Harnessing single amino acid catalysis
The development of two catalytic asymmetric synthetic methods is presented and culminates with studies of their application to the synthesis of a natural product. The intramolecular variant of the Morita-Baylis-Hillman (MBH) reaction has remained almost untouched by asymmetric catalysis. A significant advance in the field is demonstrated with the development of a highly enantioselective intramolecular MBH reaction employing a co-catalytic system of N-methylimidazole (NMI) and pipecolinic acid (Pip). The optimization of various reaction parameters and the use of protic conditions (THF-H2O, 3:1) afforded the desired products in up to 82% yield and 80% ee. The extension of this methodology to include the use of vinylogous reaction partners in the Rauhut-Currier (RC) reaction has been achieved, establishing the first highly enantioselective RC reaction. A single amino acid derivative of cysteine, in the presence of potassium tert-butoxide and a critical concentration of water in acetonitrile, was demonstrated to function as a highly selective catalyst providing products in up to 95% ee. Finally, the application of the MBH and RC reactions to the synthesis of complex molecules presents highly useful methodology for the formation of a new C–C bond in the generation of densely functionalized enantiopure products. Preliminary studies toward the application of this methodology to the stereoselective synthesis of (+)-Sch 642305 are described. Examination of the catalyst’s ability to dictate the stereoselectivity of the key step (catalyst control) and allow the synthesis of both the natural product, and difficult-to-obtain unnatural stereoisomeric analogs, will be the subject of on-going studies.