Synthesis of Densely Functionalized Cyclopropanes via Diastereoselective Nucleophilic Additions to in Situ Generated Cyclopropenes

This thesis is concerned with the development and application of methods for the diastereoselective synthesis of substituted cyclopropanes. The methodology described in this dissertation is based on the addition of nucleophiles to highly reactive cyclopropene intermediates, to which a variety of oxygen and nitrogen-based nucleophiles can be efficiently employed in this transformation. The presented methodology provides easy access to di-, tri- and tetrasubstituted cyclopropanes which is divided into three chapters and describes not only the methodology developed in our research group but also other synthetic routes to densely substituted cyclopropanes. Chapter one is a review of synthetic methodologies for the preparation of densely substituted chirally-rich cyclopropanes with three stereocenters. The first part of the chapter will describe the stereoselective addition of zinc carbenoids to substituted alkenes. The following section will cover recent advances in the field of transition-metal-catalyzed carbene chemistry. Other methods including Michael-initiated ring closure and C-H activation reactions will be discussed in the final part of chapter one. Chapter two focuses on intermolecular formal nucleophilic substitution of bromocyclopropanes with azoles and anilines. The developed methodology aims for the construction of stereodefined di- and trisubstituted cyclopropanes. Formal substitution of bromocyclopropanes proceeds via the dehydrohalogenation of bromocyclopropane generating cyclopropene in situ followed by subsequent addition of a nitrogen-based nucleophile with efficient selectivity control achieved by thermodynamically driven epimerization of enolizable carboxamides or directing effect of a substituent on a three-membered cycle. Chapter three describes a highly efficient and diastereoselective synthesis of tetrasubstituted donor-acceptor cyclopropanes that can be obtained in a homochiral form from corresponding bromocyclopropyl carboxylic acids. A single chiral center on bromocyclopropane dictates the configuration of the other two stereocenters that are successively installed via a sterically controlled addition of a nucleophile to a chiral trisubstituted cyclopropene, followed by a thermodynamically driven epimerization of the resulting enolate intermediate. This new "dual-control" strategy was successfully employed to the synthesis of densely substituted cyclopropanes in inter- and intramolecular fashion