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

英国每年有15.6万人死于癌症，政府在1999年宣布了一项重大倡议，强调癌症治疗是国家高度优先考虑的领域。为了支持这一倡议，他们在抗击癌症方面额外投入了2.1亿美元，每年额外投入2000万美元专门用于研究。一个比较成功的癌症治疗策略是开发新的化疗药物。在过去的几年里，一些最成功和最有前途的药物是从海洋生物中分离出来的天然产物。最有希望的先导化合物之一是磷唑A。它对整个人类癌细胞系的细胞抑制活性被评估为G150 <1.6 nM，其尚未确定的作用方式，其前所未有的结构特征和供应的稀缺性使磷唑A成为全合成的优先目标，可以产生克数量的材料。能够实现这一点的全合成对制药工业具有相当重要的意义。我们的合成策略是模块化的，利用我们最近复兴的Maitland-Japp和相关的脱羧Maitland-Japp （DMJ）和酰化Maitland-Japp （AMJ）反应来形成功能化的四氢吡喃（THP）环。这些反应的锅、原子和步骤经济性质将使适当功能化的四氢吡喃单元的有效合成成为可能，这些单元将偶联形成天然产物。这种路径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，它还允许方便地合成1的类似物。这项工作是及时的，具有挑战性和冒险性的，适合EPSRC资助。然而，如果成功，它将导致更短，更有效和通用的路线，可以产生克数量的这种重要分子。因此，我们寻求EPRSC资助人力和消耗品来进行磷唑A的合成。

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.