Synthesis of Biologically Active Natural Products

描述（由申请人提供）：本提案包括五个不相关的项目，以制备结构新颖的、具有生物活性的天然产物，这些天然产物具有作为药物的潜在利益，并在进行这些合成时，开发具有普遍利益和实用性的新合成方法。(1)将使用二氢吡啶盐的新型Diels-桤木反应作为关键步骤来合成抑制破骨细胞分化并因此可能在治疗骨质疏松症中具有价值的共生亚胺。(2)脯氨酸衍生的生物碱jenamidine A、SB-311099和epohelmins A和B最近从多种来源分离得到，并具有有效的生物活性。将开发新的化学方法来合成这些天然产物，以确认分配并为进一步的生物学评价提供材料。(3)一种不寻常的双环大环内酯，Sch 642305抑制细菌DMA引发酶，EC50为70微摩尔，使其成为开发新抗菌剂的领导者。将制备立体化学上更简单的大环内酯前体，并通过反式环迈克尔反应将其转化为Sch 642305，该反应作为获得这种类型环系统的新颖且可能非常有效的途径。(4)Abyssomicin 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。将使用分子内Diels-Alder反应进行仿生合成以形成环己烷环。环氧化和环氧化物的开环将完成合成。(5)Bisabosqual A抑制酿酒酵母、白色念珠菌、HepG2细胞和大鼠肝脏微粒体角鲨烯的合成，IC 50值分别为0.43、0.25、0.95和2.5 μ g/mL，并对多种酵母菌具有广泛的抗真菌活性。四环框架和立体化学使合成成为一个具有挑战性的问题，这将使用我们在四环核心合成中开发的化学进行。(6)以香茅醛的吖嗪为原料，制备了数克的C2-对称肼和衍生的C2-对称二胺，并探讨了它们在不对称合成中的应用。这些天然产物靶点是治疗骨质疏松症和癌症以及开发新抗生素的先导。在这些研究的过程中，将开发出更经济地制备药物的通用新方法。

DESCRIPTION (provided by applicant): 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 new synthetic 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 DMA primase 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 values of 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.