Donor–acceptor cyclopropanes are a versatile class of synthetic intermediates, compatible in a broad range of ring-opening reactions and formal cycloadditions, and employed in numerous natural product syntheses. We have developed new Lewis acid mediated cycloadditions for the synthesis of five-membered heterocycles, and applied existing a transition metal catalyzed cyclopropane cycloaddition method toward the synthesis of complex alkaloids. First, described is the development of a Lewis acid mediated (3 + 2) cycloaddition of donor–acceptor cyclopropanes with isocyanates, isothiocyanates and carbodiimides. This reaction was found in certain cases to proceed with excellent stereochemical fidelity, providing access to an array of enantioenriched thioimidates and amidines. Second, we targeted the Melodinus alkaloids for total synthesis due to their unique structural features. Synthetic efforts toward scandine, the parent of the natural product family, are detailed herein. Our approach features a palladium catalyzed formal (3 + 2) cycloaddition of a vinyl cyclopropane and a β-nitrostyrene to rapidly assemble the central cyclopentane core of the natural product. Initial efforts focused on the synthesis and application of a 1,1-divinylcyclopropane to the formal (3 + 2) cycloaddition reaction, whereas later work entailed the use of a mono-vinylcyclopropane with the goal of installing the second requisite vinyl group at a later stage using modern C–H functionalization technologies.