Section 66
Chapter 65,336

Multicomponent, Enantioselective Michael-Michael-Aldol-β-Lactonizations Delivering Complex β-Lactones

Van, K.N.; Romo, D.

Journal of Organic Chemistry 83(2): 632-643


ISSN/ISBN: 1520-6904
PMID: 29219311
DOI: 10.1021/acs.joc.7b02543
Accession: 065335668

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Optically active, tertiary amine Lewis bases react with unsaturated acid chlorides to deliver chiral, α,β-unsaturated acylammonium salts. These intermediates participate in a catalytic, enantioselective, three-component process delivering bi- and tricyclic β-lactones through a Michael-Michael-aldol-β-lactonization. In a single operation, the described multicomponent, organocascade process forms complex bi- and tricyclic β-lactones by generating four new bonds, two rings, and up to four contiguous stereocenters. In the racemic series, yields of 22-75% were achieved using 4-pyrrolidinopyridine as Lewis base. In the enantioselective series employing isothiourea catalysts, a kinetic resolution of the initially formed racemic Michael adduct appears operative, providing yields of 46% to quantitative (based on 50% max) with up to 94:6 er. Some evidence for a dynamic kinetic asymmetric transformation for tricyclic-β-lactone 1d was obtained following optimization (yields up to 61%, 94:6 er) through a presumed reversible Michael.

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