Convergent syntheses of bryostatins

多年来，从植物、动物和其他形式的生命(如微生物)中分离出了许多化合物和天然产物。其中一些毒性很大，但另一些已被证明是发现新药物的有用线索，例如青霉素和头孢菌素等抗生素，以及用于治疗某些癌症的紫杉醇。大约20年前，从一种海洋动物--苔藓虫滤食动物--布卢加--中分离出了一组非常复杂的天然产物--苔藓抑素，尽管最近有研究表明，这些化合物实际上是由一种与苔藓虫共生的微生物产生的。苔藓抑素立即被认为具有强大的抗癌活性，自那以来一直引起药物和合成化学家的极大兴趣。虽然在患者接受苔藓他汀类药物治疗时会观察到一些副作用，但当苔藓他汀类药物与其他化疗药物联合使用时，情况会有明显的改善。苔藓抑素还被发现具有许多其他潜在的有用生物活性，如刺激免疫系统，逆转中风造成的损害，以及在动物模型中增强记忆力。虽然在这一领域还有更多的工作要做，但对苔藓他汀类药物的实际作用模式已经有了部分了解。尽管有这些令人兴奋的生物活性，苔藓他汀类药物的供应仍然存在严重的问题。迄今为止，它们都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，而且也非常不可靠，例如，最近已经停止了一个生产苔藓他汀类药物的水产养殖方案。苔藓他汀类化合物是由有机化学家合成的，但早期的合成时间很长，且不收敛，因此没有增加苔藓他汀类药物的供应以进行生物学评价。最近，已经设计出了类似bryostatin的化合物。其中一些化合物具有天然苔藓抑素的活性，目前正在进行临床评价。本工作的目的是开发一种新的、更收敛的苔藓素合成方法，为生物评价提供材料。最初，这项工作将针对以前从未制备过的苔藓他汀类药物的亚组。一旦确定了实现这一目标的化学方法，它将被用于完成其他苔藓类药物的合成和更简单的类似物的生物评价。它被提议进行的合成已经研究了很多年。希望在大约30个线性步骤，即顺序步骤中完成自然产生的Bryostatin的合成。到目前为止，已成功开展了第一批26项工作。还需要为最后四步寻找试剂和条件，然后完成天然苔藓他汀类化合物的合成。

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.