Ti-Catalyzed Nitrene Transfer Reactions

项目摘要 该提案的目标是设计新的钛催化的氧化氮烯转移反应， 模块化，并选择性地组装吡咯衍生物和双官能化炔。的理由 发展钛催化氮烯转移的一个重要原因是，钛在地球上是丰富的，通常是生物相容的， 消除了精细化学合成中对有效去除和回收催化剂的需要。此外，早 过渡金属通常可以获得与后过渡金属不同的结构和基元反应步骤， 开辟了新的键合形成策略，其可以与现有技术互补或正交。 研究的第一阶段涉及开发从炔和芳环合成[2+2+1]吡咯的方法。 具有化学选择性和区域选择性的二氮烯。利用我们实验室获得的钛催化的初步数据， [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 设计具有改进的选择性和更温和的反应条件的新催化剂体系， 和工程系统，用于高效、选择性和模块化生产高价值生物活性靶标， 他汀类药物立普妥 建议研究的第二阶段将扩展我们对[2+2+1]的机械理解 吡咯催化等初步结果设计相关的钛催化串联键 形成结合不同不饱和偶联配偶体的反应。这一阶段将导致催化 由简单炔起始材料合成其他N-杂环的方法以及氧化方法 炔的双官能化。 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。吡咯是该类化合物中的一类重要化合物，具有广泛的生物活性。尽管许多 虽然存在形成吡咯的多组分反应，但一般合成方法的开发仍然是一个挑战。 由于吡咯单元的独特反应性特征，通过设计通用方法， 吡咯和相关的杂环，合成化学家将有快速和收敛的方式获得不同的， 新的分子结构和积木，最终将允许新的 小分子类药物结构，

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