On the regioselectivity for the Michael addition of thiols to unsymmetrical fumaric derivatives

Article abstract of DOI:10.1016/j.tet.2003.10.007

The regiochemistry of the Michael addition of thiols to unsymmetrical fumaric derivatives was investigated. Conjugate addition of thiols to unsymmetrical fumaric diester was well controlled by the presence of lithium cation and one of the two possible regioisomers was prepared in a highly selective manner. Fumaric ester amides underwent the regioselective Michael addition that was controlled by the presence or absence of the base; either of the regioisomers was prepared as an almost diastereomerically pure form. The present control of the regiochemistry can be explained by the factors of change of active site for the addition by the coordination or non-coordination of proton or lithium cation to the carbonyls. To clarify the origin of the regioselectivity, the relative rates of the conjugate addition of thiol to acrylate derivatives were measured under competitive conditions. Ethyl acrylate reacted with thiol faster than tert-butyl acrylate and the rate difference was enhanced by the presence of lithium cation. In the presence of base, ethyl acrylate gave the adducts much faster than acrylamide, while under non-basic conditions acrylamide showed higher reactivity than the ester. This regioselectivity was also observed in the Michael/aldol reaction and multi-substituted γ-butyrolactones were prepared in a stereoselective manner. The thio groups introduced here served as a leaving group and a convenient stereoselective synthesis of β-, γ- and δ-lactams was developed.