Biosynthetic and Biomimetic Investigations into Roseophilin

 描述（由申请人提供）：亲玫瑰素的天然产生是自然界中可能发生的前所未有的转变的一个很好的例子。了解生产机制将为以仿生方式复制这种强大的反应性提供重要见解。虽然roseophilin与灵菌红素生物碱的相似性提供了对其生物合成的一些理解，但目前的信息状态不允许制定具体的路线。Roseophilin是从灰维链霉菌（Streptomycesgriseovirdis）细菌中分离出来的，该细菌还产生相关的灵菌红素R1和去氯亲脂素。据信指导其生物合成的基因簇包含RedG酶的四个同源物，RedG酶指导相关化合物链脲菌素B的环化。因此，假设， 这四种酶有助于观察到的产生亲玫瑰素的不寻常的环化事件。为了检测酶的活性，将合成提议的中间体，二甲基十一烷基灵菌红素和灵菌红素R2。合成中间体将用于喂养实验，以确定酶如何与分子和产生的产物反应。环化反应也将在实验室中通过合成产生关键的自由基物质来模拟，这些自由基物质被认为存在于复杂的天然结构的途中。灵菌红素R2在氧化条件下的直接反应将用于筛选该自由基的反应性，同时还将产生巴顿酯类似物以受控方式直接产生所需的自由基中间体。这些结构的合成将提供重要的信息，需要推导出非凡的生物合成的roseophilin。这些知识将有助于促进未来的仿生碳环化努力，这将证明在以简单的方式靶向更复杂的化合物方面是有用的。

 DESCRIPTION (provided by applicant): The natural production of roseophilin is an excellent example of the unprecedented transformations that can occur in nature. Understanding the mechanism of production will provide major insights into reproducing such powerful reactivity in a biomimetic fashion. While the similarity of roseophilin to the prodigiosin alkaloids offers some understanding of its biosynthesis, the current state of information does not allow a concrete route to be formulated. Roseophilin was isolated from the bacterium Streptomyces griseovirdis, which has also produced the related prodigiosin R1 and deschlororoseophilin. The gene cluster believed to direct their biosynthesis contains four homologues of the enzyme RedG, which directs the cyclization of the related compound, streptorubin B. Therefore, it is hypothesized that these four enzymes assist in the unusual cyclization events observed to produce roseophilin. To examine the activity of the enzymes, the proposed intermediates, dimethylundecylprodigiosin and prodigiosin R2, will be synthesized. The synthetic intermediates will be used in feeding experiments to determine how the enzymes react with the molecules and the products that are produced. The cyclization events will also be mimicked in the laboratory by synthetically generating the key radical species believed to exist en route to the complex natural structure. Direct reaction of prodigiosin R2 under oxidative conditions will be used to screen the reactivity of this radical, while a Barton ester analogue will also be produced to directly generate the desired radical intermediate in a controlled fashion. The synthesis of these structures will provide access to vital information needed to deduce the extraordinary biosynthesis of roseophilin. This knowledge will help foster future endeavors in biomimetic carbocyclizations, which will prove useful in targeting more complex compounds in a facile manner.