Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides
Open Access
- 9 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-8
- https://doi.org/10.1038/s41467-020-15134-x
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (1R01GM132300)
This publication has 76 references indexed in Scilit:
- An overview of the synthetic routes to the best selling drugs containing 6-membered heterocyclesBeilstein Journal of Organic Chemistry, 2013
- Heterocyclic chemistry in crop protectionPest Management Science, 2013
- Modular Functionalization of Allenes to Aminated StereotriadsJournal of the American Chemical Society, 2012
- Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocyclesBeilstein Journal of Organic Chemistry, 2012
- Allene Functionalization via Bicyclic Methylene AziridinesOrganic Letters, 2011
- Stereospecific Ring Expansion of Chiral Vinyl AziridinesOrganic Letters, 2011
- Pyrimidine Chemistry in Crop ProtectionHETEROCYCLES, 2006
- Enantiocontrolled Synthesis of 2,6-Disubstituted Piperidines by Desymmetrization of meso-η-(3,4,5)-Dihydropyridinylmolybdenum Complexes. Application to the Total Synthesis of (−)-Dihydropinidine and (−)-AndrachcinidineJournal of the American Chemical Society, 2003
- Rearrangement of ammonium ylides produced by intramolecular reaction of catalytically generated metal carbenoids. Part 2. Stereoselective synthesis of bicyclic aminesJournal of the Chemical Society, Perkin Transactions 1, 2001
- An Early Clinical Phase II Evaluation of Paroxetine, a New Potent and Selective 5HT-Uptake Inhibitor in Patients with Depressive IllnessPharmacopsychiatry, 1982