Enantio- and Diastereoselective Two-Pot Synthesis of Isoquinuclidines from Glutaraldehyde and N‑Aryl Imines with DFT Calculations

A pot-economic method for the enantio- and diastereoselective synthesis of a [2.2.2] azabicyclic isoquinuclidine system is developed. This protocol involves the proline-catalyzed direct Mannich reaction-cyclization/IBX-mediated site-selective oxidation/NaBH4-reduction sequence between glutaraldehyde...

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Bibliographic Details
Published in:Journal of organic chemistry 2019-10, Vol.84 (19), p.12408-12419
Main Authors: Ramaraju, Panduga, Pawar, Amol Prakash, Iype, Eldhose, Mir, Nisar A, Choudhary, Sachin, Sharma, Devinder Kumar, Kant, Rajni, Kumar, Indresh
Format: Article
Language:English
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Summary:A pot-economic method for the enantio- and diastereoselective synthesis of a [2.2.2] azabicyclic isoquinuclidine system is developed. This protocol involves the proline-catalyzed direct Mannich reaction-cyclization/IBX-mediated site-selective oxidation/NaBH4-reduction sequence between glutaraldehyde and imines to generate in situ chiral 1,2-DHPs, followed by the diastereoselective Diels–Alder reaction with N-aryl maleimides furnishing isoquinuclidines in overall five steps. A variety of isoquinuclidines having five-contiguous chiral centers, including an all-carbon quaternary, were prepared with high yields (up to 78%) and excellent stereoselectivity (>50:1 dr, and up to >99:1 er). DFT calculations support the observed high stereoselective reaction outcome.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.9b01865