Regio- and Diastereoselective Carbometalation Reaction of Cyclopropenes

[Image: see text] The various facets of the chemistry of cyclopropane derivatives, the smallest carbocycle, are amazingly diverse and continue to fascinate theoreticians, synthetic or structural chemists having interest in fundamental physical, medicinal chemistry, and natural product synthesis. The challenges generated by this intriguing cyclic arrangement of only three tetravalent carbons represent a wide area of the chemical spectrum. From fundamental aspects of bonding through the synthesis of highly strained molecules, the understanding of the mode of action in biological systems to the selective cleavage into acyclic substrates makes the chemistry of these small rings fascinating. Therefore, efficient routes to prepare differently polysubstituted cyclopropanes have always been of a primordial importance. In the past decade, we and others have expanded the scope of the carbometalation reaction of cyclopropenes as a broad and general method to the formation of stereodefined cyclopropane derivatives. Although cyclopropenes, with their even higher strain energy, easily undergo addition reactions of organometallic reagents, their carbometalation reactions generate new regio-, diastereo-, and enantioselectivity issues that needed to be addressed. These various stereochemical aspects accompanied our research from its origins to today, and we are proposing in this Account, a didactic overview of the different ways by which cyclopropenes can lead to the formation of polysubstituted cyclopropanes or open-products possessing several stereogenic centers as a single regio- and diastereomer. We initially launched our research campaign on the chemistry of these strained three-membered rings by the regio- and diastereoselective copper-catalyzed carbomagnesiation of enantiomerically enriched cyclopropenyl carbinols. The directing alcohol governed both the regio- and diastereoselectivity of the addition and also served as a good leaving group as it undergoes a selective 1,2-elimination reaction to provide enantioenriched alkylidenecyclopropanes in excellent yields and enantiomeric excesses. Then, we turned our attention to the regio- and stereoselective synthesis of stereodefined tri- and tetrasubstituted cyclopropanes through the diastereoselective addition to sp(2)- monosubstituted cyclopropenyl ester derivatives. With the aim to further expand this concept to the formation of penta- and hexa-substituted cyclopropanes as single isomer, we had first to design the preparation of the required 1,2-disubstituted cyclopropenes that would control the regioselective addition of the organometallic derivatives. The synthesis of penta- and hexa-substituted cyclopropanes was then reported for the first time as a single regio- and diastereomer. It should be noted that the in situ formed cyclopropyl-metal intermediate is configurationally stable and can be subsequently functionalized with pure retention of the configuration by addition of electrophiles. Then, the enantioselective-catalyzed carbometalation reaction of achiral cyclopropenes allowed the synthesis of several new classes of cyclopropane derivatives in high enantiomeric ratios. Finally, by combining the regio- and diastereoselective carbometalation reaction of a cyclopropene with a subsequent reaction of the resulting cyclopropylmetal species, a selective carbon–carbon bond cleavage was observed to lead to the preparation of acyclic substrates possessing several stereocenters including a quaternary carbon stereogenic center. Our original vision of using strain within an embedded double bond in a three-membered ring has provided new routes to the stereoselective synthesis of polysubstituted cyclopropanes and has been extremely successful, as it represents a current new tool for the synthesis of persubstituted cyclopropanes as a single diastereomer.