New Radical and Fluorination Methods for the Syntheses of Pharmaceuticals

提案摘要：本研究提案的重点是发现创新的有机合成方法，重点是开发目前没有替代方法的新键形成技术。我们计划探索两个主要主题：(A)商品化学品在合成过程中的新应用；(B)合成药物和农用化学相关基序的新单电子过程。对于第一个主题，我们将继续探讨工业熏蒸剂硫酰氟（SO2F2）的使用。我们已经发现SO2F2可以用于在单个反应釜中实现多步反应。这笔拨款描述了我们未来对开发新的硫酰氟介导反应的探索，目前没有竞争性的单锅替代品。我们还将研究基于so2f2的新型药物相关反应试剂的合成。预计这些方法将提高药品和农用化学品生产的效率，从而降低成本。第二个主题(B)，基于单电子过程，被细分为三个主要领域。首先，我们将探索我的实验室最近在手性1,4-二胺合成方面的突破应用，使用现有技术很难合成手性1,4-二胺。我们计划为这些相对未被充分开发的手性1,4-二胺准备一个小的文库，并探索它们作为药物生产的手性配体的基序以及用于治疗HIV的蛋白酶抑制剂的成分。其次，我们将探索对映选择性自由基环化的新策略，这是一个很少有解决方案的领域。我们将探索的策略是利用关键的刘易斯酸加速单电子还原来促进选择性自由基的形成和环化。这一领域的成功将提供新的、有效的药物合成途径。最后，我们将探索新的自由基氟捕获剂用于合成。氟在现代药物中无处不在，任何新的发展都有助于降低现有药物的成本，并使新药物的研究成为可能。我们最近发现现有的亲电氟化试剂可以应用于单电子过程。这一发现开辟了合成氟化的新领域。尽管这些试剂取得了成功，但这些试剂的氟转移速度不够快，无法捕获许多高活性物质。本提案概述了一类新的C-F自由基转移剂的探索，并探索了它们在目前使用现有合成技术无法实现的转化中的应用。

Summary of Proposal:       This research proposal focuses on the discovery of innovative synthetic organic methods with a focus on developing new bond formation technologies for which there are currently no alternative. We plan to explore two main themes: (A) new applications of commodity chemicals in synthetic processes and (B) new single electron processes for the synthesis of pharmaceutically- and agrochemically-relevant motifs. For the first theme, we will continue to explore the use of sulfuryl fluoride (SO2F2), an industrial fumigant. We have found that SO2F2 can be used to enable multi-step reactions in a single reaction pot. This grant describes our future exploration of the development of new sulfuryl fluoride-mediated reactions for which there are currently no competitive one-pot alternatives. We will also examine the synthesis of new SO2F2-based reagents for pharmaceutically-relevant reactions. These methods are anticipated to enable greater efficiency and, thus lower the cost, of pharmaceutical and agrochemical production.       The second theme (B), based on single electron processes, is subdivided into three main areas. First, we will explore applications of a recent breakthrough from my laboratory on the synthesis of chiral 1,4-diamines, which are laborious to synthesize using existing technology. We plan to prepare a small library of these relatively underexplored chiral 1,4-diamines and explore their use both as motifs in chiral ligands for pharmaceutical production as well as components of protease inhibitors for use in the treatment of HIV. Second, we will explore new strategies for enantioselective radical cyclizations, an area that has very few solutions. The strategy that we will explore utilizes a key Lewis acid-accelerated single electron reduction to promote selective radical formation and cyclization. Success in this area will provide new, efficient synthetic routes to pharmaceuticals. Finally, we will explore new radical fluorine trapping agents for use in synthesis. Fluorine is ubiquitous in modern pharmaceuticals, and any new developments help cut the cost of existing medications and allow the study of new ones. We recently discovered that existing electrophilic fluorination reagents can be applied to single electron processes. This discovery has created a new field of synthetic fluorination. Despite the success of these reagents, the rate of fluorine transfer for these reagents is not sufficiently fast to trap many highly reactive species. This proposal outlines the exploration of a new class of C-F radical transfer agents and explores their use in transformations that are not currently possible using existing synthetic technology.