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

这项提案的目标有两个，并包括发展和概念上的进步。 热力学催化和氟雕刻。这两个目标的实现将提升综合和 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。乍一看， 这两个方向似乎是不同的，它们都严重依赖可见光催化。然而，它们偏离了一个 另一种是激发态光催化剂被猝灭的方式。一次通过三重敏化(右旋能量 转移)，以及另一种通过设置到激发态催化剂或从激发态催化剂设置。 传统催化具有降低势垒和促进反应的效果，但最终不会改变 反应的热力学(或自发方向)。我们的长期目标是制定战略，实现 使以前不可能的能量合成成为可能的系统--此外，它有望使能量合成成为可能 合成也是如此。实现这一目标，将带来研究大分子的新工具、新的合成方法。 实现这一目标将需要发展不受微观原理约束的反应。 可逆性，即可用于向系统注入能量的不可逆反应，以及利用和储存能量的能力 作为热力学货币的能量可以用来驱动反应。更具体的是，我们寻求利用独联体到- 环烯烃的反式光异构化反应识别能量泵浦反应，定义能量货币，并发展 用充满活力的货币来推动反应的战略，否则这些反应是不可能的。实现这些目标 有望通过发展新的赋能(忽略光子能量)反应来合成和 方法以及开发利用可用能量和时空控制的生物工具 与光激活的过程相关联。 这项提议的第二个方向还涉及一种非正统的合成方法。与其他元素不同，氟 有能力调节分子的性质及其在人体内的行为。氟掺入 近年来，对制药的研究呈指数级增长，但我们获得有机氟的合成能力 出人意料的有限。由于氟在元素周期表上的位置，C-F键的选择性安装是 极具挑战性。氟雕刻是有机氟合成的另一种方法，从低成本开始 成本较高的全氟芳烃，并选择性地雕刻出所需的高价值有机氟。它已经显示出巨大的希望；提供 快速获取有机氟。我们的长期目标是推动氟雕刻的概念，并提供 扩大对结构复杂程度空前的有机氟的获取。这一新发现的能力预计将导致 更好地了解氟在人类健康感兴趣的分子中所起的作用。

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, endergonic synthesis, possible- additionally it is expected to enable exergonic synthesis as well. 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 as 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 control 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.