Novel Transannulation Strategies for the Synthesis of Polycyclic Sesquiterpenoid Natural Products.

随着抗生素耐药性超级细菌的兴起，政府和公众对开发新的抗生素以对抗这种新出现的健康威胁施加了巨大压力。政府统计数据显示，英国医院感染MRSA的人数从2001年的7247人左右增加到2004年的7684人。减少这些感染已被卫生部指定为优先事项，卫生部要求国民保健服务到2008年将感染减少50%，然而，上一个全年报告的数字（2005年）显示仅减少了6%！除了对抗抗生素耐药性细菌外，政府还宣布了一项重大举措，强调癌症治疗是国家高度优先的领域。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。寻找新的治疗线索的更成功的策略之一是从植物和动物来源的提取物的筛选。这一领域最显著的成就是发现了紫杉醇（一种二萜类天然产物）及其在癌症治疗中的应用。萜类化合物类天然产物已经从大量的天然来源中分离出来，并且具有丰富的结构多样性。这种结构多样性导致了广泛的生物活性。在过去的50年里，一系列地钱提取物已被证明具有令人印象深刻的抗生素和抗癌剂活性。然而，直到最近30年才阐明了活性成分的结构。从结构和生物学的角度来看，一些最令人兴奋的化合物是pinguisane型倍半萜类化合物，如pinguisenol 1，acutifolone A 2和deoxo-pinguisone 3，它们已被证明对金黄色葡萄球菌和Gaffkya tetragena微生物和肉瘤37小鼠癌细胞表现出相当大的活性。这些令人鼓舞的初步结果，加上迫切需要找到新的治疗方法，使得开发一种通用方法来获得piguisane型结构对制药工业具有相当重要的意义，因此，对抗疾病。我们对这些天然产物的合成策略利用了我们在中型碳环transannulation反应中的专业知识。我们最近开发了允许在1步中从共同的9元环前体形成1、2和3中存在的双环[4.3.0]壬烷环体系的条件，并且作为单一对映异构体。我们构建9元环前体的固有模块化性质将允许在选择用于加工成天然产物和天然产物的类似物所需的适当官能度方面有很大的自由度。研究这种新型的转环反应是非常冒险的，因为这些相对知之甚少的反应以前没有被用于天然产物的合成。这一工作将使我们对环化反应有更深入的了解。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。更重要的是，如果成功的话，它将导致一个更短，更有效和通用的对映选择性路线，可以产生克量的这些分子，并扩大我们的理解，transannulation反应的中等大小的环。因此，我们寻求EPRSC的人力和消耗品的资金进行pinguisenol 1，acutifolone A 2和deoxo-pinguisone 3的合成。

With the rise of antibiotic resistant superbugs there has been great pressure from government and the public for the development of new antibiotics to combat this emerging threat to health. Government statistics show that the number of infections of MRSA in UK hospitals have increased from around 7247 in 2001 to 7684 in 2004. The reduction of these infections has been designated a priority by the Department of Health, which has charged the NHS to reduce infections by 50% by 2008, however, the figures for the last full year reported (2005) show a reduction by only 6%! In addition to combating antibiotic resistant bacteria the government has also announced 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 finding new therapeutic leads is the screening of extracts from plant and animal sources. The most notable success in this area was the discovery of Taxol, a diterpenoid natural product, and its use in cancer therapy. The terpenoid class of natural products have been isolated from a vast array of natural sources and have a rich structural diversity. This structural diversity leads to a wide profile of biological activity. Over the last 50 years, extracts from a range of liverworts have been shown to have impressive activity as antibiotics and anti cancer agents. However, it is only in the last 30 years that the structures of the active components have been elucidated. Some of the most exciting compounds from both an architectural and biological view point are the pinguisane-type sesquiterpenoids, such as pinguisenol 1, acutifolone A 2 and deoxo-pinguisone 3, which have been shown to exhibit sizable activity against Staphylococcus aureus and Gaffkya tetragena micro organisms and sarcoma 37 mice cancer cells. These encouraging preliminary results, coupled with the urgency to find new treatments, makes the development of a general method to access the piguisane-type structure of considerable importance to the pharmaceutical industry, and hence, the fight against disease.Our synthetic strategy to these natural products exploits our expertise in transannulation reactions of medium sized carbocycles. We have recently developed conditions which allow for the formation of the bicyclo[4.3.0]nonane ring system present in 1, 2 and 3 from a common 9-membered ring precursor in 1 step and as a single enantiomer. The inherently modular nature of our construction of the 9-membered ring precursor will allow a great deal of latitude in selecting the appropriate functionality required for elaboration into the natural products and analogues of the natural product. Investigation of the novel transannulation reaction is highly adventurous as these relatively poorly understood reactions have not previously been used in the synthesis of natural products. This work will enable us to gain further understanding into a transannulation reactions in general. This work is timely, challenging and adventurous making it appropriate for EPSRC funding. More importantly, if successful it will lead to a shorter, more efficient and versatile enantioselective route which can generate gram quantities of these molecules and extend our understanding of transannulation reactions of medium sized rings. We therefore seek EPRSC funding for manpower and consumables to carry out the syntheses of pinguisenol 1, acutifolone A 2 and deoxo-pinguisone 3.