45334-G1
Metal Alkoxide-Mediated Regio- and Stereoselective C-C Bond-Forming Reactions for Complex Molecule Synthesis
Over the life of this grant, we have discovered a significant number of new reductive cross-coupling reactions in organic chemistry: 1) Alkene–alkyne (for the synthesis of stereodefined allylic systems) 2) Alkyne–imine (for the synthesis of unsaturated 1,5-amino alcohols, lactams or pyrroles) 3) Alkene–imine (for the synthesis of saturated 1,5-amino alcohols and piperidines) 4) Allene–alkyne (for the synthesis of 1,4-dienes or cross-conjugated trienes) 5) Allene–imine (for the synthesis of complex allylic amines) 6) Alkyne–allylic alcohol (for the synthesis of 1,4-dienes) 7) Vinylsilane–allylic alcohol (for the synthesis of Z-trisubstituted alkenes) - manuscript submitted 8) Allylic alcohol–imine (for the synthesis of stereodefined homoallylic amine) - manuscript in preparation These reactions, although not yet rendered catalytic in the metal (Ti or Mg), define unique and powerful bond construction processes in organic chemistry. Due to the low cost of the metal-containing reagents, benign nature of the byproducts (TiO2 and magnesium (II) salts), and substrate-controlled stereoselection, these reactions in their current form should be of great utility in organic chemistry. We have began to demonstrate the utility of these processes in total syntheses of complex bioactive natural products. To date, we have applied some of our reductive coupling reactions to the total syntheses of macbecin I and callystatin (these achievements were both published in Angewandte Chemie this year). We have initiated research aimed at applying all of our novel convergent coupling reactions to the synthesis and discovery of complex molecules that possess therapeutically valuable properties. Progress on this front will be reported continually over the course of my academic career.
