Progress toward the Total Synthesis of Jogyamycin Using a Tandem Ichikawa/Winstein Rearrangement.

Jogyamycin is a densely functionalized aminocyclopentitol that displays potent antiprotozoal activity. Herein, we report a route toward this natural product that utilizes an unprecedented transformation involving a tandem Ichikawa-Winstein rearrangement to install the C-1/C-2 diamine core. Attempts to further functionalize the C-3/C-4 alkene en route to jogyamycin are also discussed.

Tunable Aziridinium Ylide Reactivity: Non-covalent Interactions Enable Divergent Product Outcomes.

Methods for rapid preparation of densely functionalized and stereochemically complex N-heterocyclic scaffolds are in demand for exploring potential bioactive chemical space. This work describes experimental and computational studies to better understand the features of aziridinium ylides as intermediates for the synthesis of highly substituted dehydromorpholines. The development of this chemistry has enabled the extension of aziridinium ylide chemistry to the concomitant formation of both a C-N and a C-O bond in a manner that preserves the stereochemical information embedded in the substrate. Additionally, we have uncovered several key insights that describe the importance of steric effects, rotational barriers around the C-N bond of the aziridinium ylide, and non-covalent interactions (NCIs) on the ultimate reaction outcome. These critical insights will assist in the further development of this chemistry to generate N-heterocycles that will further expand complex amine chemical space.

Strategies for the Syntheses of Pactamycin and Jogyamycin.

Pactamycin and jogyamycin are aminocyclopentitol natural products, where each core carbon bears a stereodefined alcohol or amine moiety. Their structural complexity, coupled with the diversity of functional groups coexisting in a condensed space, make them fascinating synthetic targets in their own right. Pactamycin and its derivatives bind to the 30S ribosomal subunit and display activity against parasites responsible for drug-resistant malaria and African sleeping sickness; however, efforts to develop their therapeutic potential have been hampered by their cellular toxicity. Interestingly, bioengineered analogues display differences in selectivity and toxicity towards mammalian cells, spurring efforts to develop flexible strategies to thoroughly probe structure-activity relationships (SAR), particularly in analogues lacking the C7 hydroxyl group of pactamycin. This review compares and contrasts approaches towards pactamycin and jogyamycin, including two successful total syntheses of the former. The implications of each route for preparing analogues to inform SAR and lead to compounds with increased selectivity for binding malarial over human ribosomes are briefly discussed.

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides.

The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new C-C bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.