The Stereoselective Synthesis of Heterocycles Through Cation-Triggered Annulation

该项目福尔斯EPSRC合成有机化学研究领域，由于其在医药和农业化学工业中的价值沿着其在天然产物中的广泛存在，因此从简单和容易获得的起始原料立体选择性合成高度官能化的饱和杂环的方法是非常可取的。例如，哌啶（6元饱和氮杂环）是FDA列出的小分子药物中第三大最普遍的环系统，吡咯烷、（四氢）-呋喃和（四氢）-吡喃也在前十二位中。不仅起始材料必须容易获得，而且该过程需要廉价，高效和原子经济。Donohoe小组已经建立了一种这样的方法，使用六氟异丙醇（HFIP）作为极性和氢键溶剂的独特性质，使烯烃的立体选择性官能化成为可能。最近，这已被应用于通过高烯丙醇与活化醇反应以生成具有高立体选择性的新的C-C和C-O键来合成氧杂环。使用亚化学计量量的Ti（OiPr）4和HFIP作为溶剂从醇亲电试剂产生碳阳离子，其在正式的内-开环环化中被富电子烯烃捕获，产生水作为唯一的化学计量副产物。有可能将这种方法扩展到其他杂环的合成，目前正在进行的含氮杂环的合成工作。我们的目标是改善目前的加氢胺化方法，虽然有先例，但通常依赖于使用昂贵的金属催化剂，并且缺乏非对映选择性和产物的官能化。一旦实现这一目标，将进一步使产品多样化，以增加其作为医药和农业化学工业基础材料的效用。此外，我们希望通过使用不对称金属催化剂使该过程具有对映选择性，这将使该方法更适用于天然产物的合成。最后，我们希望通过合成在配位和药物化学中具有广泛用途的其他复杂杂环来探索这一过程的局限性。将评价环中含有两个杂原子的其它杂环，从而得到另外一类高度官能化的分子。总的来说，这种方法的发展旨在提供一个更有效的和选择性的替代目前的方法，用于访问饱和杂环，而不影响成本或操作简单性。此外，我们希望所获得的复杂分子将被证明是医药和农业化学的有用构建块，为“类铅”化合物提供3D模板。

This project falls within the EPSRC Synthetic Organic Chemistry research area.Methods for the stereoselective synthesis of highly functionalized saturated heterocycles from simple and readily available starting materials are highly desirable due to their value in medicinal and agro- chemical industries along with their widespread presence in natural products. For example, piperidines, the 6-membered saturated nitrogen heterocycles are the third most prevalent ring system in small molecule drugs listed by the FDA, with pyrrolidines, (tetrahydro) -furans and -pyrans also featuring in the top twelve. Not only do the starting materials have to be easily accessible but the process needs to be cheap, efficient and atom economical. One such method has been established in the Donohoe group, using the unique properties of hexafluoroisopropanol (HFIP) as a polar and hydrogen bonding solvent to enable the stereoselective functionalization of alkenes. Recently, this has been applied to the synthesis of oxygen heterocycles through reaction of a homoallylic alcohol with an activated alcohol to generate a new C-C and C-O bond with high stereoselectivity. The use of sub-stoichiometric amounts of Ti(OiPr)4 and HFIP as the solvent generates a carbocation from the alcohol electrophile which is trapped by an electron rich olefin in a formal endo-trig cyclisation, generating water as the only stoichiometric by-product. There is potential to extend this methodology to the synthesis of other heterocycles with work currently underway on the synthesis of nitrogen containing heterocycles. We aim to improve on the current hydroamination methods, which although well precedented, often rely on the use of expensive metal catalysts and suffer from a lack of diastereoselectivity and functionalization of the product. Once this has been achieved, further diversification of the products will be undertaken in order to increase their utility as building blocks in the medicinal and agro- chemical industries. In addition, we hope to make the process enantioselective, through the use of asymmetric metal catalysis, this would in turn make the methodology more applicable to the synthesis of natural products. Finally, we hope to probe the limits of this process through the synthesis of other complex heterocycles which have a wide array of uses in coordination and medicinal chemistry. Other heterocycles containing two heteroatoms in the ring will be evaluated giving an additional class of highly functionalized molecules. Overall, the development of this methodology aims to offer a more efficient and selective alternative to the current methods for accessing saturated heterocycles without compromising cost or operational simplicity. In addition, we hope that the complex molecules accessed will prove to be useful building blocks for medicinal and agro- chemistry giving 3D Templates for "Lead-Like" compounds.