Contra-Thermodynamic Catalysis and Fluorine Sculpting; Two Counter Cultural Approaches to Synthesis

项目总结/摘要 这项建议的目标是双重的，包括发展和概念上的进步， 热力学催化和氟雕塑。这两个目标的实现将提升综合领域， 通过开发合成和化学生物学工具对人类健康产生积极影响。虽然乍一看 方向看起来完全不同，它们都严重依赖于可见光。然而，他们偏离了一个 另一种是以激发态光催化剂被猝灭的方式。一种通过三重态敏化（德克斯特能量 转移），另一个通过SET到激发态催化剂或从激发态催化剂转移。 传统的催化具有降低能垒和促进反应的作用，但最终不会改变反应的性质。 反应的热力学（或自发方向）。我们的长远目标是制定策略， 一种使以前不可能的或吸能的合成成为可能的系统。 实现这一目标，将为大分子的研究带来新的工具，新的合成方法。实现这一 目标将需要发展不受微观可逆性原则约束的反应，即 不可逆的反应，可以用来泵能量到系统中，以及利用和储存能量的能力 可以用来驱动反应的热力学货币。更具体地说，我们试图利用顺式到反式 环烯烃的光异构化：识别能量泵送反应，定义能量货币，并开发 战略花费精力充沛的货币，以推动反应，否则是不可能的。实现这些目标 预期通过开发新的吸能（忽略光子能量）反应来实现合成， 方法以及利用现有能源和时空的生物工具的发展 与光激活过程相关的控制。 这一建议的第二个方向也涉及一种非正统的综合方法。与其他元素不同，氟 具有调节分子特性及其在人体内行为的能力。氟掺入 近年来，制药业的发展呈指数级增长，但我们获得有机氟的合成能力 非常有限由于氟在周期表上的位置，C-F键的选择性安装是 非常具有挑战性。氟雕刻是一种有机氟合成的替代方法，其开始于低浓度的氟。 成本低的全氟芳烃，并选择性地分离出所需的高价值有机氟。它显示了巨大的希望;提供 快速获取有机氟。我们的长期目标是推进氟雕刻的概念，并提供 扩大了获得结构空前复杂的有机氟的机会。这种新发现的能力预计将导致 更深入地了解氟在与人类健康有关的分子中所起的作用。

Project Summary/Abstract The objectives of this proposal are two-fold and include the development and conceptual advancement of contra- thermodynamic catalysis and fluorine sculpting. The realization of both objectives will elevate the field of synthesis and positively impact human health through the development of tools for synthesis and chemical biology. While at first blush the directions appear disparate, they both rely heavily on visible light photocatalysis. However, they deviate from one another in the manner in which the excited state photocatalyst is quenched. One by triplet sensitization (Dexter energy transfer), and the other by SET to or from an excited state catalyst. Traditional catalysis has the effect of lowering energy barriers and facilitating reactions but ultimately does not alter the thermodynamics (or spontaneous direction) of the reaction. Our long term objectives are to develop strategies to realize a system that makes formerly impossible, or endergonic, synthesis possible in addition to enabling exergonic synthesis. Achieving this objective, will result in new tools for the study of large molecules, new synthetic methods. Achieving this objective will require the development of reactions which are not subject to the principles of microscopic reversibility, i.e. irreversible reactions that can serve to pump energy into the system, and the ability to harness and store the energy thermodynamic currency that can be used to drive reactions. More tangibly we seek to leverage the cis-to-trans photoisomerization of cycloalkenes to: identify energy pumping reactions, define an energetic currency, and develop strategies to spend the energetic currency to drive reactions that would be otherwise impossible. Realizing these objectives is expected to both enable synthesis via the development of new endergonic (neglecting the photon energy) reactions and methods as well as the development of biological tools that capitalize on the available energy and the spatio-temporal controlled associated with light activated processes. The second direction of this proposal also involves an unorthodox approach to synthesis. Like no other element, fluorine has the ability to modulate the properties of a molecule and its behavior within the human body. Fluorine incorporation into pharmaceuticals has seen exponential growth in recent years, and yet our synthetic capability to obtain organofluorines is surprisingly limited. Owing to fluorine’s location on the periodic table, the selective installation of C–F bonds are exceptionally challenging. Fluorine sculpting is an alternative approach to organofluorine synthesis that begins with a low cost perfluoroarene and selectively carves out the desired high-value organofluorine. It has shown great promise; providing rapid access to organofluorines. Our long term objective is to advance the concept of fluorine sculpting and provide expanded access to organofluorines of unprecedented structural complexity. This newfound ability is expected to result in greater understanding of the role fluorine plays in molecules of interest to human health.