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: 10398806
• 负责人: Scott Eric Denmark
• 金额: $ 37.78万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398806
• 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.

项目摘要/摘要 该应用程序描述了两个研究计划，旨在提高 化学合成与小分子药物发现工作有关。第一个计划旨在发明生物元素 自然使用的元素级联反应构建复杂的多环萜烯和类固醇，其中许多 拥有深刻的生物学活动。第二个程序旨在发明刻板和功能构建 可用于优化小分子在药物盘的各个阶段的块 编号和发展工作。 第一个程序的主要目的是确定一个可以启动级联的新催化系统 来自多不饱和前体的环反应。自然通过启动阳离子构建所有萜类化合物 通过质子化或电离，在排他性控制立体化学下的级联自行车 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 具有高水平立体控制的ATE多环eny系统直到最近才出现。但是，它们是有限的 他们能够引入最终产品生产所需的必要功能。通过安全带 - 该计划旨在创造手性刘易斯碱基催化的潜力，旨在创造富集的硫烷 - 将阳离子级联的启动通过赞助近端双重启动 基材中的键。因此，由此产生的多环产物将在stra- 在技​​术上至关重要的位置，将允许随后的操作成氧和含碳。 该硫酸离子引发的循环策略的进一步扩展目标是生物学上的构建 螺旋元和糖苷。 第二个程序的主要目的是创建一个小的立体盘构成，功能化，功能化的库 可以作为插件引入的三维构建块，以优化和多样化 药物发现计划中的小分子候选人。研究面临的主要问题之一 制药行业的发现工作是可用的化学特征之间的不匹配 - 有能力的筛选文库以及通过关联和与与之相互作用进行干预所需的特征 生物分子靶标。这个问题是由于缺乏可靠且可预测安装的可靠方法 在手动和AU中具有适当功能（氧，氮）具有适当功能的三维碳中心 Tomated平台。通过系统地检查小，ste-耦合的立体化学结果 重新启示含硼的构件和对其机制的严格理解 简介，该计划将为医学化学界提供构成“立体的试剂” 以瓶中为中心”；即离货架插件以加速发现计划。潜在的影响 CESS Research Enterprises也可以消除麻烦的副产品。