Synthetic Methods to Make Emerging Fluorinated Groups More Accessible

项目摘要/摘要 考虑到目前市场上20-25%的药物中含有一个或多个氟原子 活性成分(其中几种出现在世界卫生组织的基本药物清单上)，显然氟 化学继续对药物开发产生深远影响。然而，尽管具有无可争辩的重要性 在现代药物化学中，氟原子和氟基团的研究存在着历史上的滞后 上个世纪在制药业中的应用。造成这种滞后的原因通常可以归因于 人工可及性，因为在分子上安装氟的方法一直臭名昭著地依赖于有害的 试剂，例如F2和HF。而将例如CF3、OCF3和SCF3基团结合在络合物上的方法 在过去的几十年里，分子变得更加安全和容易获得(自那以来，这些组织 在药物设计中变得司空见惯)，仍然有一些氟化基团具有未开发的潜力 目前还不容易合成。本提案具体确定了SF5、N(CF3)2和N(CF3)(CF2H)基团 作为理想的主题，已经显示出希望，但由于以下事实，仍未充分就业 几乎没有用户友好的方法来制作它们。 因此，拟议的工作集中在解决合成化学瓶颈上，这些瓶颈是 阻碍了这些氟化基团的应用的实现。例如，已经研究了SF5基团 作为CF3或t-Bu基团的生物等位元替代物，但仅有芳基-SF5化合物可用 在商业上。鉴于最近SF5Cl的可及性增加，我们现在可以设想扩大 C(SP3)-SF5成键的可能性范围。具体地说，SF5自由基化学可以与应变- 释放官能化形成新的“杂化生物等位体”，在分子中增加另一维的灵活性 设计。还设想了一些方法来合成和检测一些第一批苄基-SF5化合物，如 以及药物化学工具包的其他潜在构建块。N(CF3)2基团(明显不同 从N-CF3)可以说比SF5组更难访问/探索，但它已经显示出如下前景 一种亲脂性的NO2基团替代品。虽然所有已知的方法到目前为止使该组严格要求F2或AHF， 我们的方法寻求合理的方法来完全绕过这些试剂。这将使N(CF3)2 该小组可供更广泛的科学家社区使用。最后，N(CF3)(CF2H)基团显然是 它们都是最难接近的，但它很容易成为N(CF3)2基团的有趣替代品，因为它添加了 作为亲脂性氢键供体的能力。我们已经设想了一些方法来避免当前的 依赖有毒的SF4气体。总而言之，使SF5、N(CF3)2和N(CF3)(CF2H)基团更安全的方法将实现 研究它们的物理性质以及如何利用它们来设计潜在的候选药物。

PROJECT SUMMARY/ABSTRACT Considering 20-25% of pharmaceuticals on the market today contain one or more fluorine atoms in their active ingredient (several of which appear on the WHO’s List of Essential Medicines), it is evident that fluorine chemistry continues to have a profound impact on drug development. Yet, despite the indisputable significance of fluorine atoms and fluorinated groups in modern medicinal chemistry, there has been a historical lag in their implementation in pharmaceuticals over the last century. The reason for this lag can most often be attributed to synthetic accessibility, as methods to install fluorine on molecules have been notoriously reliant on hazardous reagents, e.g., F2 and HF. While methods to incorporate, for instance, CF3, OCF3, and SCF3 groups on complex molecules have become far safer and more accessible in the last few decades (and these groups have since become commonplace in drug design), there remain a number of fluorinated groups with untapped potential that cannot be easily synthesized yet. This proposal specifically identifies the SF5, N(CF3)2, and N(CF3)(CF2H) groups as desirable motifs that have demonstrated promise yet continue to be underemployed due to the fact that there are virtually no user-friendly methods to make them. Accordingly, the proposed work is centered on addressing the synthetic chemistry bottlenecks that are preventing the realization of applications of these fluorinated groups. For one, the SF5 group has been studied as a bioisosteric replacement for a CF3 or t-Bu group, but only aryl-SF5 compounds have been made available commercially. Given the recent increase in accessibility of SF5Cl, we can now envision ways to expand the realm of possibility in C(sp3)–SF5 bond formation. Specifically, SF5 radical chemistry can be merged with strain- release functionalization to form novel “hybrid bioisosteres” that add another dimension of flexibility in molecular design. Methods are also envisioned to synthesize and examine some of the first benzylic-SF5 compounds, as well as other potential building blocks for the medicinal chemistry toolkit. The N(CF3)2 group (notably distinct from N–CF3) is arguably even less accessible/explored than the SF5 group, but it has demonstrated promise as a lipophilic NO2 group alternative. While all known methods make this group to date strictly require F2 or aHF, our approaches seek reasonable ways to circumvent these reagents altogether. This will make the N(CF3)2 group available to a significantly broader community of scientists. Lastly, the N(CF3)(CF2H) group is evidently the least accessible of them all, but it is liable to be an interesting alternative to the N(CF3)2 group with its added ability to serve as a lipophilic hydrogen-bond donor. We have envisioned ways to make this that avoid the current reliance on toxic SF4 gas. In all, safer methods to make the SF5, N(CF3)2, and N(CF3)(CF2H) groups will enable the study of their physical properties and how to leverage them in the design of potential drug candidates.