Synthetic Approaches for Building Tricyclic Cage-like Motifs Found in Indoxamycins

Indoxamycins A-F, a novel class of polyketides, were isolated from the saline culture of marine-derived actinomyces by Sato et al. in 2009. Intriguing stereochemical complexity involving tricyclic [5.5.6] cage-like structures with six consecutive chiral centers challenged many organic chemists. Chemical ingenuity, implementation of pioneered reactions along with fine chemical transformations allowed not only the rapid construction of the central core but also allowed minor structural revision and paved the information to delineate the absolute stereostructures of these complex polyketide marine natural products. To achieve the central core structure in indoxamycins A-F, reactions like the Ireland-Claisen rearrangement, an enantioselective 1,6-enyne reductive cyclization, and one-pot cascade reactions of 1,2-addition/oxa-Michael/methylenation were employed. Using the chiral pool approach, the readily available R-carvone was employed as a cost-effective starting material to achieve the concise total syntheses of (-)-indoxamycins A and B, in which Pauson-Khand, Cu-catalyzed Michael addition and tandem retro-oxa-Michael addition/1,2-addition/oxa-Michael addition reactions were employed. The antipodes, (+)-indoxamycins can be easily accessed by simply switching to S-carvone as the starting material. Synthetically prepared indoxamycins A-F are devoid of antiproliferative properties, which disagree with the work reported by Sato and co-workers for (-)indoxamycins A and F. Nevertheless, ready access to such complex natural products allows probing the untapped potential biological activities of these polyketides including cytotoxicity. A concise overview of interesting, key chemical transformations including named reactions in establishing the architecture of indoxamycins was compiled to inspire organic chemists and help reinvigorate novel strategies for the asymmetric synthesis as well as the development of novel derivatives of indoxamycins with unique physicochemical and biological properties.

Automated summary

Indoxamycins A-F, a novel class of polyketides with intriguing stereochemical complexity, were isolated from marine-derived actinomyces in 2009. Synthetic methods involving pioneering reactions and fine chemical transformations were employed to rapidly construct the central core of these compounds, leading to a better understanding of their absolute stereostructures and potential biological activities.