Synthesis of Biologically Active Natural Products

这项提案由五个无关的项目组成，以制备结构新颖、具有生物活性的天然 作为药物的潜在感兴趣的产品，并在进行这些合成时，开发新的合成 将是普遍感兴趣和实用的方法。(1)抑制破骨细胞分化的共生亚胺 并因此可能在治疗骨质疏松症方面有价值，将使用新型Diels- 阿尔德反应以二氢吡啶盐为关键步骤。(2)由脯氨酸衍生的生物碱金刚烷胺A， SB-311099和Ephhelmins A和B是最近从各种来源分离出来的，并具有强大的 生物活性。将开发新的化学方法来合成这些天然产物，以确认 作业，并为进一步的生物学评估提供材料。(3)一种不常见的双环大环内酯，Sch 642305对细菌DMaprimase的抑制作用为70微摩尔，使其成为开发的领先者 新的抗菌剂。将制备一种立体化学上更简单的大环内酯前体并将其转化为 通过跨环迈克尔反应合成SCH 642305是一种新的和潜在的非常有效的方法 振铃系统。(4)阿比索米星C对多种革兰氏阳性菌具有抗菌活性 包括致病性金黄色葡萄球菌菌株和耐药菌株。一种仿生合成将 使用分子内Diels-Alder反应形成环己烷环。环氧化和 环氧化物的开环将完成合成。(5)双双酚A对角鲨烯有抑制作用 酿酒酵母、白色念珠菌、HepG2细胞和大鼠肝脏的合成及其IC50值 分别为0.43、0.25、0.95和2.5微克/毫升，具有广泛的抗真菌活性 酵母菌。四环骨架和立体化学使合成成为一个具有挑战性的问题，这将 使用我们在合成四环核心中开发的化学进行。(6)C2-对称 联氨和衍生的C2对称二胺是从 香茅醛的氮杂氮及其在不对称合成中的应用将被探索。这些天然产品目标是 用于治疗骨质疏松症和癌症以及开发新抗生素的领先企业。在课程中 在这些研究中，将开发出具有普遍用途的新方法，用于制备更多的药物 从经济上讲。

This proposal consists of five unrelated projects to prepare structurally novel, biologically active natural products of potential interest as drugs and, in carrying out these syntheses, to develop newsynthetic methods that will be of general interest and utility. (1) Symbioimine, which inhibits osteoclast differentiation and may therefore be of value in the treatment of osteoporosis, will be synthesized using the novel Diels- Alder reaction of a dihydropyridinium salt as the key step. (2) The proline-derived alkaloids jenamidine A, SB-311099, and epohelmins A and B were recently isolated from a variety of sources and have potent biological activity. New chemistry will be developed to synthesize these natural products to confirm the assignments and provide material for further biological evaluation. (3) An unusual bicyclic macrolide, Sch 642305 inhibits bacterial DMAprimase with an EC50 of 70 micromolar making it a lead for the development of new antibacterial agents. A stereochemically simpler macrolide precursor will be prepared and converted to Sch 642305 by a trans-annular Michael reaction as a novel and potentially very efficient route to this type ring system. (4) Abyssomicin C shows antibiotic activity against a variety of Gram-positive bacteria including pathogenic Staphyloccocus aureus strains and drug-resistant strains. A biomimetic synthesis will be carried out using an intramolecular Diels-Alder reaction to form the cyclohexane ring. Epoxidation and ring opening of the epoxide will complete the synthesis. (5) Bisabosqual A inhibits the microsomal squalene syntheses from Saccharomyces cerevisiae, Candida albicans, HepG2 cell and rat liver with IC50 valuesof 0.43, 0.25, 0.95 and 2.5 microgram/mL, respectively, and has broad antifungal activities against various yeasts. The tetracyclic framework and stereochemistry make the synthesis a challenging problem which will be carried out using chemistry developed in our synthesis of the tetracyclic core. (6) A C2-Symmetric hydrazine and the derived C2-symmetric diamine have been prepared in multi-gram quantities from the azine of citronellal their utility in asymmetric synthesis will be explored. These natural product targets are leads for the treatment of osteoporosis and cancer and for the development of new antibiotics. In the course of these studies new methods will be developed that are of general utility for preparing drugs more economically.