Visible Light Promoted Fluorination for Application to PET Imaging

项目摘要 已经广泛证明，将氟并入分子中可以改变分子的物理性质。 化合物的性质和生物活性。虽然各种实用的催化剂 已经建立了用于后期19 F化学的方法， 用于18F的实用方法，能够获得广泛的基板。常规 在放射化学中用于访问C-F键的方法对于脂肪族化合物是高度专业化的。 对于芳基化合物，使用有机金属试剂或化学计量的氧化剂。 理想情况下，一个稳定的策略将发生在室温下，并依赖于丰富和稳定的 有机基质如苯甲酸和廉价的氟化物盐。虽然交叉- 偶联方法能够在过渡存在下促进这种类型的反应 金属催化剂，一个长期存在的挑战，特别是在芳基醚，是有效的还原 从低价过渡金属络合物中消除碳-氟键。 在这项研究策略中，我们提出了一种反应性，高价金属氟化物物种 使用光催化剂，同时仍然依赖于方便的芳基起始材料。除了表演 作为过渡金属的氧化剂，我们提出在其还原状态下的光催化剂可以 活化芳基酯以被主过渡金属催化剂捕获。这种酯可以很容易地 原位制备或由相应的羧酸预合成， 对放射化学家来说是可行的光氧化还原催化剂与过渡金属的统一 催化剂已有先例，但尚未应用于化学工业。这种双重 预测催化体系能够使刘易斯碱性和质子分子在 温和的条件。如果成功的话，这个反应将提供第一个光驱动的例子， 放射性药物的合成。由于氟在生物活性分子中的普遍存在， 甚至19 F的这种化学的成功将代表该领域的有价值的进步。具体 目的1讨论了活化芳基的光促进光催化剂的设计和优化。 酯盐酸盐的褪具体目标2提出了活化脂肪族酯的合成。具体目标3 讨论了该方法学在放射性药物开发中的应用。

Project Summary The incorporation of fluorine into molecules has been widely demonstrated to alter the physical properties as well as bioactivity of chemical compounds. While a variety of practical catalytic fluorination methods have been established for late-stage 19F chemistry there are relatively few practical methods for 18F that enable access to a broad scope of substrates. Conventional methods for accessing C-F bonds in radiochemistry are highly specialized for aliphatic compounds and utilize organometallic reagents or stoichiometric oxidants for aryl compounds. Ideally, a fluorination strategy would occur at room temperature and rely on abundant and stable organic substrates such as benzoic acids and inexpensive fluoride salts. Although cross- coupling methods are capable of promoting this type of reaction in the presence of a transition metal catalyst, a long-standing challenge, especially in aryl fluorination, is the effective reductive elimination of carbon-fluorine bonds from a low-valent transition metal complex. In this research strategy, we propose accessing a reactive, high-valent metal fluoride species with a photocatalyst, while still relying on convenient aryl starting materials. In addition to acting as an oxidant for the transition metal, we propose that the photocatalyst in its reduced state can activate an aryl ester for capture by the main transition metal catalyst. This ester can be easily made in situ or pre-synthesized from the corresponding carboxylic acid, making the procedure amenable to a radiochemist. The unification of a photoredox catalyst with a transition metal catalyst has precedent, however, has not yet been applied to fluorination chemistry. This dual catalytic system is predicted to enable the fluorination of Lewis basic and protic molecules under mild conditions. And, if successful, this reaction would provide the first example of light-driven synthesis of radiopharmaceuticals. Due to the prevalence of fluorine in bioactive molecules, the success of this chemistry with even 19F would represent a valuable advance in the field. Specific aim 1 discusses the design and optimization of the light promoted fluorination of activated aryl esters. Specific aim 2 presents the fluorination of activated aliphatic esters. And, specific aim 3 discusses the application of this methodlogy to the development of radiopharmaceuticals.