Self-Regeneration of Chirality with l-Cysteine through 1,3-Dipolar Cycloadditions between Diazoalkanes and Enantiomerically Pure Thiazolines: Experimental and Computational Studies

Abstract

Enantiopure 2-thia-4-azabicyclo[3.1.0]hexanes, which can be considered constrained cysteines, have been obtained from l-cysteine by application of the "self-regeneration of chirality" concept. The key intermediates are homochiral thiazolines that can be prepared in multigram scale and react smoothly with a series of diazoalkanes providing Δ¹-pyrazolines except for phenyldiazomethane that yield the isomeric Δ²-pyrazolines. Nitrogen extrusion in Δ¹-pyrazolines and further reduction of the sulfinyl group yielded the target compounds in good overall yield. Computational studies of the cycloaddition reaction were used for determining the polarity of the process and explaining the observed stereoselectivity. Additional topological studies were employed for determining the influence of noncovalent interactions in the stereochemical course of the reaction, which showed to be a highly asynchronous concerted process.