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Exploiting the Maitland-Japp Reaction. A Highly Convergent Total Synthesis of Phorboxazole A.

利用梅特兰-贾普反应。

基本信息

批准号：
EP/C514750/2
负责人：
Paul Clarke
金额：
--
依托单位：
University of York
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FC514750%2F2
关键词：
Exploiting Maitland Japp Reaction.Highly

项目摘要

With 156,000 people dying each year in the UK because of cancer, the government announced in 1999, a major initiative highlighting cancer treatment as an area of high national priority. In support of this initiative they have invested an extra 210M in the battle against cancer, with an additional 20M a year specifically targeted for research. One of the more successful strategies for cancer treatment is the development of new chemotherapeutic agents. Over the last few years some of the most successful and promising agents have been natural products isolated from marine organisms. One of the most promising lead compound is phorboxazole A. Its potent cytostatic activity assessed as G150 <1.6 nM against an entire panel of human cancer cell lines, its as yet undetermined mode of action, its unprecedented structural features and its scarcity of supply combine to make phorboxazole A a priority target for a total synthesis which can yield gram quantities of the material. A total synthesis which can deliver this would be of considerable importance to the pharmaceutical industry.Our synthetic strategy is a modular one exploiting our recent renaissance of the Maitland-Japp and the related decarboxylative Maitland-Japp (DMJ) and acylative Maitland-Japp (AMJ) reactions for the formation of the functionalised tetrahydropyrans (THP) rings present in 1. The pot, atom and step economic nature of these reactions will enable the efficient synthesis of suitably functionalised tetrahydropyran units which will be coupled to form the natural product. The inherently modular nature of this route will allow a great deal of latitude in selecting the appropriate functionality required for coupling. In addition, it will also allow for the expedient synthesis of analogues of 1. This work is timely, challenging and adventurous making it appropriate for EPSRC funding. However, if successful it will lead to a shorter, more efficient and versatile route, which can generate gram quantities of this important molecule. We therefore seek EPRSC funding for manpower and consumables to carry out the synthesis of phorboxazole A.

英国每年有15.6万人死于癌症，政府于1999年宣布了一项重大举措，强调癌症治疗是国家优先考虑的领域。为了支持这一倡议，他们已经额外投入了2.1亿美元用于对抗癌症，每年还专门投入2000万美元用于研究。癌症治疗的更成功的策略之一是开发新的化学治疗剂。在过去的几年里，一些最成功和最有前途的药剂是从海洋生物中分离出来的天然产品。其中最有前途的先导化合物是佛波唑A。其对整个人类癌细胞系的有效细胞生长抑制活性评估为G150 <1.6 nM，其尚未确定的作用模式，其前所未有的结构特征及其供应的稀缺性联合收割机组合使得佛波唑A成为可产生克量材料的全合成的优先靶标。一个全合成，可以提供这将是相当重要的制药industrial. We的合成策略是一个模块化的一个利用我们最近复兴的Maitland-Japp和相关的脱羧Maitland-Japp（DMJ）和乙酰化Maitland-Japp（AMJ）反应的功能化四氢吡喃（THP）环的形成1。这些反应的罐、原子和步骤经济性质将使得能够有效合成适当官能化的四氢吡喃单元，其将偶联以形成天然产物。这种路由固有的模块化特性将允许在选择耦合所需的适当功能时有很大的自由度。此外，它还将允许1的类似物的便利合成。这项工作是及时的，具有挑战性和冒险性，使其适合EPSRC的资金。然而，如果成功的话，它将导致一种更短，更有效和更通用的途径，可以产生克量的这种重要分子。因此，我们寻求EPRSC的人力和消耗品的资金，以进行甲恶唑的合成。