Synthesis of Biologically Active Natural Products

描述(由申请人提供)：这项提案包括五个无关的项目，以制备具有潜在兴趣的结构新颖、具有生物活性的天然产物作为药物，并在进行这些合成时，开发将引起普遍兴趣和实用的新的合成方法。(1)以二氢吡啶盐的Diels-Alder反应为关键步骤，合成了可抑制破骨细胞分化的共生亚胺，可能在治疗骨质疏松症方面有价值。(2)从多种来源中分离得到具有较强生物活性的脯氨酸类生物碱Jenamidine A、SB-311099和Ephhelmins A、B。将开发新的化学方法来合成这些天然产物，以确认其分配，并为进一步的生物评价提供材料。(3)SCH 642305是一种特殊的双环大环内酯类化合物，对细菌DNA底物酶有抑制作用，其EC50值为70微摩尔，是新抗菌药物开发的先行者。一种立体化学上更简单的大环内酯类前体将被制备并通过跨环迈克尔反应转化为SCH 642305，作为这类环系的一条新的和潜在的非常有效的路线。(4)阿司索米星C对多种革兰氏阳性菌，包括致病性金黄色葡萄球菌和耐药菌株具有抗菌活性。将使用分子内Diels-Alder反应来进行仿生合成以形成环己烷环。环氧化物的环氧化和开环反应将完成合成。(5)双酚A对酿酒酵母、白色念珠菌、HepG2细胞和大鼠肝脏的角鲨烯合成有抑制作用，IC50值分别为0.43、0.25、0.95和2.5微克/毫升，对多种酵母菌具有广泛的抗真菌活性。四环的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时开发的化学来进行。(6)从香茅醛的氮杂环上合成了多克量的C2对称的肼和C2对称的二胺，并探索了它们在不对称合成中的应用。这些天然产品靶标是治疗骨质疏松症和癌症以及开发新抗生素的先导。在这些研究过程中，将开发出具有普遍实用价值的新方法，以便更经济地制备药物。

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.