $ 11.51万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387451
• 关键词: 3-Dimensional; Biological; Biomimetics; Boron; Carbon; Catalysis; Cations; Characteristics; Chemicals; Communities; Complex; Coupling; Cyclization; Drug Industry; Epoxy Compounds; Generations; Glycosides; Ions; Libraries; Manuals; Methods; Nature; Nitrogen; Outcome; Oxygen; Pharmaceutical Chemistry; Positioning Attribute; Preparation; Process; Production; Property; Public Health; Reaction; Reagent; Research; Research Proposals; Steroids; System; Terpenes; Therapeutic; Therapeutic Agents; analog; base; chemical synthesis; drug candidate; drug development; drug discovery; functional group; improved; inorganic phosphate; ionization; pi bond; programs; protonation; screening; small molecule; small molecule therapeutics; stereochemistry; thioether

PROJECT SUMMARY/ABSTRACT This application describes two programs of research aimed at improving the efficiency and selectivity of chemical synthesis relevant to small molecule drug discovery efforts. The first program seeks to invent biomi- metic cascade reactions used by Nature to construct complex polycyclic terpenes and steroids many of which have profound biological activities. The second program seeks to invent stereodefined and functional building blocks that can be used to optimize therapeutic properties of small molecules at various stages of drug discov- ery and development efforts. The primary objective of the first program is to identify a new catalytic system that can initiate a cascade of ring forming reactions from polyunsaturated precursors. Nature constructs all terpenoids by initiating cationic cascade cyclizations under exquisite control of stereochemistry through either protonation or ionization of reac- tive groups (phosphates, epoxides). Chemical analogs of this natural process that have the same ability to cre- ate polycyclic systems with high levels of stereocontrol have only recently emerged. However, they are limited in their ability to introduce the requisite functionality needed for the production of the final product. By harness- ing the potential of chiral Lewis base catalysis, this program seeks to create enantiomerically enriched thiirani- um ions which will enable the initiation of the cationic cascade by spontaneously engaging the proximal double bonds in the substrate. The resulting polycyclic product will thus contain a thioether functional group at a stra- tegically crucial position that will allow subsequent manipulations into oxygen and carbon containing moieties. Further extensions of this sulfenium ion initiated cyclization strategy target the construction of biologically ac- tive spiroacetals and glycosides. The primary objective of second program is the creation of a small library of stereodefined, functionalized, three-dimensional building blocks that can be introduced as plugins for the optimization and diversification of small molecule candidates in drug discovery programs. One of the major problems facing the research and discovery efforts in the pharmaceutical industry is the mismatch between the chemical characteristics of avail- able screening libraries and the kinds of characteristics needed to intervene by association and interaction with biomolecular targets. This problem arises from the lack of robust methods that reliably and predictably install three dimensional carbon centers bearing appropriate functionality (oxygen, nitrogen) in both manual and au- tomated platforms. By systematic examination of the stereochemical outcome of the coupling of small, ste- reodefined boron-containing building blocks and a rigorous understanding of the mechanisms of their introduction, this program will provide the medicinal chemistry community with reagents that constitute “stereo- centers in a bottle”; namely off the shelf plugins to accelerate discovery programs. The potential impact on pro- cess research enterprises is also significant by eliminating troublesome byproducts.

项目总结/摘要 本申请描述了两个研究项目，旨在提高催化剂的效率和选择性。 与小分子药物发现工作相关的化学合成。第一个项目旨在发明生物医学， 自然界使用的模拟级联反应来构建复杂的多环萜烯和类固醇，其中许多 具有深刻的生物学活性。第二个项目旨在创造立体化和功能化的建筑 可用于在药物发现的各个阶段优化小分子治疗特性的模块， 努力和发展。 第一个计划的主要目标是确定一种新的催化系统，可以启动级联反应， 多不饱和前体的成环反应。大自然通过引发阳离子来构建所有萜类化合物 通过反应的质子化或电离，在精确的立体化学控制下进行级联环化， 活性基团（磷酸盐、环氧化物）。这种自然过程的化学类似物具有相同的能力， 具有高度立体控制的多环系统最近才出现。然而，它们是有限的 它们引入生产最终产品所需的必要功能的能力。用马具- 利用手性刘易斯碱催化的潜力，该计划旨在创造对映体富集的硫杂反式- 这将能够通过自发地接合近端双链引发阳离子级联 基板中的键合。因此，所得多环产物将在结构上含有硫醚官能团。 这将允许随后操作成含氧和碳部分。 这种硫离子引发的环化策略的进一步扩展靶向生物活性的构建。 活性螺缩醛和糖苷。 第二个计划的主要目标是建立一个小型的立体定向的，功能化的， 可以作为插件引入的三维构建块，用于优化和多样化 小分子候选药物发现计划。研究所面临的主要问题之一， 在制药工业中的发现努力是有用的化学特性之间的不匹配， 能够筛选文库和需要通过关联和与 生物分子靶点这个问题是由于缺乏可靠和可预测地安装 在手动和Au中均具有适当官能度（氧、氮）的三维碳中心。 Tomed平台通过系统地研究小分子、小分子、小分子和小分子偶联的立体化学结果， 重新定义的含硼结构单元和对其机制的严格理解， 介绍，该计划将提供药物化学界的试剂，构成“立体， 瓶子里的中心”;即现成的插件，以加速发现程序。对亲- cess研究企业通过消除麻烦的副产品也是重要的。