Ti-Catalyzed Nitrene Transfer Reactions

Ti 催化的氮烯转移反应

• 批准号: 10389505
• 负责人: Ian Albert Tonks
• 金额: $ 11.17万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389505
• 关键词: Alkynes; Anti-Inflammatory Agents; Anticoagulants; Architecture; Arthritis; Blood coagulation; Carbon; Catalysis; Communities; Coupling; Data; Development; Electrons; Excision; FDA approved; Goals; Hydrazines; Imines; Laboratories; Lead; Methods; Molecular; Nitriles; Nitrogen; Oxidants; Oxidation-Reduction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Planet Earth; Public Health; Pyrazoles; Reaction; Reagent; Recovery; Research; Research Personnel; Statistical Data Interpretation; Stroke prevention; Structure; System; Technology; Titanium; Transition Elements; Work; catalyst; celecoxib; chemical synthesis; design; functional group; insight; nitrene; novel; novel therapeutics; oxidation; scaffold; small molecule; tool

Project Summary The goal of this proposal is to design new Ti-catalyzed oxidation reactions to modularly assemble pyrazole derivatives and difunctionalize alkynes. The rationale for developing Ti catalysis is that Ti is earth-abundant and generally nontoxic, which obviates the need for efficient catalyst removal and recovery in fine chemical synthesis. Early transition metals can access different structures and elementary reaction steps than late transition metals, resulting in bond forming strategies that are complementary or orthogonal to existing technology. First, the proposed research concerns developing new dual catalytic strategies for the [2+2+1] synthesis of pyrazoles. Using preliminary data gained in our laboratory on stoichiometric oxidation-induced N-N reductive elimination reactions, we will explore single-electron catalytic and photocatalytic strategies for oxidant turnover. Development of a catalytic strategy for electronegative bond couplings like N-N coupling will ultimately lead to mild and general dual catalyst systems for the rapid, modular construction of high-value bioactive pyrazoles, and also open avenues for advancing other challenging bond coupling reactions in catalysis. Further, we will design selective alkyne carboamination reactions, building off of preliminary results into this reaction class. Alkyne carboamination reactions can lead to iminocyclopropanes and unsaturated imines, each of which are valuable heterocycle building blocks. Our strategy for selective reaction design will be to use ISPCA, a new statistical analysis method we have developed that aids in determination of key control factors in a reaction. Concurrent refinement of ISPCA along with carboamination catalysis will yield both synthetically practical reactions, as well as a tool and roadmap for other catalysis researchers to follow in designing selective reactions. Finally, we will use our mechanistic insight of Ti redox catalysis to design new multicomponent alkyne oxidation reactions. A key focus of this work will be to develop strategies that incorporate more heteroatoms into the products, using our preliminary discoveries in dual catalysis and N-N reductive elimination. These reactions will result in catalytic methods to rapidly produce functional-group rich carbon scaffolds. Relevance to public health. Nitrogen heterocycles constitute the single most prevalent class of functional groups in FDA-approved small-molecule drugs: 59% of all unique small molecule drugs contain at least one N- heterocycle. Pyrazoles are an important class within this group, and have broad bioactivity. Although many reactions to form pyrazoles exist, their synthesis often relies on using potentially toxic and explosive hydrazines, and have well-established regioselectivity limitations. A general synthesis of pyrazoles that overcomes these limitations is an unmet challenge. By designing methods to pyrazoles, and more generally to the catalytic formation of weak bonds like N-N bonds, synthetic chemists will have rapid and convergent access to diverse and novel molecular architectures. These building blocks will aid in the development of new small molecule drug- like architectures for the biomedical community.

项目摘要 本论文的目标是设计新的钛催化氧化反应来组装吡唑 衍生物和双官能化炔。开发Ti催化剂的基本原理是Ti是地球上丰富的， 通常无毒，这避免了在精细化学合成中有效去除和回收催化剂的需要。 早期过渡金属可以获得与后过渡金属不同的结构和基元反应步骤， 导致与现有技术互补或正交的键合形成策略。 首先，所提出的研究涉及开发新的双催化策略用于[2+2+1]合成 吡唑。利用实验室获得的化学计量氧化诱导的N-N还原的初步数据， 消除反应，我们将探索单电子催化和光催化氧化剂周转策略。 开发用于电负性键偶联（如N-N偶联）的催化策略将最终导致 温和且通用的双催化剂系统，用于快速、模块化构建高价值生物活性吡唑，以及 也为推进催化中其他具有挑战性的键偶联反应开辟了途径。 此外，我们将设计选择性的炔碳胺化反应，建立了初步的结果到这个 反应类。炔碳胺化反应可产生亚氨基环丙烷和不饱和亚胺， 它们是有价值的杂环结构单元。我们的选择性反应设计策略是使用ISPCA， 我们开发了一种新的统计分析方法，有助于确定反应中的关键控制因素。 ISPCA沿着碳胺化催化的同时精制将产生综合实用的 反应，以及其他催化研究人员在设计选择性反应时遵循的工具和路线图。 最后，我们将利用我们对钛氧化还原催化的机理认识来设计新的多组分炔 氧化反应这项工作的一个关键重点将是开发将更多杂原子纳入 利用我们在双催化和N-N还原消除方面的初步发现，合成了这些产物。这些反应 将导致催化方法快速产生富含官能团的碳支架。 与公共卫生的相关性。氮杂环构成了单一的最普遍的官能化的类别。 在FDA批准的小分子药物中，59%的独特小分子药物含有至少一个N- 杂环。吡唑类化合物是该类化合物中的重要一类，具有广泛的生物活性。尽管许多 存在形成吡唑的反应，它们的合成通常依赖于使用潜在有毒和爆炸性的肼， 并具有公认的区域选择性限制。吡唑的一般合成克服了这些问题， 局限性是一个尚未满足的挑战。通过设计吡唑类化合物的方法，更一般地， 形成弱键，如N-N键，合成化学家将有快速和收敛的方式获得不同的 和新颖的分子结构。这些基本组成部分将有助于开发新的小分子药物- 比如生物医学领域的建筑。