Total Synthesis of (±)-Baphicacanthcusine A Enabled by Sequential Ring Contractions.

Reported herein is the first total synthesis of the poly-pseudoindoxyl natural product baphicacanthcusine A. The synthesis leverages the oxidative rearrangement of indoles to pseudoindoxyls to install vicinal pseudoindoxyl heterocycles in a diastereoselective manner. Key steps include an acid-mediated cyclization/indole transposition, two diastereoselective oxidative ring contractions, and a site-selective C-H oxygenation. The synthesis of the oxidation precursors was guided by recognition of an element of hidden symmetry. This work provides a foundation for the chemical synthesis of other poly-pseudoindoxyl alkaloids.

Merging Strategy, Improvisation, and Conversation to Solve Problems in Target Synthesis.

Total synthesis has long been depicted as the quest to conquer the structures created by nature, requiring an unflinching, single-minded devotion to the task. The goal is achieved by chemists with grit, strength of will, and a competitive spirit. While there is some truth to this viewpoint, it does not fully capture the rich experiences gained in this research realm. In our lab, strategic planning, improvisation, and conversation have worked in concert to enable progress. This Account summarizes our efforts to synthesize four different bioactive targets: merrilactone A, rocaglamide, phomactin A, and tetrapetalone A. Certain missteps were integral to success in these synthetic projects. As such, we include the hiccups, and their roles in the evolution of the strategies, along with the results that aligned with our expectations.Two of these projects (merrilactone A and rocaglamide) culminated in the total synthesis of the targets. The challenges presented by merrilactone A spawned a new design strategy for pentannulation using Nazarov cyclization chemistry. This work demonstrated that Lewis acid catalysis is often a viable electrocyclization strategy in activated, polarized pentadienyl cation intermediates. We sought to apply the same logic to the rocaglamide target, but precursors we prepared did not behave according to plan. This situation pushed us to adapt our approach to match the innate reactivity of the substrate, resulting in an on-the-spot improvisation that was not only integral to the success of the project but also expanded our understanding of pentadienyl cation chemistry. In the other two projects (phomactin A and tetrapetalone A), we did not complete a total synthesis but did build the polycyclic core of the target. Even though the hetero [4 + 2] cycloaddition plan for assembling the macrocyclic oxadecalin ring system of phomactin A failed, the original experimental design still enabled us to solve the problem. Through a wholly unanticipated series of events, our focus on the oxadecalin ring system primed us for the discovery of a sequential iodoaldol/oxa-Michael sequence, using the original [4 + 2] building blocks. Then, the bridging ring present in phomactin A demanded we implement this sequence in a transannular fashion. Finally, our successful synthesis of the tetrapetalone core was enabled by consultations with others in the community. Each bond formation seemed to require different expertise, and in three separate instances (C-N cross-coupling, diastereoselective ring-closing metathesis, and oxidative dearomatization) synthetic challenges were overcome through conversation and collaboration.In our experience, the amount of creative power we summon during a target synthesis project correlates directly with the magnitude of the structural challenges we face. When reactivity surprises us, we analyze the problem anew, consult with colleagues, and improvise with the tools at hand. The inevitable misbehavior of a complex system is a strong motivating force, and one that has helped to shape our research program for nearly two decades.

Correction: Convergent synthesis of thiodiazole dioxides from simple ketones and amines through an unusual nitrogen-migration mechanism.

[This corrects the article DOI: 10.1039/D3SC04478E.].

Convergent synthesis of thiodiazole dioxides from simple ketones and amines through an unusual nitrogen-migration mechanism.

We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting from methyl ketones and primary amines. This one-pot, three-component coupling employs 2,3-dimethylimidazole-1-sulfonyl azide triflate as a coupling reagent and oxidant. The transformation is scalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to 89% yield. In addition, 15N- and 13C-labeling studies suggest a mechanism involving a 1,2-nitrogen migration. Together with the mechanistic studies, DFT calculations provide insight into the reaction pathway and set the stage for further exploration of the mechanistic nuances of reactions that use sulfamoyl azides. In combination with the demonstrated modularity of the approach reported herein, the derivatization of the thiodiazole dioxide products highlights the potential of this methodology to rapidly access diverse chemical structures.