Abstract
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.
Highlights
The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses
The ability to improve upon existing preparations of known compounds, enable alternate retrosynthetic approaches to useful building blocks, and increase opportunities to explore novel chemical space outside of ‘flatland’
We were encouraged by Rowlands report of a single example of the formation of a dehydropiperidine in 21% yield (Fig. 1b) from a vinylaziridine[49]. This reaction presumably occurs through intramolecular formation of an aziridinium ylide, followed by [2,3]-rearrangement; only one invertomer undergoes the desired cyclization
Summary
This efficient transformation, which forms new C–C and C–N bonds and two adjacent stereocenters in a stereospecific intermolecular two-fragment coupling, prompted us to undertake further studies of aziridinium ylides to extend the scope to unbiased aziridines. We reasoned appending a vinyl group to the carbene precursor 1i (Fig. 2c) could facilitate the desired ring expansion of aziridinium ylide 1j– k over competing cheletropic extrusion to 1l. This transformation represents a net [3+3] annulation of a vinyl carbenoid and a bicyclic aziridine; depending on the mechanism, transfer of stereochemical information from the aziridine to the dehydropiperidine with good fidelity could be envisaged. The intermediacy of an unusual aziridinium ylide species is followed by a stereospecific rearrangement that secures access to enantioenriched products
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