Ti-Catalyzed Nitrene Transfer Reactions

Ti 催化的氮烯转移反应

基本信息

批准号：
9137888
负责人：
Ian Albert Tonks
金额：
$ 36.86万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-05-31
项目状态：
已结题

项目摘要

Project Summary The goal of this proposal is to design new Ti-catalyzed oxidative nitrene transfer reactions to rapidly, modularly, and selectively assemble pyrrole derivatives and difunctionalize alkynes. The rationale for developing Ti-catalyzed nitrene transfer is that Ti is earth-abundant and generally biocompatible, which obviates the need for efficient catalyst removal and recovery in fine chemical synthesis. Furthermore, early transition metals can often access different structures and elementary reaction steps than late transition metals, opening up new bond forming strategies that may be complementary or orthogonal to existing technology. The first phase of research concerns developing generalizable [2+2+1] pyrrole syntheses from alkynes and diazenes that are chemo- and regioselective. Using preliminary data gained in our laboratory on Ti-catalyzed [2+2+1] reactions, we will explore empirical catalyst and substrate effects on regioselectivity, use kinetic and mechanistic insight to design new catalyst systems with improved selectivity and milder reaction conditions, and engineer systems for the efficient, selective, and modular production of high value bioactive targets such as the statin Lipitor. The second phase of the proposed research will expand upon our mechanistic understanding of [2+2+1] pyrrole catalysis and other preliminary results from our laboratory to design related Ti-catalyzed tandem bond forming reactions that incorporate different unsaturated coupling partners. This phase will result in catalytic methods for the synthesis of other N-heterocycles from simple alkyne starting materials and for the oxidative difunctionalization of alkynes. 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. Pyrroles care an important class within this group, and have broad bioactivity. Although many multicomponent reactions to form pyrroles exist, the development of a general synthetic method remains an unmet challenge due to the unique reactivity profile of the pyrrole unit. By designing general methods to pyrroles and related heterocycles, synthetic chemists will have rapid and convergent access to diverse and novel molecular architectures and building blocks that will ultimately allow for widespread distribution of new small molecule drug-like architectures to the biomedical community

项目摘要该提案的目的是设计新的Ti催化氧化氮转移反应，以迅速模块化和选择性地组装吡咯衍生物并扩散炔烃。理由开发Ti催化的硝基转移是Ti是土壤丰富的，通常是生物相容性的，消除了有效的化学化学合成中有效去除和恢复的有效催化剂的需求。此外，很早过渡金属通常可以访问不同的结构和基本反应步骤，而不是晚过渡金属，打开可能与现有技术互补或正交的新债券形成策略。研究的第一阶段涉及开发可推广[2+2+1]的吡咯合成的丙烯和重氮烯是化学和区域选择性的。使用在Ti-catalyed的实验室中获得的初步数据 [2+2+1]反应，我们将探索经验催化剂和底物对区域选择性的影响，使用动力学和设计具有提高选择性和温和反应条件的新催化剂系统的机械洞察力，以及高效，选择性和模块化产生高价值生物活性目标的工程系统作为他汀类药物。拟议研究的第二阶段将扩展我们对[2+2+1]的机械理解吡咯催化和其他实验室的其他初步结果到设计相关的TI催化串联键形成结合不同不饱和耦合伙伴的反应。此阶段将导致催化从简单炔烃起始材料和氧化作用的其他N-杂环合成的方法炔烃的双功能化。与公共卫生有关。氮杂环构成了最普遍的功能类 FDA批准的小分子药物中的组：在所有独特的小分子药物中，有59％至少含有一个N- 杂环。吡咯人关心该组中的重要阶级，并且具有广泛的生物活性。虽然很多存在对形成吡咯的多组分反应，一般合成方法的发展仍然是由于吡咯单元的独特反应性概况，未得到挑战。通过设计一般方法吡咯并相关的杂环，合成化学家将迅速且收敛地访问多样化和新颖的分子体系结构和建筑块，最终将允许新的分布生物医学群落的小分子型体系结构