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

生物学重要分子（例如药物）的快速和选择性合成是化学家的一个重要且持续的目标。有必要能够使用尽可能环境友好的有效方法来制造这样的分子。该提案涉及开发一种非常温和的方法，用于选择性构建某类生物相关化合物（即多取代手性环戊烷和γ-内酯）。有许多方法可用于合成手性环戊烷，然而，在本提案中开发的方法有可能成为构建此类系统的最温和和最直接的方法。我们的初步研究结果表明，我们可以合成手性环戊烷通过自由基过程，简单地通过加热适当的化合物在醇中的存在下的醋酸锰（III）。该过程操作简单，不需要任何特殊的实验程序。使用自由基化学的手性环戊烷的形成以前已经报道过。这些报道中的大多数利用有机锡化合物来实现所需的转化。有机锡化合物具有高毒性，不仅存在处置危险，而且通常难以从所需产品中完全去除。醋酸锰（III）的使用克服了这些问题;锰副产物很容易使用标准技术去除。使用乙酸锰（III）相对于有机锡化合物的其他重要益处包括：能够产生更高度官能化的产物，因此其更容易转化为所需材料;使用更广泛的自由基前体的潜力，这不仅增加了合成的灵活性，而且还允许合成更广泛的化合物。这两种优势将在本研究中得到充分的探索。在乙酸锰（III）介导的反应期间可能发生的另一个过程是杂环（例如γ-内酯）的形成。该提议的另一个目的是开发使用乙酸锰（III）化学的具有多达四个连续手性中心的γ-内酯的选择性合成。这些分子将含有一个全碳手性中心（季中心）。选择性合成带有季中心的手性分子仍然是合成有机化学家的一个具有挑战性的领域。我们的目标是开发一个非常温和的方法来构建这样的系统。我们目前有一个有效的路线，以功能分化的分子轴承的四元中心，我们相信有潜力成为一个非常有价值的积木为有机化学家。在该项目的初始阶段开发的温和合成方法将在各种生物学和结构上有趣的分子的有效合成中得到证明。总之，本建议的目的是开发一种非常温和和操作简单的方法，用于高选择性合成环戊烷和γ-内酯，这将适用于广泛的生物学和结构上感兴趣的分子。

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.