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.

Keywords: Michael addition; desymmetrization; enamine catalysis; organocatalysis; quantum-chemical calculations.

scheme 1

Desymmetrization strategy for the generation of morphans.

scheme 2

Synthesis of a model substrate and proof-of-concept transformations. Reagents and conditions: a) Hoveyda–Grubbs II catalyst, methyl acrylate, CH₂Cl₂, 45 °C, 48 h; b) QuadraSil AP, 0.5 mg per mg of substrate, CH₂Cl₂, RT; c) propylamine (20 mol %), CH₂Cl₂, RT; d) propylamine (20 mol %), PhCO₂H (20 mol %), CH₂Cl₂, RT.

Figure 1

Free-energy profile for the cyclization of 2 v catalyzed by methylamine at the CPCM-M06-2X/6-311+G(d,p) level of theory (G_rel values in kcal mol⁻¹ at 45 °C, 1 mol L⁻¹).

Figure 2

Transition states of the aminothiourea-catalyzed Michael reaction forming enantiomeric adducts of the endo diastereomer computed at the CPCM-M06-2X/6-311+G(d,p) level of theory.

scheme 3

Computer-aided catalyst design of 4 l.