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

合成多环倍半萜天然产物的新型跨环策略。

• 批准号: EP/F005970/1
• 负责人: Paul Clarke
• 金额: $ 37.47万
• 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: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF005970%2F1
• 关键词: Novel; Transannulation; Strategies; Synthesis; Polycyclic

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.

随着抗生素耐药性超级细菌的兴起，政府和公众面临着巨大的压力，要求开发新的抗生素来应对这一新出现的健康威胁。政府统计显示，英国医院的MRSA感染人数已从2001年的约7247人增加到2004年的7684人。卫生部已将减少这些感染列为优先事项，并要求NHS到2008年将感染人数减少50%，然而，报告的上一全年（2005年）的数字仅减少了6%！除了对抗抗生素耐药细菌之外，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。为了支持这一举措，他们额外投入了 2.1 亿美元用于抗击癌症，每年另外投入 2000 万美元专门用于研究。寻找新治疗线索的更成功策略之一是筛选植物和动物来源的提取物。该领域最显着的成功是紫杉醇（一种二萜类天然产物）的发现及其在癌症治疗中的应用。萜类天然产物已从大量天然来源中分离出来，并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，一系列地钱的提取物已被证明具有令人印象深刻的抗生素和抗癌活性。然而，直到最近30年，活性成分的结构才被阐明。从结构和生物学角度来看，一些最令人兴奋的化合物是 pinguisane 型倍半萜类化合物，例如 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 微生物以及肉瘤 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，加上寻找新疗法的紧迫性，使得开发一种获取piguisane型结构的通用方法对于制药业以及对抗疾病具有相当重要的意义。我们对这些天然产物的合成策略利用了我们在中型碳环转环反应方面的专业知识。我们最近开发了一种条件，允许在 1 步中从常见的 9 元环前体形成存在于 1、2 和 3 中的双环[4.3.0]壬烷环系统，并作为单一对映体。我们构建的 9 元环前体的固有模块化性质将允许在选择精制天然产物和天然产物类似物所需的适当功能时有很大的自由度。对新型转环反应的研究是非常冒险的，因为这些相对知之甚少的反应以前从未用于天然产物的合成。这项工作将使我们能够进一步了解一般的跨环反应。这项工作是及时的、具有挑战性和冒险性的，因此适合 EPSRC 的资助。更重要的是，如果成功，它将导致一种更短、更有效和通用的对映选择性路线，可以产生克数量的这些分子，并扩展我们对中等大小环的转环反应的理解。因此，我们寻求 EPRSC 的人力和消耗品资金来进行 pinguisenol 1、acutifolone A 2 和 deoxo-pinguisone 3 的合成。