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.

项目摘要/摘要 本申请描述了两个旨在提高效率和选择性的研究计划 与小分子药物发现相关的化学合成。第一个项目寻求发明生物-- Mtic级联反应被自然界用来构建复杂的多环萜类和类固醇，其中许多 具有深刻的生物活性。第二个项目旨在发明定型的和功能性的建筑 可用于在药物发现的不同阶段优化小分子治疗性能的块- 每一项和发展努力。 第一个计划的主要目标是确定一种新的催化系统，它可以引发一系列 多不饱和前体的成环反应。自然界通过引发阳离子来构建所有的萜类化合物 通过质子化或电离反应的立体化学精确控制下的级联环化反应-- 活性基团(磷酸盐、环氧化物)。这一自然过程的化学类似物具有同样的能力-- 具有高水平立体控制的ATE多循环系统最近才出现。然而，它们是有限的 他们有能力引入生产最终产品所需的必要功能。通过马具- 利用手性路易斯碱催化的潜力，该计划寻求创建富含对映体的硫氰酸根- 将能够通过自发地与近端双链接合来启动阳离子级联的UM离子 基材中的键。因此，所得到的多环产物将在层上含有硫醚官能团- 非常关键的位置，这将允许后续操作进入含氧和含碳的部分。 这一硫离子引发的环化策略的进一步扩展以构建生物活性Ac为目标。 活性螺缩醛和糖苷。 第二个方案的主要目标是创建一个小型图书馆， 可作为插件引入的三维构建块，用于优化和多样化 药物发现项目中的小分子候选者。这项研究面临的主要问题之一是 制药行业的发现努力是有益的化学特性之间的不匹配- 能够筛选文库以及需要通过关联和相互作用进行干预的特性类型 生物分子靶标。出现这个问题的原因是缺乏可靠且可预测地安装的健壮方法 具有适当官能度(氧、氮)的三维碳中心在手动和Au中都有。 托马台。通过对小分子、小分子和小分子间相互作用的立体化学结果的系统研究，得出结论。 重新定义了含硼的积木，并对其机理进行了严格的理解 引言，这个项目将为药物化学界提供构成“立体--”的试剂 以瓶子为中心“；即现成的插件，以加速发现程序。对亲政府的潜在影响 CES研究企业通过消除麻烦的副产品也具有重要意义。