Organocatalytic Domino Michael-Aldol Reactions for the Construction of Heterocyclic Natural Products

大量的天然产物含有杂环基序。虽然已经使用了许多方法，但文献中已知的有机催化多米诺反应很少。本项目将利用醛醇/乙烯基醇醛醇反应和Michael反应结合有机催化合成手性杂环化合物骨架。特别是首次合成了天然产物yaequinolone、lachone C和marmycin A。吖喹诺酮是多环手性色烯。它们分离自真菌菌株青霉属（Penicillium sp.）FKI-2140的培养液，并显示出对卤虫（卤虫）的生长抑制活性。Lachnone C是最近分离的色酮，分离自丝状真菌Lachnum sp. BCC 2424。Lachnones轻度抑制结核分枝杆菌的生长。使用上述反应顺序，我们将合成marmycins的杂环部分。它们是新的angucycline类的细胞毒性醌类化合物，分离自一种与链霉菌属相关的海洋沉积物来源的放线菌的培养液。用光谱学和晶体学方法确定了两个化合物的总体结构和绝对构型。Marmycin A对几种癌细胞系显示出显著的细胞毒性，其中一些在纳摩尔浓度下。对于marmycin A，肿瘤细胞的细胞毒性似乎与诱导适度的细胞凋亡和细胞周期的GI期阻滞相一致。

A large number of natural products contain heterocycie motifs. Although many approaches have been used, there are only few organo-catalytic domino reactions known in the literature. In this project, aldol/vinylogous aldol and Michael reactions will be combined with organo catalysis to give chiral complex heterocycie scaffolds. In particular, the natural products yaequinolone, lachnone C and marmycin A will be synthesized for the very first time. Yaequinolones are polycyclic chiral chromenes. They were isolated from the culture broth of the fungal strain Penicillium sp. FKI-2140 and showed growth inhibitory activity against brine shrimp {Artemia salina). Lachnone C is a recently isolated chromone, isolated from the filamentous fungus Lachnum sp. BCC 2424. Lachnones mildly inhibited the growth of Mycobacterium tuberculosis. Using the reaction sequence outlined above, we will synthesize the heterocyclic part of the marmycins. They are new cytotoxic quinones of the angucycline class and were isolated from the culture broth of a marine sediment-derived actinomycete related to the genus Streptomyces. The gross structures and absolute configurations of both compounds were determined by spectroscopic and crystallographic methods. Marmycin A displayed significant cytotoxicity against several cancer cell lines, some at nanomolar concentrations. For marmycin A, tumor cell cytotoxicity appeared to coincide with induction of modest apoptosis and arrest in the GI phase of the cell cycle.