Biosynthetic and Biomimetic Investigations into Roseophilin

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 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.