SELECTIVE METHODS FOR SYNTHESIS WITH STRAINED MOLECULES AND CARBENOIDS

应变分子和类胡萝卜素的选择性合成方法

• 批准号: 8135284
• 负责人: JOSEPH M FOX
• 金额: $ 38.62万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-05 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135284
• 关键词: Address; Alkenes; Biological Sciences; Chemistry; Complex; Cyclization; Cyclopropanes; DNA Sequence Rearrangement; Development; Family; Funding; Glycols; Goals; Grant; Health; Human; Ligands; Methodology; Methods; Organic Synthesis; Outcome; Paper; Pathway interactions; Play; Process; Protocols documentation; Publishing; Pyrrolizidine Alkaloids; Reaction; Research; Rhodium; Ring Compound; Role; Sucrose; Transition Elements; United States National Institutes of Health; carbene; catalyst; computer studies; cycloaddition; cyclopropane; design; diazo compound; drug discovery; flustramine A; insight; interest; small molecule

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop selective methods for organic synthesis with strained molecules and rhodium carbenoids. The specific aims of the proposal are: Aim 1 is to develop stereoselective transformations of strained three-membered ring compounds. Modes of reactivity that will be explored will include carbometallation reactions, cycloaddition reactions, and transition metal catalyzed rearrangements. Of particular interest is the unusual ability of strained molecules to control the stereochemical outcome of such reactions. Aim 2 is to develop ligands that expand the types of diazo compounds that can be utlized in Rh-carbenoid chemistry. Because Rh-carbeniods are critical to the synthesis of cyclopropenes and cyclopropanes, addressing the limitations of the chemistry of Rh-carbenes is a fundamental component to advancing the utility strained molecules in synthesis. Of particular interest is the development of ligands that facilitate reactions of ?-alkyldiazo compounds, which are susceptible to ?-hydride elimination. With insight from computational studies, catalysts will be designed that can navigate away from undesired reaction pathways and provide desired products with maximum selectivity. Aim 3 is to develop general, stereoselective methods for the synthesis of medium ring trans-cycloalkenes. Also developed will be new stereospecific reaction chemistry that transfers the planar chirality of the alkene to newly created stereocenters in products. Reactions to be studied include transannular cyclization reactions, and intramolecular cycloaddition reactions. Applications will include the development of a unified approach to the synthesis of a family of naturally occuring pyrrolizidine alkaloids. PUBLIC HEALTH RELEVANCE: Organic synthesis plays a central role in the advancement of human health, and the increasing complexity of small molecule targets has required increasingly sophisticated methodology for organic synthesis. Synthetic methodology has been cited by former NIH director Elias Zerhouni as being "the number one stumbling block" for the biological sciences. The objective of this proposal is to develop methodologies that will overcome existing limitations in organic synthesis, and thereby accelerate the process of drug discovery.

描述（由申请人提供）：拟议研究的目标是开发使用应变分子和铑卡宾进行有机合成的选择性方法。该提案的具体目标是：目标1是发展应变三元环化合物的立体选择性转化。将探讨的反应模式将包括碳代甲烷反应、环加成反应和过渡金属催化的重排。特别令人感兴趣的是应变分子控制这种反应的立体化学结果的不寻常的能力。目的二是开发新的配体，以扩大可用于铑类卡宾化学的重氮化合物的类型。由于Rh-卡宾对环丙烯和环丙烷的合成至关重要，因此解决Rh-卡宾的化学限制是推进合成中的实用应变分子的基本组成部分。特别令人感兴趣的是促进？-烷基重氮化合物，这是敏感的？-氢化物消除从计算研究的洞察力，催化剂将被设计，可以导航远离不需要的反应途径，并提供所需的产品具有最大的选择性。目的三是发展具有立体选择性的中环反式环烯烃的合成方法。还将开发新的立体特异性反应化学，将烯烃的平面手性转移到产物中新产生的立体中心。待研究的反应包括跨环环化反应和分子内环加成反应。应用将包括一个统一的方法来合成一个家庭的自然发生的吡咯里西啶生物碱的发展。公共卫生关系：有机合成在促进人类健康方面发挥着核心作用，并且小分子靶标的日益复杂性要求有机合成的方法学日益复杂。前美国国立卫生研究院院长埃利亚斯·泽胡尼（Elias Zerhouni）将合成方法论称为生物科学的“头号绊脚石”。该提案的目的是开发克服有机合成中现有限制的方法，从而加速药物发现的过程。