Regioselective synthesis of enantiopure 1,2- and 1,3-dispirooxindoles along with a DFT study

Abstract

In the present study, a library of important enantiopure dispirooxindole [indolizidine, pyrrolizidine, and pyrrolidine] derivatives with three or four contiguous and two quaternary stereogenic centers using different amino acids (pipecolic acid, sarcosine, proline and hydroxyproline) were synthesized in high yields (up to 96%) through a regio- and diastereoselective (up to 99 : 1) multicomponent 1,3-dipolar cycloaddition strategy. Based on the results, the alteration of amino acids led to a change in the regioselectivity and unusual regioisomers (pyrrolizidine versus indolizidine/pyrrolidine) were obtained to construct a novel enantiopure 1,3-dispirooxindole skeleton. The stereochemical outcome of the cycloaddition was determined by single crystal X-ray diffraction analysis and the self-disproportionation of enantiomers (SDE) test confirmed the enantiomeric purity of the desired products. The mechanism and differences in the regioselectivity of the 1,3-dipolar cycloaddition reactions between the stable azomethane ylides obtained from ninhydrin, pipecolinic acid, and proline with (E)-2-oxoindolin-3-ylideneacetyl sultam were theoretically studied through DFT calculations at the M06-2X/6-31G(d,p) level in methanol.