New Radical and Fluorination Methods for the Syntheses of Pharmaceuticals

药物合成的新自由基和氟化方法

• 批准号: RGPIN-2020-04653
• 负责人: Sammis, Glenn
• 金额: $ 2.62万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740096
• 关键词: New; Radical; Fluorination; Methods; Syntheses

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.

提案摘要：据报道，这项研究提案的重点是发现创新的合成有机方法，重点是开发目前无法替代的新成键技术。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)用于合成与药物和农用化学相关的模体的新的单电子过程。对于第一个主题，我们将继续探索工业熏蒸剂硫酰氟(SO2F2)的使用。我们发现，SO2F2可以在一个反应罐中实现多步反应。这笔赠款描述了我们未来在开发新的硫酰氟介导的反应方面的探索，目前还没有竞争性的一锅锅替代方法。我们还将研究基于SO2F2的新试剂的合成，用于与药物相关的反应。这些方法有望提高制药和农用化学品生产的效率，从而降低成本。他说，第二个主题(B)以单电子过程为基础，细分为三个主要领域。首先，我们将探索我的实验室最近取得的一项突破在合成手性1，4-二胺方面的应用，利用现有技术合成手性1，4-二胺是很费力的。我们计划准备一个相对未被开发的手性1，4-二胺的小文库，并探索它们作为制药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反应的新策略，这是一个几乎没有解决方案的领域。我们将探索的策略利用关键的Lewis酸加速的单电子还原来促进选择性自由基的形成和环化。这一领域的成功将为制药提供新的、高效的合成途径。最后，我们将探索用于合成的新型自由基氟捕捉剂。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。这一发现开创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还不够快，不足以捕获许多高活性物种。这项建议概述了一类新的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用途。