Convergent syntheses of bryostatins

多年来，许多化合物，天然产物，已从植物，动物和其他形式的生命，如微生物中分离出来。其中一些是非常有毒的，但另一些已被证明是发现新药的有用线索，例如青霉素和头孢菌素等抗生素，以及已出现的用于治疗某些癌症的紫杉醇。大约20年前，从一种海洋动物Buluga neritina（苔藓虫滤食性动物）中分离出一组新的非常复杂的天然产物，即苔藓抑素，尽管最近发现这些化合物实际上是由与苔藓虫共生的微生物产生的。苔藓抑素立即被认为具有有效的抗癌活性，并已相当大的兴趣，医药和合成化学家。虽然当患者用苔藓抑素治疗时观察到一些副作用，但当苔藓抑素与其他化疗药物联合使用时，有明显的改善。还发现苔藓抑素具有许多其他潜在有用的生物活性，如刺激免疫系统、逆转中风所致损伤和增强动物模型的记忆。尽管在这一领域还有更多的工作要做，但苔藓抑素的实际作用方式已部分了解。尽管有这些令人兴奋的生物活性，但苔藓抑素的供应仍存在严重问题。迄今为止，它们一直是从天然海洋来源中分离出来的，但这在环境上是不可接受的，也是非常不可靠的，例如，用于生产苔藓抑素的水产养殖方案最近已经停止。苔藓抑素已经由有机化学家合成，但是早期的合成非常长并且不收敛，因此没有增加用于生物评价的苔藓抑素的供应。最近已经设计了苔藓抑素样化合物。其中一些具有天然苔藓抑素的活性，并在临床evaluation.The本工作的目标是开发一个新的和更收敛的合成苔藓抑素，可用于生物评价提供材料。最初的工作将针对一个亚组的苔藓抑素，这还没有准备好。一旦化学实现这一目标已被整理出来，它将被应用于完成其他苔藓抑素和生物学评价更简单的类似物的合成。希望在约30个线性步骤（即顺序步骤）中完成天然存在的苔藓抑素的合成。到目前为止，其中的前26个项目已经成功实施。仍然需要找到最后四个步骤的试剂和条件，然后完成天然存在的苔藓抑素和类似物的合成。

Over the years, many compounds, natural products, have been isolated from plants, animals and other forms of life, e.g. micro-organisms. Some of these are very toxic but others have proved to be useful leads for the discovery of new pharmaceuticals, e.g. antibiotics such as the penicillins and cephalosporins, and taxol which has emerged for the treatment of certain cancers. About 20 years ago, a new group of very complex natural products, the bryostatins, was isolated from a marine animal, Buluga neritina, a bryozoan filter feeder, although more recently it has emerged that these compounds are actually produced by a micro-organism which cohabits with the bryozoan. The bryostatins were immediately recognized as having potent anti-cancer activity and have been of considerable interest to medicinal and synthetic chemists since. Although some side effects are observed when patients are treated with bryostatins, there are marked improvements when the bryostatins are prescribed in combination with other chemotherapies. The bryostatins have also been found to have many other potentially useful biological activities such as stimulation of the immune system, reversal of damage due to a stroke and memory enhancement in animal models. The actual modes of action of the bryostatins are partly understood although more remains to be done in this area.Notwithstanding these exciting biological activities, there are severe problems in the supply of bryostatins. To date they have been isolated from the natural marine source, but this is environmentally unacceptable and also very unreliable, for example, an aquaculture programme for the production of bryostatins has recently been discontinued. The bryostatins have been synthesized by organic chemists, but the early syntheses were very long and were not convergent, and so did not add to the supply of bryostatins for biological evaluation. More recently bryostatin like compounds have been designed. Some of these possess the activities of the natural bryostatins and are under clinical evaluation.The objectives of the present work are to develop a new and more convergent synthesis of bryostatins which can be used to provide material for biological evaluation. Initially the work will target a sub-group of bryostatins which has not been prepared before. Once the chemistry to achieve this objective has been sorted out, it will be applied to complete syntheses of other bryostatins and simpler analogues for biological evaluation.The synthesis which it is proposed to carry out has been studied for many years. It is hoped to complete the synthesis of a naturally occurring bryostatin in about thirty linear, i.e. sequential, steps. To date the first twenty six of these have been carried out successfully. It remains to find reagents and conditions for the final four steps and then to complete syntheses of naturally occurring bryostatins and analogues.