Diastereoselective Formation of Cyclopentanes and Gamma-Lactones Mediated by Manganese(III)

对化学家来说，快速和选择性地合成具有重要生物学意义的分子(如药物)是一个重要的和持续的目标。有必要使用高效的工艺来制造这种分子，尽可能对环境无害。这项建议涉及开发一种非常温和的方法来选择性地构建一类特定的生物相关化合物(即多取代手性环戊烷和伽马-内酯)。手性环戊烷的合成方法很多，但在本方案中开发的方法有可能成为构建此类体系的最温和、最直接的方法。我们的初步结果表明，我们可以通过自由基过程合成手性环戊烷，只需在乙醇中加热适当的化合物，在醋酸锰(III)的存在下即可。这一过程在操作上很简单，不需要任何特殊的实验程序。利用自由基化学方法合成手性环戊烷的研究已有报道。这些报告中的大多数使用有机锡化合物来实现所需的转化。有机锡化合物毒性很大，不仅存在处置危险，而且通常很难从所需产品中完全去除。醋酸锰(III)的使用克服了这些问题；使用标准技术可以很容易地去除锰副产品。与有机锡化合物相比，使用醋酸锰的另一个重要好处包括：能够产生更高官能化的产品，因此更容易转化为所需的材料；使用更广泛的自由基前驱体的可能性，不仅增加了合成的灵活性，而且允许合成更多种类的化合物。这两个优势都将在本研究中得到充分挖掘。在醋酸锰(III)催化的反应中，另一个可能发生的过程是杂环(如伽马-内酯)的形成。这项建议的另一个目的是利用醋酸锰(III)化学开发一种选择性地合成具有最多四个邻接手性中心的伽马-内酯。这些分子将包含一个全碳手性中心(一个四元中心)。对于合成有机化学家来说，选择性地合成带有四元中心的手性分子仍然是一个具有挑战性的领域。我们的目标是开发一种非常温和的方法来构建这样的系统。我们目前有一条有效的途径来获得带有四元中心的功能分化分子，我们相信它有可能成为有机化学家非常有价值的基石。在这个项目的初始阶段开发的温和的合成方法将在各种生物和结构感兴趣的分子的有效合成中得到展示。总之，这项建议的目的是开发一种非常温和和操作简单的方法，用于高选择性地合成环戊烷和伽马-内酯，该方法将适用于广泛的生物和结构感兴趣的分子。

The rapid and selective synthesis of biologically important molecules (e.g. pharmaceuticals) is an important and continuing goal for chemists. It is necessary to be able to make such molecules using efficient processes which, as far as possible, are environmentally benign. This proposal involves the development of an exceedingly mild method for the selective construction of a certain class of biologically relevant compounds (namely poly-substituted chiral cyclopentanes and gamma-lactones). There are many methods available for the synthesis of chiral cyclopentanes however the method to be developed within this proposal has the potential to be the most mild and straightforward method for the construction of such systems. Our preliminary results indicate that we can synthesise chiral cyclopentanes via a free radical process, simply by heating an appropriate compound in alcohol in the presence of manganese(III) acetate. This process is operationally straightforward to conduct and does not require any special experimental procedures. The formation of chiral cyclopentanes using free-radical chemistry has been previously reported. Most of these reports utilise organotin compounds to effect the desired transformation. Organotin compounds are highly toxic and present not only a disposal hazard but are often difficult to remove completely from the desired product. The use of manganese(III) acetate overcomes these issues; the manganese by-products are readily removed using standard techniques. Further important benefits of using manganese(III) acetate over organotin compounds include: the ability to produce more highly functionalised products which are therefore more readily transformed into the desired materials; the potential to use a wider variety of radical precursors which, not only adds flexibility to the synthesis, but also allows a wider variety of compounds to be synthesised. Both of these advantages will be fully explored in this research. Another process which may occur during manganese(III) acetate mediated reactions is the formation of heterocyclic rings (e.g. gamma-lactones). A further aim of this proposal is to develop a selective synthesis of gamma-lactones bearing up to four contiguous chiral centres using manganese(III) acetate chemistry. These molecules will contain one all carbon chiral centre (a quaternary centre). The selective synthesis of chiral molecules carrying quaternary centres remains a challenging area for synthetic organic chemists. Our aim is to develop a very mild method for the construction of such systems. We currently have an efficient route to a functionally-differentiated molecule bearing a quaternary centre which we believe has the potential to be a very valuable building block for organic chemists. The mild synthetic methods developed during the initial phases of this project will be demonstrated in the efficient syntheses of a variety of biologically and structurally interesting molecules. In summary, the aim of this proposal is to develop an exceptionally mild and operational simple method for the highly selective synthesis of cyclopentanes and gamma-lactones which will be applicable to a wide range of biologically and structurally interesting molecules.