Intermolecular [5+2] cycloadditions: Novel five-atom components, serial [5+2]/[4+2] cycloadditions, and application to the synthesis of biologically active targets

Cycloaddition reactions are among the most synthetically useful individual processes for rapidly increasing molecular complexity. The Wender group has been involved in designing and developing new transition metal-catalyzed cycloaddition reactions that are theoretically forbidden in the absence of a catalyst or are difficult to achieve. Examples of these include the recent development of rhodium-catalyzed intra- and intermolecular [5+2] cycloadditions. These cycloadditions provide fundamentally new strategies for the synthesis of compounds containing seven-membered rings. In addition to introducing these new reactions, efforts have been made to render them practical and efficient.; An efficient, preparative scale synthesis of 1-(2-methyoxyethoxy)-1-vinylcyclopropane and the investigation of the utility of this reagent as a new five-carbon component in metal-catalyzed [5+2] cycloadditions is reported. A new cycloaddition protocol is also described that proceeds up to 12-fold faster and with 10-fold less catalyst than previously described. This procedure is readily conducted on a small or preparative scale.; A novel, serial [5+2]/[4+2] cycloaddition process is reported. This process employs readily available starting materials that are predictably converted into highly functionalized polycyclic products. The serial cycloadditions are readily conducted on a small or preparative scale.; The utility of the intermolecular [5+2] cycloaddition is illustrated by its use in the synthesis of biologically active targets. The rational design of biologically active targets, relying on X-ray structural information and known SAR combined with molecular modeling, is described. The synthesis and biological evaluation of these molecules is also reported.; Finally the first examples of transition metal-catalyzed aza-[5+2] cycloadditions of cyclopropyl imines and alkynes for the synthesis of azepines is described. The reported serial imine formation/aza-[5+2] cycloaddition reactions enable an azepine synthesis from three commercially available starting materials in a single reaction vessel. This reaction has also been explored with a substituted imine, yielding a single regioisomer, and has been demonstrated on a preparative scale.; In conclusion, intermolecular [5+2] cycloadditions have been demonstrated to be practical and efficient in the synthesis of seven-membered ring containing compounds.