SYNTHESIS OF BIOLOGICALLY ACTIVE NATURAL PRODUCTS

该提案由七个不相关的项目组成，旨在制备结构新颖，具有生物活性的天然产物，并探索具有普遍意义的新合成方法。(1)完成新型吡咯喹啉类化合物马氏酸和马氏碱的首次合成。这些生物碱抑制几种g蛋白偶联受体。(2)开发并应用了新方法，首次合成了富米喹唑啉A、B、G、I和曲霉素。该项目将通过合成氧化程度更高的富米喹唑啉C、D、E、H、财政素A、B和柠檬酸吲哚来完成。(3)新型二萜抗生素guanacastepene似乎是通过破坏膜来发挥作用，将采用新的途径制备到氢偶氮环系统。(4) Haterumalide B和Haterumalide NA （oocydin 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，具有细胞毒性，对乳腺癌细胞具有选择性毒性。将开发一种利用烯丙基溴或醋酸酯与乙烯基锡烷的Stille偶联来构建跳过的氯二烯单元的有效途径。(5) Cytoskyrin A、graciliformin和rugulosin是罕见的双蒽醌类天然产物，具有强大的生物活性和结构新颖性。它们将以苯基二甲基硅基作为潜在羟基，通过生物发生途径合成。(6) Phloeodictine A和Al-A7区胍类含氨基盐天然产物，具有细胞毒性和抗菌作用。在模型研究中，通过在n -酰基胺的酰基上加入格氏试剂，然后将酰胺烷基化，开发了一种合成这些化合物的新途径。这将扩展到天然产物和类似物。(7)在25℃下，Meldrum酸衍生物的Mn（III）基氧化环化反应几乎瞬间发生，生成主要的环己烯产物。本文将进一步研究这些环化反应的机理及其综合应用。

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.