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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.

In this thesis transition metal promoted cycloadditions of trhee-strained carbocycles were carried out. On one hand, the chemistry of alkydlidenecyclopropenes (ACPs) was explored. Despite the abudant number of cycloadditions involving this systems, their enantioselective versions are scarce. In this context, using a low valent cobalt catalyst, a novel enantioselective intramolecular cycloaddition of ACPs and alkynes was succesfully developed. Moreover, mechanistic experiments and computational analysis of the reaction allowed us to stablish an unkonwk mechanism. In addition, the advantages of cobalt was applied in a intramolecular (3+2+2) cycloaddition of ACPs, alkynes and alkenes construction several polycarbocyclic scaffolds. Moreover, the intramolecular cycloaddition of ACPs with alkenes, allenes and dienes catalysed by cobalt was further analysed. The intermolecular cycloaddition of ACPs and trifluoromethyl ketones was also developed. By employing bulky biaryl phosphines as ligands several exo-methylene trifluoromethyl tetrahydrofurans could be synthetize in good yields albeit in low diastereomeric control. Finally, a novel (3+2) cycloaddition of cyclopropenes tethered to alkynes was accomplished. Employing a low valent cobalt catalyst several cyclopentadienes were synthetize with good efficinect. In addition, the syntehtic utility of this trasnformation was proved by the synthesis of several cyclopentadienyl rhodium complexes.

[ES] La cicloadición 1,3-dipolar entre alquinos y azidas ("Click Chemistry") catalizada por cobre (I), para formar 1,2,3-triazoles, es una de las reacciones más populares debido a su fiabilidad, especificidad y biocompatibilidad. Este tipo de mecanismos tienen el potencial de acortar los procedimientos y optimizarlos consiguiendo una economía atómica del 100%, además tienen la posibilidad de llevar a cabo la reacción en distintas condiciones y en un gran número de disolventes distintos, incluyendo el agua. Esta combinación de factores hace que las reacciones tipo "click" sean de gran utilidad para el diseño y la síntesis de una gran variedad de compuestos en condiciones óptimas de reacción. Un gran avance sería el descubrimiento de una reacción tipo "click" para amidas y esteres, que son compuestos químicos que se encuentran tanto en la naturaleza como en los laboratorios y de los cuales se conocen numerosos métodos sintéticos, sin embargo, estos no suelen ser sostenibles y generalmente requieren de reactivos peligrosos y condiciones violentas de reacción. Por estos motivos, en este trabajo se ha propuesto la síntesis de esteres y amidas a partir de la apertura de anillo de derivados de la ciclopropenona en presencia de aminas y alcoholes según los mecanismos de "Click Chemistry", utilizando distintas condiciones de reacción (temperatura, disolventes, catalizadores, etc.)., [EN] 1,3-dipolar cycloaddition between alkynes and azides catalyzed by copper (I) (click reaction), to form 1,2,3-triazoles, is one of the most popular reactions due to its reliability, specificity, and biocompatibility. Click reactions have the potential to perform shorter procedure and optimize them, achieving an atomic economy of 100%, and operate in different conditions and in many conventional solvents, including water. This combination of factors makes click reactions of great utility for the design and synthesis of a plethora compounds under optimal reaction conditions. A great advance would be the discovery of a click reaction for amides and esters synthesis, which are common chemicals in Nature, industry and academic laboratories. Indeed, a plethora of synthetic methods have been developed over the years, however, these methods are not sustainable and generally require harsh reagents or reaction conditions. For these reasons, in this work has been proposed the synthesis of esters and amides form the ring-opening of cyclopropenones derivatives in the presence of amines and alcohols according to the mechanisms of Click Chemistry.

[ES] La cicloadición 1,3-dipolar entre alquinos y azidas ("Click Chemistry") catalizada por cobre (I), para formar 1,2,3-triazoles, es una de las reacciones más populares debido a su fiabilidad, especificidad y biocompatibilidad. Este tipo de mecanismos tienen el potencial de acortar los procedimientos y optimizarlos consiguiendo una economía atómica del 100%, además tienen la posibilidad de llevar a cabo la reacción en distintas condiciones y en un gran número de disolventes distintos, incluyendo el agua. Esta combinación de factores hace que las reacciones tipo "click" sean de gran utilidad para el diseño y la síntesis de una gran variedad de compuestos en condiciones óptimas de reacción. Un gran avance sería el descubrimiento de una reacción tipo "click" para amidas y esteres, que son compuestos químicos que se encuentran tanto en la naturaleza como en los laboratorios y de los cuales se conocen numerosos métodos sintéticos, sin embargo, estos no suelen ser sostenibles y generalmente requieren de reactivos peligrosos y condiciones violentas de reacción. Por estos motivos, en este trabajo se ha propuesto la síntesis de esteres y amidas a partir de la apertura de anillo de derivados de la ciclopropenona en presencia de aminas y alcoholes según los mecanismos de "Click Chemistry", utilizando distintas condiciones de reacción (temperatura, disolventes, catalizadores, etc.)., [EN] 1,3-dipolar cycloaddition between alkynes and azides catalyzed by copper (I) (click reaction), to form 1,2,3-triazoles, is one of the most popular reactions due to its reliability, specificity, and biocompatibility. Click reactions have the potential to perform shorter procedure and optimize them, achieving an atomic economy of 100%, and operate in different conditions and in many conventional solvents, including water. This combination of factors makes click reactions of great utility for the design and synthesis of a plethora compounds under optimal reaction conditions. A great advance would be the discovery of a click reaction for amides and esters synthesis, which are common chemicals in Nature, industry and academic laboratories. Indeed, a plethora of synthetic methods have been developed over the years, however, these methods are not sustainable and generally require harsh reagents or reaction conditions. For these reasons, in this work has been proposed the synthesis of esters and amides form the ring-opening of cyclopropenones derivatives in the presence of amines and alcohols according to the mechanisms of Click Chemistry.

[ES] La cicloadición 1,3-dipolar entre alquinos y azidas ("Click Chemistry") catalizada por cobre (I), para formar 1,2,3-triazoles, es una de las reacciones más populares debido a su fiabilidad, especificidad y biocompatibilidad. Este tipo de mecanismos tienen el potencial de acortar los procedimientos y optimizarlos consiguiendo una economía atómica del 100%, además tienen la posibilidad de llevar a cabo la reacción en distintas condiciones y en un gran número de disolventes distintos, incluyendo el agua. Esta combinación de factores hace que las reacciones tipo "click" sean de gran utilidad para el diseño y la síntesis de una gran variedad de compuestos en condiciones óptimas de reacción. Un gran avance sería el descubrimiento de una reacción tipo "click" para amidas y esteres, que son compuestos químicos que se encuentran tanto en la naturaleza como en los laboratorios y de los cuales se conocen numerosos métodos sintéticos, sin embargo, estos no suelen ser sostenibles y generalmente requieren de reactivos peligrosos y condiciones violentas de reacción. Por estos motivos, en este trabajo se ha propuesto la síntesis de esteres y amidas a partir de la apertura de anillo de derivados de la ciclopropenona en presencia de aminas y alcoholes según los mecanismos de "Click Chemistry", utilizando distintas condiciones de reacción (temperatura, disolventes, catalizadores, etc.)., [EN] 1,3-dipolar cycloaddition between alkynes and azides catalyzed by copper (I) (click reaction), to form 1,2,3-triazoles, is one of the most popular reactions due to its reliability, specificity, and biocompatibility. Click reactions have the potential to perform shorter procedure and optimize them, achieving an atomic economy of 100%, and operate in different conditions and in many conventional solvents, including water. This combination of factors makes click reactions of great utility for the design and synthesis of a plethora compounds under optimal reaction conditions. A great advance would be the discovery of a click reaction for amides and esters synthesis, which are common chemicals in Nature, industry and academic laboratories. Indeed, a plethora of synthetic methods have been developed over the years, however, these methods are not sustainable and generally require harsh reagents or reaction conditions. For these reasons, in this work has been proposed the synthesis of esters and amides form the ring-opening of cyclopropenones derivatives in the presence of amines and alcohols according to the mechanisms of Click Chemistry.

[ES] La cicloadición 1,3-dipolar entre alquinos y azidas ("Click Chemistry") catalizada por cobre (I), para formar 1,2,3-triazoles, es una de las reacciones más populares debido a su fiabilidad, especificidad y biocompatibilidad. Este tipo de mecanismos tienen el potencial de acortar los procedimientos y optimizarlos consiguiendo una economía atómica del 100%, además tienen la posibilidad de llevar a cabo la reacción en distintas condiciones y en un gran número de disolventes distintos, incluyendo el agua. Esta combinación de factores hace que las reacciones tipo "click" sean de gran utilidad para el diseño y la síntesis de una gran variedad de compuestos en condiciones óptimas de reacción. Un gran avance sería el descubrimiento de una reacción tipo "click" para amidas y esteres, que son compuestos químicos que se encuentran tanto en la naturaleza como en los laboratorios y de los cuales se conocen numerosos métodos sintéticos, sin embargo, estos no suelen ser sostenibles y generalmente requieren de reactivos peligrosos y condiciones violentas de reacción. Por estos motivos, en este trabajo se ha propuesto la síntesis de esteres y amidas a partir de la apertura de anillo de derivados de la ciclopropenona en presencia de aminas y alcoholes según los mecanismos de "Click Chemistry", utilizando distintas condiciones de reacción (temperatura, disolventes, catalizadores, etc.)., [EN] 1,3-dipolar cycloaddition between alkynes and azides catalyzed by copper (I) (click reaction), to form 1,2,3-triazoles, is one of the most popular reactions due to its reliability, specificity, and biocompatibility. Click reactions have the potential to perform shorter procedure and optimize them, achieving an atomic economy of 100%, and operate in different conditions and in many conventional solvents, including water. This combination of factors makes click reactions of great utility for the design and synthesis of a plethora compounds under optimal reaction conditions. A great advance would be the discovery of a click reaction for amides and esters synthesis, which are common chemicals in Nature, industry and academic laboratories. Indeed, a plethora of synthetic methods have been developed over the years, however, these methods are not sustainable and generally require harsh reagents or reaction conditions. For these reasons, in this work has been proposed the synthesis of esters and amides form the ring-opening of cyclopropenones derivatives in the presence of amines and alcohols according to the mechanisms of Click Chemistry.

Cyclopropenes are unsaturated, three-membered ring systems that are highly strained and as a result, serve as highly useful building blocks in the field of synthetic chemistry. The electron rich double bond of cyclopropenes makes them ideal substrates for electrophilic Lewis acids, such as gold catalysts. Gold catalysts readily activate cyclopropenes towards ring-opening and given the strain of these ring systems, reactions are often highly facile and can result in substantial increases in molecular complexity. Thus, the gold-catalysed reactions of cyclopropenes represent a highly versatile field of chemistry, especially considering that substitution around the cyclopropene ring can be used to control regio-, diastereo- and enantioselectivity. Despite this potential however, research into gold-catalysed reactions of cyclopropenes remains relatively undeveloped compared to the gold-catalysed reactions of other C–C multiple bonds (i.e. alkynes, alkenes and allene). It has therefore been the aim of this thesis to help contribute to this field by investigating the rearrangements that occur when derivatives of cyclopropenyl carbinols are reacted with gold catalysts. Cyclopropenyl carbinols are a particularly useful class of cyclopropene given that the alcohol moiety serves as a tethering point for further functionalisation. It has been the discovery of this thesis that cyclopropenyl propargyl ethers, derived from C1-substituted cyclopropenyl carbinols, undergo initial ring-opening followed by a Claisen rearrangement in the presence of a gold catalyst, to form highly substituted furans. Cyclopropenyl allyl ethers can also undergo gold-catalysed ringopening and a Claisen rearrangement (followed by additional chemical transformations) to diastereoselectively form highly substituted tetrahydrofurans. Alternatively, cyclopropenyl sulfonamides obtained from the Mitsunobu coupling of C3-substituted cyclopropenyl carbinols, have also been reacted with gold catalysts. Cyclopropen

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 orthogo

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.

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 orthogo

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 orthogo

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.

Substituted cyclopropenes have recently attracted attention as stable "mini-tags" that are highly reactive dienophiles with the bioorthogonal tetrazine functional group. Despite this interest, the synthesis of stable cyclopropenes is not trivial and their reactivity patterns are poorly understood. Here, the synthesis and comparison of the reactivity of a series of 1-methyl-3-substituted cyclopropenes with different functional handles is described. The rates at which the various substituted cyclopropenes undergo Diels-Alder cycloadditions with 1,2,4,5-tetrazines were measured. Depending on the substituents, the rates of cycloadditions vary by over two orders of magnitude. The substituents also have a dramatic effect on aqueous stability. An outcome of these studies is the discovery of a novel 3-amidomethyl substituted methylcyclopropene tag that reacts twice as fast as the fastest previously disclosed 1-methyl-3-substituted cyclopropene while retaining excellent aqueous stability. Furthermore, this new cyclopropene is better suited for bioconjugation applications and this is demonstrated through using DNA templated tetrazine ligations. The effect of tetrazine structure on cyclopropene reaction rate was also studied. Surprisingly, 3-amidomethyl substituted methylcyclopropene reacts faster than trans-cyclooctenol with a sterically hindered and extremely stable tert-butyl substituted tetrazine. Density functional theory calculations and the distortion/interaction analysis of activation energies provide insights into the origins of these reactivity differences and a guide to the development of future tetrazine coupling partners. The newly disclosed cyclopropenes have kinetic and stability advantages compared to previously reported dienophiles and will be highly useful for applications in organic synthesis, bioorthogonal reactions, and materials science.