Synthesis of Biologically Important Furanosteroids

呋喃甾体是一类新型真菌代谢物，其中一些是磷脂酰肌醇3-激酶（PI-3激酶）的有效抑制剂，磷脂酰肌醇3-激酶是一种在细胞生命周期中起关键作用的酶。然而，已知的这类药物毒性太大，不能作为抗肿瘤药物发展。正因为如此，人们对开发新的合成途径来合成天然存在的化合物和更简单的类似物产生了浓厚的兴趣。该项目致力于开发一种简洁的呋喃类固醇合成方法，这种方法应该同样适用于生物学上重要的天然产物以及结构类似物。所提出的方法利用了一系列反应，从现成的起始材料到最终目标化合物，而不分离中间结构。更具体地说，我们将探索绿柱石、去甲氧基绿柱石、绿柱石醇、去甲氧基绿柱石醇、wortmannin和去乙酰氧基wortmannin的合成方法。合成所有这些化合物的关键步骤是炔与恶唑的分子内Diels-Alder/反-Diels-Alder反应生成桥接中间体，该中间体无需分离即可立即进行反-Diels-Alder反应生成呋喃环。考虑到最终化合物的复杂性，这种策略允许非常短的合成方案。在有机和大分子化学项目的支持下，达特茅斯学院化学系的Peter a . Jacobi教授正在开发新的方法，以有效合成真菌自然产生的一类独特分子的代表，称为呋喃类固醇。其中一些化合物是一种酶的有效抑制剂，这种酶在细胞的生命周期中起着关键作用。因此，它们有望成为一类新的治疗以细胞快速增殖为特征的疾病的药物，比如癌症。然而，已知的这类药物毒性太大，不能作为抗肿瘤药物发展。因此，人们对开发新的合成途径来合成天然存在的化合物和更简单的类似物有着浓厚的兴趣，但由于合成这些化合物的巨大困难，这一领域的进展一直很缓慢。Jacobi教授和他的学生正在开发一种简洁的合成呋喃类固醇的方法，这种方法应该同样适用于具有重要生物学意义的天然产物以及结构类似物。最终，这些研究可能会导致发现天然产物的更简单的类似物，这些类似物具有增强的生物活性，但毒性明显更低，并且更具位点特异性。

The furanosteroids are a class of novel fungal metabolites, several of which are potent inhibitors of phosphatidylinositol 3-kinase (PI-3 kinase), an enzyme that plays a key role in the life cycle of cells. However, the known members of this class are far too toxic and non-selective for development as anti-tumor agents. Because of this, there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs. This project addresses the development of a concise synthetic approach to the furanosteroids that should be equally applicable to the biologically important natural products as well as structural analogs. The methodology proposed takes advantage of a sequence of reactions, leading from readily available starting materials to the final target compounds without isolation of intermediate structures. More specifically, synthetic approaches will be explored for the preparation of viridian, demethoxyviridin, viridiol, demethoxyviridiol, wortmannin and desacetoxywortmannin. The key step in the synthesis of all of these compounds is an intramolecular Diels-Alder/retro-Diels-Alder reaction of an alkyne with an oxazole to give a bridged intermediate that, without isolation, immediately undergoes a retro-Diels-Alder reaction to produce a furan ring. This strategy allows for remarkably short synthetic schemes given the complexity of the final compounds. With the support of this award from the Organic and Macromolecular Chemistry Program, Professor Peter A. Jacobi, of the Department of Chemistry at Dartmouth College, is developing new methods for the efficient synthesis of representatives of a unique class of molecules, produced naturally by fungi, known as the furanosteroids. Some of these compounds are potent inhibitors of an enzyme that plays a key role in the life cycle of cells. As such, they hold promise as a new class of therapeutic agents for diseases characterized by rapid cell proliferation, as is the case in cancer. However, the known members of this class are far too toxic and non-selective for development as anti-tumor agents. Thus, there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs, but progress in this area has been slow because of the great difficulties associated with synthesizing these compounds. Professor Jacobi and his students are developing a concise synthetic approach to the furanosteroids, that should be equally applicable to the biologically important natural products as well as structural analogs. Ultimately, these studies could lead to the discovery of simpler analogs of the natural products that have enhanced biological activity but are significantly less toxic and more site specific.