Computational studies on the asymmetric induction in intramolecular 1,3-dipolar cycloaddition of (S)-5-phenyl-morpholin-2-one

The intramolecular 1,3-dipolar cycloaddition reactions of chiral morpholinone-derived azomethine ylides with tethered alkenes and alkynes have been investigated by semi-empirical methods and ab initio quantum mechanics. The observed efficient direction of the asymmetric induction in the 1,3-dipolar cycloaddition has been modelled from a comparison of the energies of the four possible transition states arising from addition to either face of E- or Z-configured ylides. In the reaction of morpholinone with hex-5-enal, the most favourable transition state is shown to be the anti-addition to the E-ylide (Eact ∼12 kcal/mol by HF/3-21G). By contrast, reaction with hex-5-ynal led to anti-addition from the Z-ylide (Eact ∼19 kcal/mol by HF/3-21G) exhibiting the lowest transition state energy. The resulting trends of relative transition state energy are in excellent agreement with the experimental observations.