Wednesday, April 2, 2025
4/2/2025
Development of new methods and strategies for the synthesis of complex molecules - PROJECT SUMMARY Our laboratory is interested in studying artificial assembly of natural products with promising biological activities and developing new reactions. Securing short, scalable, and flexible synthetic routes tests the limitations of chemical methods and provides access to unnatural analogs that would otherwise be beyond the reach. This approach often necessitates development of new transformations and synthetic strategies that streamline the assembly of the desired scaffolds. Therefore, vertical advancements in the fields of chemistry and related areas of biology can be anticipated. Over the past several years, we succeeded in developing new synthetic routes to several families of natural products, including indoloterpenoids, anthraquinone-xanthone heterodimers, labdane diterpenes, quassinoids, and mutilins. We demonstrated a new radical-polar crossover polycyclization that allowed for concise assembly of the tricyclic core found in indoloterpenoids and led to the synthesis of emindole SB, the simplest member of the family. As a corollary to these studies, we also developed a catalytic intermolecular formal ene reaction between ketone-derived silyl enol ethers and alkynes, which exhibited high selectivity for generation of quaternary centers. We subsequently completed the synthesis of nodulisporic acid C, a potent parasiticidal agent, where we employed a diverse set of tactics to assemble disparate polycyclic motifs and a sensitive indole moiety. In a continuation of these studies, we developed a powerful annulation reaction, which allowed for direct assembly of complex terpenoid motifs and led to the synthesis of forskolin, a densely functionalized labdane diterpenoid. Further studies of the annulation spanned a broader range of polycyclic scaffolds and ultimately resulted in short syntheses of quassin and pleuoromutilin. In another effort, we developed a short synthesis of acremoxanthone A, an anthraquinone-xanthone heterodimer with antibacterial activity. Driven by these investigations, we also developed hydrogen atom transfer (HAT)-initiated semipinacol rearrangements of tertiary allylic alcohols where the outcome of the reaction was under strong catalyst control. Based on our findings, we proposed that these transformations involve catalysis by alkylcobalt complexes and developed the first asymmetric HAT-initiated hydrofunctionalization, which allowed for cyclization of dialkyl(vinyl)carbinols to the corresponding enantioenriched epoxides. A significant component of our future efforts will focus on identification of new ways to control reactivity in HAT- initiated process, which remains a significant challenge. These studies will capitalize on our previous discoveries to uncover new transformations for assembly of complex structural motifs and will also employ natural product synthesis as a way to interrogate the limitations of our methods. Overall, new chemical reactions and new synthetic strategies are expected to result.
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