Progress toward the Total Synthesis of Nogalamycin Using a Benzyne Cycloaddition Strategy.

Nogalamycin (NOG) is a member of the anthracycline glycoside natural products; no total syntheses have yet been reported, and there is minimal understanding of how the aglycone substitution pattern and identities of the A- and D-ring sugars impact the anticancer activity and toxicity. This paper reports progress toward a modular approach to NOG that could enable systematic structure-activity relationship studies. Key steps include a regioselective benzyne cycloaddition and reductive ring-opening to assemble a versatile AB core for analogue synthesis.

Recent updates and future perspectives in aziridine synthesis and reactivity.

In this review, selected recent advances in the preparation and reactivity of aziridines using modern synthetic approaches are highlighted, while comparing these new strategies with more classical approaches. This critical analysis is designed to help identify current gaps in the field and is showcasing new and exciting opportunities to move the chemistry of aziridines forward in the future.

Re-Evaluation of Product Outcomes in the Rh-Catalyzed Ring Expansion of Aziridines with N-Sulfonyl-1,2,3-Triazoles.

N-heterocycles are prevalent in pharmaceuticals and natural products, but traditional methods often do not introduce significant stereochemical complexity into the ring. We previously reported a Rh-catalyzed ring expansion of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. However, later studies employing ketone-containing carbene precursors showed that [3,9]-bicyclic aziridine formation competes with production of the desired heterocyclic scaffolds. In light of these surprising results, our initial findings were re-examined both experimentally and computationally to reveal how noncovalent interactions and restricted bond rotation in the aziridinium ylide intermediate promote this unexpected reaction pathway.

Rh-Catalyzed Aziridine Ring Expansions to Dehydropiperazines.

Piperazines are prevalent in pharmaceuticals and natural products, but traditional methods do not typically introduce stereochemical complexity into the ring. To expand access to these scaffolds, we report Rh-catalyzed ring expansions of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. Productive ring expansion proceeds via a pseudo-1,4-sigmatropic rearrangement of an aziridinium ylide species. However, the structural features of the carbene precursor are important, as pyridotriazoles undergo competing cheletropic extrusion to furnish ketimines.

Aziridinium Ylides: Underutilized Intermediates for Complex Amine Synthesis.

Harnessing the chemistry of onium ylide intermediates generated from transition metal catalysis is a powerful strategy to convert simple precursors into complex scaffolds. While the chemistry of onium ylides has been studied for over three decades, transformations of aziridinium ylides have just recently emerged as a versatile way to exploit the strain of these reactive intermediates to furnish densely functionalized N-heterocycles in a highly stereocontrolled manner. Herein, we provide a short overview of the key concepts and recent developments in this area, with a focus on how mechanistic studies to delineate the factors controlling the reactivity of aziridinium ylides can stimulate fruitful future investigations.