Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 44, Pages 23819-23826Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202110173
Keywords
asymmetric catalysis; domino ring-opening cyclization; epoxidation; heterocycles; one-pot reactions
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Funding
- University of Salerno [ORSA187525]
- PON RI 2014-2020
- University of Bologna (RFO funds 2020)
- Universita degli Studi di Salerno within the CRUI-CARE Agreement
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This study demonstrates an enantioselective one-pot catalytic strategy for the synthesis of dihydroquinoxalinones, using a combination of catalysts and intermediates to achieve high enantioselectivity in the formation of medicinally relevant heterocycles. The reusability of the organocatalyst and the mechanistic insights into the DROC process provide valuable information for further development of enantioselective synthesis strategies.
An enantioselective one-pot catalytic strategy to dihydroquinoxalinones, featuring novel 1-phenylsulfonyl-1-cyano enantioenriched epoxides as masked alpha-halo acyl halide synthons, followed by a domino ring-opening cyclization (DROC), is documented. A popular quinine-derived urea served as the catalyst in two out of the three steps performed in the same solvent using commercially available aldehydes, (phenylsulfonyl)acetonitrile, cumyl hydroperoxide and 1,2-phenylendiamines. Medicinally relevant 3-aryl/alkyl-substituted heterocycles are isolated in generally good to high overall yield and high enantioselectivity (up to 99 % ee). A rare example of excellent reusability of an organocatalyst at higher scale, subjected to oxidative conditions, is demonstrated. Mechanistically, labile alpha-ketosulfone has been detected as the intermediate involved in the DROC process. Theoretical calculations on the key epoxidation step rationalize the observed stereocontrol, highlighting the important role played by the sulfone group.
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