Preparation of Enantioenriched Sulfonimidoyl Fluorides

本项目福尔斯属于EPSRC合成有机化学研究领域。磺酰氟（SFs）作为共价亲电试剂，近年来受到越来越多的关注。Sharpless等人对SF的“点击反应”的发展，促进在硫上容易地取代，即硫-氟化物交换（SuFex），提高了对该官能团的兴趣。磺酰亚胺氟化物（Sulfonimidoyl fluides，SIF）是一种含氮的SFs类似物，由约翰逊等人于20世纪80年代首次报道，但其合成和应用研究仍较少。重要的是，与SF对应物相比，SIF显示出改善的水解稳定性，而不影响反应性-它们显示出更快地标记特定的蛋白质残基。氮原子的可调反应性和硫原子中心的手性为SIF弹头作为化学生物学和合成工具提供了独特的前景。此外，衍生化的SIF是公认的，因此，各种药用相关的硫（VI）试剂可以得到从SIF在一个facilitymanner.To我们所知的对映体富集的SIF的合成尚未开发，因此，温和的方法，可以促进他们的合成是非常可取的。因此，这项研究的最初重点将是开发和优化一种合成光学纯形式的SIF的途径。近年来，使用手性亚磺酰胺作为分别获得光学纯的磺酰亚胺酰胺和亚砜亚胺的起始原料已被证明是一种有吸引力的策略。手性亚磺酰胺通常是工作台稳定的，并且可以使用化学计量的手性助剂或通过外消旋亚磺酰胺的动力学拆分容易地获得。因此，我们最初感兴趣的是通过形成硫-氟键从手性亚磺酰胺合成对映体富集的SIF。设想了从单一对映体富集的亚磺酰胺得到相应SIF的两种对映体的发散方法。在我们的初步工作中，我们已经成功地翻译了外消旋亚磺酰胺的氧化卤化条件，通过使用手性亚磺酰胺前体合成对映体富集的SIF。需要进一步优化以提高反应产率和e.e。我们将通过改变我们的起始材料在碳和氮上的取代基，以外消旋和对映体富集的方式建立SIF库。这将提供对取代模式可能对这些试剂的化学稳定性产生的影响的一些了解。另一个研究领域是合成SIF的替代策略，探索使用更温和的反应条件。我们有兴趣将开发的方法应用于化学探针的合成，从而检查SIF对各种反应条件的化学稳定性。然后，这些化合物可以直接与它们的SF对应物进行比较，基于所用试剂的对映异构体实现选择性反应性的可能性。总之，本项目中提出的工作将有助于更好地理解SIF功能组。通过首次合成光学纯的SIF，我们将深入了解它们的立体化学保真度和有前途的潜在化学探针，这将是医学和农业化学界感兴趣的。

This project falls within the EPSRC synthetic organic chemistry research area.Sulfonyl fluorides (SFs) have attracted increasing attention in recent years, with their ability to act as covalent electrophiles reported widely in the literature. The development of "click-reactions" to SFs by Sharpless et al., facilitating substitution at sulphur readily i.e sulfur-fluoride exchange (SuFex), has enhanced interest for this functional group. Sulfonimidoyl fluorides (SIFs), nitrogen-containing analogues of SFs, were first reported in the 1980's by Johnson et al. However, they remain an underexplored class of compounds, with few reports of their synthesis and application. Importantly, SIFs have displayed improved hydrolytic stability compared to their SF counterparts without compromising reactivity - they were shown to label specific protein residues more rapidly. The tunable reactivity at nitrogen and chirality at the sulfur centre offers unique prospects of the SIF warhead as a tool for chemical biology and synthesis. Furthermore, derivatisation of SIFs is well established, thus a variety of medicinally relevant sulfur(VI) reagents can be obtained from SIFs in a facile manner.To our knowledge the synthesis of enantioenriched SIFs has not yet been developed; thus a mild method that can facilitate their synthesis is highly desirable. Accordingly, the initial focus of this research will be to develop and optimise a route for synthesising SIFs in optically pure form. The use of chiral sulfinamides as starting materials for accessing optically pure sulfonimidamides and sulfoximines respectively has proven an attractive strategy in recent years. Chiral sulfinamides are typically bench stable and can be readily accessed using either stoichiometric chiral auxiliaries or via kinetic resolution of racemic sulfinamides. Therefore, we are initially interested in the synthesis of enantioenriched SIFs from chiral sulfinamides via the formation of a sulfur-fluorine bond. A divergent approach to both enantiomers of respective SIFs from a single enantioenriched sulfinamide is envisaged. In our preliminary work, we have successfully translated conditions for the oxidative halogenation of racemic sulfinamides for the synthesis of enantioenriched SIFs through the use of chiral sulfinamide precursors. Further optimisation to improve reaction yield and e.e is required. We will establish a library of SIFs in a racemic and enantioenriched manner by varying the substituents of our starting material at both carbon and nitrogen. This will provide some insight into the effect the substitution pattern may have on the chemical stability of these reagents. Another area of investigation would be alternative strategies to synthesise SIFs, exploring the use of milder set of reaction conditions.We are interested in applying the developed methodologies to the synthesis of chemical probes, whereby the chemical stability of SIFs to a variety of reaction conditions will be examined. These compounds can then be directly compared to their SF counterparts, with the possibility of achieving selective reactivity based on the enantiomer of the reagent employed. In summary, the work proposed in this project will contribute a greater understanding to the SIF functional group. Through the first synthesis of optically pure SIFs we will gain an insight into their stereochemical fidelity and promising potential chemical probes, which will be of interest to the medicinal and agrochemical communities.