Regiodivergent Asymmetric Pyridinium Additions: Mechanistic Insight and Synthetic Applications

A practical protocol for the first regiodivergent asymmetric addition of aryl and alkenyl organometallic reagents to substituted N‐alkyl pyridinium heterocycles is described. The couplings proceed with high regiochemical and stereochemical selectivities, and provide access to chiral 1,2,3‐ and 1,3,4...

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Bibliographic Details
Published in:Chemistry : a European journal 2022-12, Vol.28 (69), p.e202202813-n/a
Main Authors: Grigolo, Thiago A., Smith, Joel M.
Format: Article
Language:English
Subjects:
asymmetric
Asymmetry
Catalysis
Couplings
Dihydropyridine
heterocycles
Molecular Structure
Nitrogen
Paroxetine
Pyridinium
Reagents
regiodivergence
Regioselectivity
total synthesis
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Summary:A practical protocol for the first regiodivergent asymmetric addition of aryl and alkenyl organometallic reagents to substituted N‐alkyl pyridinium heterocycles is described. The couplings proceed with high regiochemical and stereochemical selectivities, and provide access to chiral 1,2,3‐ and 1,3,4‐trisubstituted dihydropyridine products, controlled by judicious choice of nitrogen activating agent. To this end, a correlation was found between the parameterized size of the activating group and the C2/C4 regioselectivity in the couplings. The utility of the described chemistry was demonstrated in two concise asymmetric syntheses of (+)‐N‐methylaspidospermidine and (−)‐paroxetine. A regiodivergent asymmetric dearomatization of readily accessible pyridines has enabled the redox‐economic synthesis of both (+)‐N‐Methylaspidospermidine and (−)‐Paroxetine. A mechanistic rationale for the regiodivergent pyridinium additions and evaluation of their scope was also explored.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202202813