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Activated cyclopropanes have been extensively used in synthetic chemistry as precursors for cycloaddition reactions. The rationale behind this is their ability to undergo ring-opening when activated by a Lewis acid, this can be enhanced further by the presence of a carbocation stabilising group like electron-rich aromatics. The stabilised dipole formed after ring opening can be trapped with suitable electrophiles such as imines and aldehydes via a [3+2] cycloaddition reaction. This results in the synthesis of pyrrolidines and tetrahydrofurans in excellent yields but moderate diastereoselectivity. Similarly, 6-membered heterocycles can be formed via a [3+3] cycloaddition reaction of activated cyclopropanes with nitrones. Now to extend the scope of the methodology, a [3+3] dipolar cycloaddition has been developed using activated 2,3 disubstituted cyclopropane diesters to access a range of highly functionalised oxazines in moderate to good yields (50-75%) and with reasonable diastereoselectivity. The use of activated symmetrical disubstituted cyclopropanes afforded the desired oxazines in a regio- and diastereocontrolled manner, while the use of unsymmetrical cyclopropanes significantly reduced the diastereoselectivity of the reaction. The stereochemistry outcome of the reaction developed was determined by nOe analyses and X-ray diffraction structures could be recorded in some examples. A new methodology has also been developed to gain access to novel N-heterocyclic- and phenol- substituted cyclopropanes in one step from the corresponding cyclopropene via a conjugated addition.

A catalytic organometallic addition-ring opening sequence of cyclopropenes that enables the efficient and highly stereoselective synthesis of multisubstituted alkenes has been developed. A possible mechanism of organoaluminium reaction is proposed. The metalloenolate resulting from ring opening can be trapped with various electrophiles, enabling a rapid increase in molecular complexity in a one-pot operation. Also, in the presence of stoichiometric magnesium halides, a range of bis-activated cyclopropenes undergo highly stereoselective ring-opening reactions to produce multisubstituted alkenyl halides. The halogen nucleophile promotes Lewis-acid mediated regioselective SNVσ attack at the sp2-carbon of cyclopropene, resulting in the formation of acyclic conjugate enolate, which can be trapped with enones to furnish more highly functionalised products. At last, copper-catalysed asymmetric conjugate reductions of β,β'-disubstituted 2-alkenylheteroarenes are reported. A range of nitrogen-containing aromatic heterocycles are able to provide effective activation of an adjacent alkene for highly enantioselective catalytic conjugate reduction reactions. Extension of the general concept to other classes of heteroarenes has been proven successful. Further manipulation of the condition is required to tolerate more hindered heteroarene substrates.

Hydroamination of cyclopropenes presents an appealing approach to increase molecular complexity. In this study we explore an earth-abundant copper-catalyzed hydroamination of cyclopropenes with pyrazoles and structurally related heterocycles under mild conditions with high regio-, diastereo-, and enantiocontrol. The observed regioselectivity favors the more hindered nitrogen of the pyrazole. Experimental and DFT studies support a unique mechanism featuring a five-centered aminocupration.

Bioorthogonal chemical reporters are small functional groups that can be metabolically incorporated into biomolecules by the cell’s native metabolic machinery. These moieties can be covalently modified with probes for detection or isolation. I applied this strategy to profile glycoproteins in Toxoplasma gondii, a prevalent intracellular parasite that infects nearly one-third of the world's population and may cause life-threatening conditions in immunocompromised patients. Using the bioorthogonal chemical reporter strategy, I identified a large, diverse set of glycosylated proteins in T. gondii including some previously unannotated proteins likely involved in modulating host-parasite interactions.In addition to glycosylated structures, parasites and host cells exchange numerous other metabolites. Simultaneous monitoring of these communication pathways requires multiple cell-compatible reactions that can be used concurrently, or “mutually orthogonal” bioorthogonal chemistries. Unfortunately, the existing toolbox of bioorthogonal chemistries is rather sparse, limiting our ability to look at multiple biomolecules in tandem. As part of Prescher lab, I have contributed to the development of novel chemical reporters for simultaneous profiling of host-pathogen crosstalk. My labmates and I established a new bioorthogonal chemical reaction—a cycloaddition between 1,3-disubstituted cyclopropenes and tetrazines—that can be used in living systems. Excitingly, this reaction can be used in tandem with common azide-alkyne chemistries for multi-component imaging. We also demonstrated that 1,3-disubstituted cyclopropenes can be used concurrently with isomeric cyclopropenes—3,3- cyclopropenes—in biological labeling applications. Both of these molecules harbor unique reaction preferences, enabling them to be used simultaneously. This was noteworthy result, since the structures of these cyclopropenes only differ by the placement of a single methyl group. I also developed another orthogonal chemical reporter for use in multi-component applications: methylene cyclopropane. This molecule exhibits unique cycoaddition reactivities and is poised to join the ranks of useful chemical reporters.

Bioorthogonal chemistries enable the selective visualization and identification of biomolecules in complex cellular environments. Significant advances in the speed and selectivity of these reactions have been reported over the past few years. Despite these successes, challenges remain in applying bioorthogonal chemistries to studies of complex biological functions. Many bioorthogonal reagents cross-react with one another, limiting their utility for visualizing multi-component processes. Additionally, many bioorthogonal reagents are not small or stable enough to label native biomolecules in living systems. To address these issues, I have developed new classes of functionalized cyclopropenes for bioorthogonal labeling experiments. These small motifs are stable in cells and other environments, yet robustly reactive with tetrazines and various 1,3-dipoles. Cyclopropenes can also be readily tuned to elicit desired covalent reactivity, facilitating the development of “mutually orthogonal” bioorthogonal transformations. I utilized these bioorthogonal cyclopropene chemistries to target glycans and proteins, as well as to tag cells with imaging agents for in vivo cell tracking.