| Cycloaddition reactions are among the most powerful tools in synthetic chemistry. Representative of this power is the Diels-Alder cycloaddition, the premier method for the construction of cyclohexyl systems. Extension of this methodology for the generation of functionalized cycloheptanes, a long sought-after goal, has recently been realized in a general fashion. In the rhodium(I)-catalyzed [5+2] cycloaddition, vinylcyclopropanes are able to function effectively as homologated diene equivalents in their reaction with various pi-systems. Reported herein are the first examples of intramolecular cycloadditions with substrates bearing substitution on the cyclopropane. The role of the substituent, as well as the catalyst, has been investigated and it has been found that excellent control can be exercised over the regio- and stereochemical outcome of the cycloadditions. The cyclopropyl stereochemistry is retained during the reaction, with cis- and trans-cyclopropane isomers providing complementary diastereomeric cycloadducts. Based upon the stereo- and regiochemical control developed from his study, an approach to the tremulane family sesquiterpenes is presented.; The intermolecular [5+2] cycloaddition of vinylcyclopropanes has previously been limited to vinylcyclopropanes activated through siloxy- or alkoxy-substitution. The possibility that this process could be influenced by steric effects prompted the present study, describing the first examples of simple, unactivated, vinylcyclopropanes being utilized to achieve intermolecular [5+2] cycloadditions. A systematic study of the effect of cyclopropane substitution on the rate and efficiency of the cycloaddition is presented. Substitution at the 1-position of the vinylcyclopropane with alkyl or silicon functionality is found to accelerate the cycloaddition. The first studies on the regioselectivity of the intermolecular cycloaddition enabled by this advance show that the cycloaddition proceeds in a highly regioselective fashion, providing efficient access to 1,3,5-differentially trisubstituted cycloheptadienes.; Also described is 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. Optimization of the reaction led to the development of conditions that allow for cycloadditions up to 12-fold faster and with 10-fold less catalyst than previously described, allowing for the economical, large scale (up to 100 mmol) production of substituted cycloheptenones. |
