Enantioselective desymmetrization of prochiral cyclohexanones by organocatalytic intramolecular Michael additions to α,β-unsaturated esters.
A new catalytic asymmetric desymmetrization reaction for the synthesis of enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, has been developed. Employing a cyclohexanediamine-derived primary amine organocatalyst, a range of prochiral cyclohexanone derivatives possessing an α,β-unsaturated ester moiety linked to the 4-position afforded the bicyclic products, which possess three stereogenic centers, as single diastereoisomers in high enantioselectivity (83-99% ee) and in good yields (60-90%). Calculations revealed that stepwise C-C bond formation and proton transfer via a chair-shaped transition state dictate the exclusive endo selectivity and enabled the development of a highly enantioselective primary amine catalyst.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK).
Adam D
AD
Gammack Yamagata
Swarup
S
Datta
Kelvin E
KE
Jackson
Linus
L
Stegbauer
Robert S
RS
Paton
Darren J
DJ
Dixon
D000588:Amines / Q000737:chemistry; D001372:Aza Compounds / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D003512:Cyclohexanones / Q000737:chemistry*; D004952:Esters; D008968:Molecular Conformation; D011789:Quantum Theory; D013237:Stereoisomerism; D013816:Thermodynamics
D000588:Amines; D001372:Aza Compounds; D001643:Bridged Bicyclo Compounds; D003512:Cyclohexanones; D004952:Esters; C458301:bicyclo(3.3.1)nonane; C036468:cyclohexanone
Michael addition; desymmetrization; enamine catalysis; organocatalysis; quantum-chemical calculations