This revised grant application details our plans to utilize, based upon preliminary findings, a cascade reaction in which a vinyl organometallic addition to a ketone initiates an apparent anionic oxy-Cope rearrangement followed by a transannular cyclization. This three step tandem reaction is capable of converting simple cyclic 2-vinyl-beta-ketoesters to complex polycyclic structures in a single transformation. Bridgehead olefin-containing molecules, medium-size rings, and complex fused ring systems are all accessible using this reaction. On the basis of these results, our specific aims involve: (1) Elucidation of the mechanism of this process using stereochemical probes. (2) Studies to explore the generality of the cascade sequence with applications to the synthesis of bridgehead olefin- containing molecules, medium-size rings, and fused ring systems. The conversion of the medium-size ring systems to fused bicyclic structures via transannular cyclizations will also be explored. (3) Application of the cascade reaction to the total synthesis of the ras farnesyltransferase inhibitors CP-225,917 and CP-263,114. These molecules are currently undergoing testing as inhibitors of tumor progression and a concise synthetic route will provide access to variants for biological evaluation.
| Morris, William J; Shair, Matthew D (2010) Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-D-pyrrolosamine Glycal of Lomaiviticin A & B via Epimerization of L-Threonine. Tetrahedron Lett 51:4310-4312 |
| Xu, Kaichen; Lalic, Gojko; Sheehan, Scott M et al. (2005) Dynamic kinetic resolution during a cascade reaction on substrates with chiral all-carbon quaternary centers. Angew Chem Int Ed Engl 44:2259-61 |
