Synthetic Methods to Make Emerging Fluorinated Groups More Accessible

项目总结/摘要 考虑到目前市场上20-25%的药物在其结构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），很明显，氟 化学继续对药物开发产生深远影响。然而，尽管无可争议的重要性 氟原子和氟化基团在现代药物化学中的地位， 在上个世纪，这种滞后的原因通常可以归因于 合成的可及性，因为将氟安装在分子上的方法众所周知地依赖于危险的环境， 试剂，例如，F2和HF。虽然将例如CF 3、OCF 3和SCF 3基团结合到复合物上的方法 在过去的几十年里，分子已经变得更加安全和更容易获得（这些群体已经从 在药物设计中变得司空见惯），仍然存在许多具有未开发潜力的氟化基团， 还不能轻易合成。该提案具体确定了SF 5、N（CF 3）2和N（CF 3）（CF2 H）基团 作为理想的图案，已表现出希望，但继续就业不足，因为事实上， 实际上没有一种用户友好的方法来制造它们。 因此，拟议的工作集中在解决合成化学瓶颈， 阻碍了这些氟化基团应用的实现。首先，研究了SF 5基团， 作为CF 3或t-Bu基团的生物电子等排替代物，但只有芳基-SF 5化合物可用 在商业上。考虑到最近SF 5Cl的可及性的增加，我们现在可以设想如何扩大SF 5Cl的应用范围。 C（sp3）-SF 5键形成的可能性领域。具体来说，SF 5自由基化学可以与应变- 释放官能化以形成新的“杂合生物电子等排体”， 设计还设想了合成和检查一些第一苄基-SF 5化合物的方法，如 以及药物化学工具包的其他潜在构件。N（CF 3）2基团（显著不同 来自N-CF 3）可以说比SF 5组更难接近/探索，但它已被证明是有希望的， 亲脂性NO2基团替代物。虽然所有已知的方法使这一组到目前为止严格要求F2或aHF， 我们的方法寻求合理的方法来完全规避这些试剂。这将使N（CF 3）2 一个更广泛的科学家群体。最后，N（CF 3）（CF2 H）基团显然是 它们中最难接近的，但它可能是N（CF 3）2基团的有趣替代物， 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电流 有毒的SF 4气体。总之，制备SF 5、N（CF 3）2和N（CF 3）（CF2 H）基团的更安全的方法将使 研究它们的物理特性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.