SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

该提案由七个不相关的项目组成，旨在制备具有潜在药物兴趣的结构新颖、生物活性的天然产物，并探索具有普遍意义的新合成方法。(1)首次合成新型吡咯并喹啉类化合物马丁奈酸和马丁奈林。 这些生物碱抑制几种G蛋白偶联受体。(2)新方法已被开发并用于首次合成富米喹唑啉A、B、G和I以及曲霉素。 该项目将通过合成更高度氧化的fumiquinazolines C、D、E和H、fiscalins A和B以及citreoindole来完成。(3)新的二萜类抗生素guanacastepene，似乎通过破坏膜的功能将使用一种新的路线制备的氢化甘菊环系统。 这种化学反应将用于维生素D的CD环系统的短合成。(4)Haterumalide B和haterumalide NA（卵环素A）是从海绵、海鞘和植物病原体中分离的新的大环内酯，其具有细胞毒性并且对乳腺癌细胞显示出选择性毒性。 一个有效的路线，这些化合物使用的烯丙基溴或乙酸酯与乙烯基锡烷的Stille偶联，以构建跳过的氯二烯单元将被开发。(5)Cytoskyrin A、gracililipine和rugulosin是不寻常的双蒽醌类天然产物，具有强大的生物活性和结构新奇。 它们将通过使用苯基二甲基甲硅烷基作为潜在羟基的生物遗传途径合成。(6)Phloeodictine A和Al-A7是含胍脒盐的天然产物，具有细胞毒性和抗菌性。 在模型研究中，通过将格氏试剂加入到N-酰基脒的酰基中，然后将脒烷基化，开发了一种制备这些化合物的通用新路线。 这将扩展到天然产物和类似物。(7)在25摄氏度下，基于Mn（III）的Meldrum酸衍生物的氧化环化几乎瞬间发生，主要产生环己烯产物。 这些环化反应的机理和合成应用将得到发展。

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.