Kinetic and thermodynamic aspects in the 1,3-dipolar cycloaddition of five-membered cyclic nitrones to α,β-unsaturated γ- and δ-lactones

The 1,3-dipolar cycloaddition of five-membered ring nitrones to the α,β-unsaturated δ-lactones is kinetically controlled, whereas the same reactions involving γ-lactones, upon heating and prolonged reaction times, display visible reversibility of the reaction and as the consequence, the formation of the more stable, thermodynamic products can be observed. Owing to this and to the high stereoselectivity of the cycloaddition, δ-lactones can be used for kinetic resolution of racemic nitrones whereas γ-ones cannot. In addition the reversibility of the cycloaddition, as well as racemization of 5-substituted 2-(5H)-furanones (γ-lactones), complicates the composition of the post-reaction mixtures and may lead to the formation of partially racemic adducts. The possible asymmetric transformation of cycloaddition involving γ-lactones, which eventually provide the most stable thermodynamic products in high yield, cannot be performed due to the low stability of cyclic nitrones which undergo decomposition.

Figure optionsDownload as PowerPoint slide

(1aS,4aR,4bS,5S)-5-tert-Butoxyhexahydrofuro[3,4-d]pyrrolo[1,2-b]isoxazol-4-(3H)-oneC12H19NO4[α]D25=+1.2 (c 0.4, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1aS,4aR,4bS,5S)

(1aS,2R,4aR,4bS,5S,6R)-2-tert-Butyldiphenylsiloxymethyl-hexahydro-5,6-O-isopropylidenedioxy-pyrrolo[1,2-b]-furo[3,4-d]isoxazol-4(3H)-oneC26H29NO6Si[α]D25=+22.5 (c 0.4, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1aS,2R,4aR,4bS,5S,6R)

(1aS,2R,3R,5aR,5bS,6S,7R)-2-Acetoxy-3-acetoxymethyl-hexahydro-6,7-O-isopropylidenedioxy-pyrrolo[1,2-b]-pyrano[3,4-d]isoxazol-5(3H)-oneC15H17NO9[α]D25=+30.7 (c 0.8, CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (1aS,2S,3R,5aR,5bS,6S,7R)