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.

项目概要/摘要 该申请描述了旨在提高效率和选择性的两个研究计划 与小分子药物发现工作相关的化学合成。第一个计划旨在发明仿生学 大自然使用的内消旋级联反应来构建复杂的多环萜烯和类固醇，其中许多 具有深远的生物学活性。第二个项目旨在发明立体和功能性的建筑 可用于在药物发现的各个阶段优化小分子的治疗特性的模块 和发展努力。 第一个项目的主要目标是确定一种新的催化系统，该系统可以引发一系列反应 多不饱和前体的成环反应。大自然通过引发阳离子构建所有萜类化合物 通过反应的质子化或电离，在立体化学的精确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 具有高立体控制水平的多环系统最近才出现。然而，它们的作用是有限的 他们有能力引入最终产品生产所需的必要功能。通过线束- 考虑到手性路易斯碱催化的潜力，该计划旨在创造对映体富集的硫杂环己烷- um 离子，这将通过自发地接合近端双离子来启动阳离子级联 基质中的键。因此，所得的多环产物将含有硫醚官能团 结构上至关重要的位置，将允许随后对含氧和碳的部分进行操作。 这种硫离子引发的环化策略的进一步扩展旨在构建生物活性 活性螺缩醛和糖苷。 第二个程序的主要目标是创建一个小型库，其中包含立体定义的、功能化的、 三维构建块可以作为插件引入，以实现优化和多样化 药物发现项目中的小分子候选者。研究和面临的主要问题之一 制药行业的发现努力是有效的化学特性之间的不匹配 能够筛选文库以及通过关联和交互进行干预所需的特征种类 生物分子靶标。这个问题是由于缺乏可靠且可预测地安装的可靠方法而产生的。 三维碳中心在手动和自动操作中都具有适当的功能（氧、氮） 番茄化平台。通过系统地检查小分子偶联的立体化学结果， 重新定义了含硼结构单元并对其机制进行了严格的理解 简介，该计划将为药物化学界提供构成“立体- 瓶子里的中心”；即加速发现计划的现成插件。对亲的潜在影响 工艺研究企业在消除麻烦的副产品方面也具有重要意义。