SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

这项提议由七个无关的项目组成，旨在制备结构新颖、具有生物活性的天然产物，如药物，并探索普遍感兴趣的新合成方法。(1)完成了新型吡咯喹啉、马丁酸和马丁内林的首次合成。这些生物碱抑制了几个G蛋白偶联受体。(2)首次开发并应用新方法合成了烟曲霉灵A、B、G、I和天冬氨酸。该项目将通过合成氧化程度更高的呋喃喹唑类化合物C、D、E和H、鱼腥草素A和B以及柠檬吲哚来完成。(3)一种新型的二萜抗生素鸟苷类化合物，它的功能似乎是通过破坏膜来实现的，它将通过一条通往氢天青环系的新路线来制备。这种化学方法将用于合成维生素D的CD环系统。(4)海藻内酯B和海藻内酯NA(卵囊素A)是从海绵、海鞘和植物病原体中分离出来的新型大环内酯类化合物，对乳腺癌细胞具有细胞毒性和选择性毒性。利用烯丙基溴或乙酸乙酯与乙烯基锡烷的Stille偶联反应来构建跳过的氯二烯单元，将开发出一条有效的合成这些化合物的路线。(5)Cytoskyrin A、graciliformin和ruulosin是一类罕见的具有较强生物活性和结构新颖性的双蒽醌类天然产物。它们将通过使用苯基二甲基硅基作为潜在羟基的生物合成路线来合成。(6)具有细胞毒性和抗菌活性的含胺盐天然产物--棕榈碱A和Al-A7地区的胍类化合物。在模型研究中，通过将格氏试剂加到N-酰胺的酰基上，然后烷基化酰胺，开发了一条合成这些化合物的一般新路线。这将扩展到天然产品和类似物。(7)在25℃的温度下，麦德鲁姆酸衍生物的基于Mn(III)的氧化环化反应几乎瞬间发生，生成的产物主要是环己烯。这些环化反应的机理和综合用途将被开发。

This proposal consists of seven unrelated projects designed to prepare structurally novel, biologically active natural products of potential interest as drugs and to explore new synthetic methods of general interest. (1) The first synthesis of the novel pyrroloquinolines martinellic acid and martinelline will be completed. These alkaloids inhibit several G-protein coupled receptors. (2) New methods have been developed and used for the first syntheses of fumiquinazolines A, B, G, and I and asperlicin. This project will be completed by the synthesis of the more highly oxidized fumiquinazolines C, D, E, and H, fiscalins A and B, and citreoindole. (3) The novel diterpene antibiotic guanacastepene that appears to function by disruption of membranes will be prepared using a novel route to the hydroazulene ring system. This chemistry will be used for a short synthesis of the CD ring system of vitamin D. (4) Haterumalide B and haterumalide NA (oocydin A) are novel macrolides isolated from a sponge, ascidian and phytopathogen that are cytotoxic and show selective toxicity to breast cancer cells. An efficient route to these compounds using a Stille coupling of an allylic bromide or acetate with a vinylstannane to construct the skipped chlorodiene unit will be developed. (5) Cytoskyrin A, graciliformin, and rugulosin are unusual bisanthraquinoid natural products that have potent biological activity and structural novelty. They will be synthesized by a biogenetic route using a phenyldimethylsilyl group as a latent hydroxy group. (6) Phloeodictine A and Al-A7 area family of guanidine containing amidinium salt natural products that are cytotoxic and antibacterial. In model studies, a general new route to these compounds has been developed by adding Grignard reagents to the acyl group of an N-acylamidine and then alkylating the amidine. This will be extended to the natural products and analogues. (7) Mn(III)-based oxidative cyclization of Meldrum's acid derivatives occurs almost instantaneously at 25 degrees celcius to give predominantly cyclohexene products. The mechanism and synthetic utility of these cyclizations will be developed.