Synthesis of complex aminoacids and the microsclerodermins

新反应的开发是现代合成有机化学最迫切的目标之一，因为化学工业对选择性、高效和环境友好的化学过程的要求越来越高。我们的目标是开发能够快速有效地合成含有耐人寻味的生物活性天然产物的复合氨基酸的方法。近年来，我们已经积累了氧化烯烃的方法的知识，并在这样做的过程中提供了构建块，这些块是完成氨基酸合成的完美材料。这项建议的目的是让读者相信：(1)合成天然产物微硬化素(它是一种有效的抗肿瘤药物)是一个值得研究的高影响领域；(2)合成本身将推动开发可用于许多其他应用的新方法和试剂，尤其是在构建复杂氨基酸和多肽方面；(3)我们拥有此类化合物的经验和专业知识，以确保合成的成功和完成。对于这样一项复杂的任务，我们可以接触到各种各样的生物筛查，特别是那些寻找抗癌活性的筛查，并将对在此过程中形成的最终化合物和中间体进行测试。这应该会确保以相对较低的支出最大限度地回报新的科学信息。这项建议中描述的化学是有趣和有用的，因为它将使我们能够以短而有效的顺序制备以前从未制备过的复杂的天然产品。在我们前进的过程中，我们将被迫探索几种有机方法的局限性，这将导致更强大的方法来进行烯烃氧化和通过一条全新的路线制备多肽。除了这种分子带来的纯粹的化学挑战外，筛选它及其前体肯定是一项值得完成的任务，因为已有报道称它具有令人兴奋的生物活性。这里描述的化学影响很大，包含方法学和合成的理想组合；它有重要的后备计划(如多肽和氨基酮类化合物的单独合成)和出版里程碑，并将发现真正有趣和有用的反应，以及为PDRA提供极好的培训。我们在合成和这些类型的分子方面也有经验，以确保项目完成。

The development of new reactions is one of the most pressing goals for modern synthetic organic chemistry because chemical industry has an ever increasing requirement for selective, efficient and environmentally friendly chemical processes. We aim to develop methods that will allow the rapid and efficient synthesis of complex aminoacid containing natural products with intriguing biological activity. Over recent years we have built up a knowledge of methods for oxidising alkenes and in so doing providing building blocks that are the perfect materials from which to accomplish the synthesis of aminoacids. The goal of this proposal is to convince the reader that (i) the synthesis of the natural product microsclerodermin (which is a potent anti-tumor agent) is a worthwhile and high impact area of research; (ii) that the synthesis itself will drive the development of new methods and reagents that are useful in many other applications, especially in the construction of complex aminoacids and peptides; (iii) we have the experience and expertise with these types of compound to ensure success and completion of the synthesis. As appropriate to such a complex undertaking, we have access to a wide variety of biological screens, especially those that search for anti-cancer activity, and tests will be performed on the final compound and intermediates formed en-route. This should ensure the biggest return of new scientific information for a relatively modest outlay. The chemistry described in this proposal is interesting and useful because it will enable us to prepare a complex natural product that has never been prepared before in a short and efficient sequence. We will be forced to explore the limitations of several organic methodologies as we go, and this will lead to more powerful methods for alkene oxidation and for the preparation of peptides via a fundamentally new route. In addition to the sheer chemical challenge posed by this molecule, it is surely a worthwhile task to screen it, and precursors to it, for the exciting biological activity that has been reported. The chemistry described herein is high impact and contains an ideal mix of methodology and synthesis; it has significant back-up plans (such as the stand-alone synthesis of peptides and aminoaclohols) and publication milestones, and will uncover really interesting and useful reactions as well providing an excellent training for a PDRA. We also have the experience with synthesis and with these types of molecules to ensure that the project is finished.