Enantioselective Desymmetrization of Prochiral Cyclohexanones by Organocatalytic Intramolecular Michael Additions to α,β‐Unsaturated Esters

Abstract

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.

Enantioselective synthesis of bicyclo[3.n.1]alkanes by chiral phosphoric acid-catalyzed desymmetrizing Michael cyclizations

“… 1 , 2 Although many creative approaches for the synthesis of these structures have been devised, 1 , 2 the preparation of enantiomerically enriched chiral bicyclo[3.n.1]alkanes by asymmetric catalysis currently represents only a small fraction of these methods. 3 , 4 In view of the present level of development, increasing the number of available catalytic enantioselective reactions to access these compounds is an important area of research. Herein, we report a new approach for the enantioselective synthesis of bicyclo[3.2.1]octanes and bicyclo[3.3.1]nonanes by chiral phosphoric acid-catalyzed Michael cyclizations of 1,3-diones onto tethered electron-deficient alkenes.…”

Organocatalytic enantioselective desymmetrisation

“…The reaction was tolerant of several different protecting groups, allowing the synthesis of multiple orthogonally protected enantiopure myo-inositol derivatives (171)(172)(173)(174). The reaction was tolerant of several different protecting groups, allowing the synthesis of multiple orthogonally protected enantiopure myo-inositol derivatives (171)(172)(173)(174).…”

Applications of large-scale density functional theory in biology

“…Quantum mechanical calculations have the potential to contribute throughout the drug discovery process, from the design of catalysts to aid molecular synthesis [256], to predicting sites on new drug candidates that might be susceptible to metabolism [257], to determining the crystal packing of solid pharmaceuticals [258,259]. Here, we focus our discussion on the problem of determining the strength of the binding between the therapeutic target (usually a protein or DNA) and small molecules or peptides.…”