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.