Thesis advisor: X. Peter Zhang / Thesis advisor: Shih-Yuan Liu / Recent advancements have witnessed the deployment of radical chemistry for the construction of diverse vital molecular structures. Among these advances, metalloradical catalysis (MRC) has been continuously demonstrated as a practical and unique approach whereby open-shell metal-centered catalysts are exploited to initiate and regulate homolytic radical processes. As stable 15e-metalloradicals, Co(II) porphyrin complexes have been proven effective in activating multifarious precursors to forge unprecedented metal-stabilized organic radicals and are capable of conducting various homolytic processes with well-confined reactivity and selectivity thanks to the support of D2-symmetric chiral porphyrin ligands. Nevertheless, the detailed mechanistic studies of the metalloradical activation of precursors, H atom abstraction (HAA), radical addition, and asymmetric induction have been largely underdeveloped. Therefore, this dissertation mainly focuses on the mechanistic investigations of radical amination and hydroxylation reactions via Co(II)-based MRC with routine experimental methods and powerful computational tools. Chapter 1: Developments on Asymmetric N-Heterobicyclization Reactions of Alkenes via Enantioselective Transition Metal Catalysis. We have viewed recent developments of asymmetric N-heterobicyclization of alkenes rendered by enantioselective transition metal catalysis incorporating first-row, second-row, and third-row transition metals. Chapter 2: Enantioselective Radical N-Heterobicyclization with A New Mode of Asymmetric Induction. We have developed asymmetric radical N-heterobicyclization of allyl sulfamoyl azides with the support of a D2-symmetric chiral bridged amidoporphyrin HuPhyrin ligand. We also revealed a new mode of asymmetric induction that the chirality of a kinetically stable chiral radical center directs the enantioselectivity of the resulting aziridines. The stable chiral radical center was formed from highly challenging enantiofacial selective radical addition and underwent subsequent stereospecific ring closure. Chapter 3: Catalytic Radical N-Heterocyclization by Metalloradical C–H Amination involving 1,7-Hydrogen Atom Abstraction. We have examined intramolecular HAA reaction and pushed its boundary from well-explored 1,5-HAA and 1,6-HAA to unusual 1,7-HAA executed by α-Co(III)-aminyl radicals, which led to the discovery of 1,7-C–H amination and 1,7-HAA triggered indirect 1,5-C–H amination with sulfamoyl azides. Chapter 4: Metalloradical Activation of Alkyl Hydroperoxides for Catalytic Radical C−H Hydroxylation. We have presented comprehensive studies on the metalloradical activation of oxidants, especially cumene hydroperoxide. We have identified ∞-Co(III)-hydroxide cumyloxyl radical species and utilized it for the development of radical C–H hydroxylation with cumyl alcohol as the byproduct. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Xiao-Xiang Zhang / Thesis advisor: James Morken / This dissertation will present three projects focusing on the development of stereoselective radical cascade reactions via metalloradical catalysis (MRC) using Co(II) D2-symmetric chiral amidoporphyrins [Co(D2-Por*)] as the catalyst. The first project demonstrated the feasibility of applying MRC for asymmetric radical cascade processes by achieving an enantioselective radical bicyclization of 1,6-enynes with diazo compounds, which constructed multi-substituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers and one trisubstituted alkene. Detailed mechanistic studies including EPR studies and DFT calculation unveiled a radical-based stepwise mechanism. The synthetic utility of this reaction was demonstrated by a series of diastereoselective transformations of the bicyclic products. In the second project, this strategy was expanded to the application of Co(II)-based MRC to catalyze radical cascade reactions involving hydrogen-atom abstraction (HAA) process. A broad array of homopropargyl ethers reacted with diazo compounds to generate enantiomerically enriched ɑ,β-disubstituted tetrahydrofurans in good yields with high diastereoselectivities and enantioselectivities. The third project explored the utilization of the established strategy to accomplish more challenging bicyclization of 1,6,8-dienynes for the construction of cycloheptadiene-fused tetrahydrofurans in regio- and diastereoselective fashions. Such 5,7-fused ring system has been widely found in natural products and bioactive species. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: X. Peter Zhang / Asymmetric C–H functionalization represents one of the central topics in modern organic chemistry, which allows for the direct installation of functional groups onto ubiquitous C–H bonds in organic molecules. Among numerous elegant strategies, transition metal-catalyzed C–H alkylation with diazo compounds represents one of the most powerful methods for C–C bond formation. Different from Fischer metallocarbene-based C–H insertion reactions, cobalt(II)-based metalloradical catalysis (MRC) is recently proven to be capable of activating acceptor/acceptor diazo compounds for radical C–H alkylation reactions via H-atom abstraction. In this dissertation, we have developed several systems by utilizing less-explored aryl and alkyl diazomethanes as new radical precursors for highly enantioselective radical C–H alkylation reactions, which permit the efficient synthesis of different optically active heterocyclic compounds. First, we have demonstrated the feasibility of using aryl aldehyde-derived sulfonylhydrazones as new radical precursors for enantioselective radical C–H alkylation to synthesis enantioenriched 2,3-dihydrobenzofuran derivatives. Notably, a general and mild way for in situ generation of diazo compounds have been identified by using 2,4,6-triisopropyl sulfonyl hydrazone as diazo precursor, which allow us to regulate the reaction temperature to achieve the high enantioselectivity for the desired radical reactions. Second, the utility of Co(II)-based MRC has been further highlighted by enantioselective indoline synthesis. Through the design and synthesis of new catalysts, the system is shown to have a broad spectrum of substrate scope, forming various 2-substituted indolines with up to 98% yield and 96% ee. A series of mechanistic studies further support the underlying stepwise radical alkylation pathway. Finally, we further expand the applicability of MRC to even more challenging diazo compounds, aliphatic diazomethanes. Starting from alkyl aldehyde-derived sulfonylhydrazones as diazo precursors, the Co(II)-based radical alkylation reactions allow for the enantioselective synthesis for common 2-substituted tetrahydrofuran structures with high yields and excellent enantioselectivities. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: X. Peter Zhang / Highly strained three membered heterocycles are a common motif in many biologically relevant molecules and represent a versatile building block for organic synthesis. Of special interest for asymmetric synthesis is the construction of enantioenriched aziridines and epoxides, which are often used as chiral synthons to introduce heteroatoms in a stereoselective fashion. Among different elegant strategies, the direct aziridination and epoxidation of the ubiquitous alkene functionality represents one of the most powerful methods to access these motifs. Given the synthetic importance of the enantioenriched smallest aza- and oxaheterocycles, the focus of this dissertation is centered on the design and use of chiral cobalt porphyrins as catalysts to develop new methodologies for the asymmetric radical aziridination and epoxidation of alkenes.In the first part of this dissertation, we focused on using carbonyl azides as nitrogen source for the enantioselective radical aziridination of alkenes. Despite its high functionality and versatility for further derivatization, carbonyl azides have never been reported as nitrogen source for intermolecular asymmetric alkene aziridination. In the second part of this dissertation, we focused on opening up a new area of research, which involves the generation and characterization of the unprecedented cobalt porphyrin-supported oxygen-centered radical species. Finally, we demonstrated the synthetic utility of these new radical species by developing a new system for the asymmetric epoxidation of alkenes through the design and development of a novel family of catalyst named “JesuPhyrin”. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Peter X. Zhang / Thesis advisor: James P. Morken / Radical reactions have attracted continuous research interest in recent year considering their diverse reactivities. Hydrogen-atom abstraction (HAA), as one type of the most well-explored radical reactions, has been identified as one of powerful tools for C–H functionalization. Reactions involving 1,4-HAA, which is typically a challenging process both entropically and enthalpically, are rather scarce, while 1,5-HAA have been well demonstrated for variety of synthetic applications. Guided by the concept of metalloradical catalysis (MRC), 1,4-HAA was for the first time utilized as the key step to achieve asymmetric construction of chiral ring structures: cyclobutanones, azetidines and tetrahydropyridines. The design of different D2-symmetric chiral amidoporphyrin as the supporting ligand is the key to all these transformations. The reactions can be conducted under mild conditions, affording corresponding ring structure in good yields with excellent selectivity. Furthermore, The combined computational and experimental studies have shed light on the mechanistic details of these new asymmetric radical intramolecular C–H alkylation processes, which are fundamentally different from existing catalytic systems involving metallocarbenes for concerted C–H insertion. We envision that these asymmetric radical processes via Co(II)-based MRC could become an alternative method for important chiral ring structures synthesis and potentially provide new opportunities for complex molecule construction. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: X. Peter Zhang / Chapter 1. Co(II)-Based Metalloradical Catalysis for Stereoselective Radical Cyclopropanation of Alkenes This Account summarizes our group’s recent efforts in developing metalloradical catalysis as a one-electron approach for catalytic radical cyclopropanation of alkenes with diazo compounds. Chapter 2. Asymmetric Radical Process for General Synthesis of Chiral Heteroaryl Cyclopropanes We have developed a Co(II)-based metalloradical system that is highly effective for asymmetric radical cyclopropanation of alkenes with in situ-generated heteroaryldiazomethanes. Through fine-tuning the cavity-like environments of newly developed D2-symmetric chiral amidoporphyrins as the supporting ligand, the optimized Co(II)-based metalloradical system is broadly applicable to pyridyl and other heteroaryldiazomethanes for asymmetric cyclopropanation of a wide range of alkenes, providing general access to valuable chiral heteroaryl cyclopropanes in high yields with excellent diastereoselectivities and enantioselectivities. Chapter 3. Enantioselective Metalloradical 1,6-C–H Alkylation of In Situ-Generated Alkyldiazomethanes for Synthesis of Chiral Piperidines We have disclosed an effective Co(II)-based metalloradical system as a fundamentally different approach to harness the potential of 1,6-HAA radical process, enabling asymmetric 1,6-C–H alkylation of in situ-generated alkyldiazomethanes to construct chiral piperidines. Supported by an optimal D2-symmetric chiral amidoporphyrin ligand, the Co(II)-catalyzed alkylation system is capable of activating a wide array of alkyldiazomethanes containing C(sp3)–H bonds with varied steric and electronic properties, providing access to chiral piperidines in good to high yields with high enantioselectivities from readily accessible 4-aminobutanal derivatives. In addition to practical attributes, such as operational simplicity and mild conditions, the metalloradical system is highlighted by its tolerance to different functional groups as well as compatibility with heteroaryl units. Chapter 4. Design and Synthesis of A Novel D2-Symmetric Chiral Porphyrin for Co(II)-Based Metalloradical Catalysis A novel D2-symmetric chiral amidoporphyrin derived from chiral cyclopropanecarboxamide containing diphenyl units has been effectively constructed based on Co(II)-catalyzed asymmetric cyclopropanation of alkenes. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: X. Peter Zhang / Among recent advances in devising different strategies for stereoselective homolytic reactions, metalloradical catalysis (MRC) has emerged as a conceptually new approach for controlling stereoselectivity of radical reactions. As stable metalloradicals, cobalt(II) complexes of D₂-symmetric chiral amidoporphyrins [Co(D₂-Por)] have proven to be effective catalysts for homolytically activating a series of diazo compounds to generate α-Co(III)-alkyl radicals for various C-centered radical transformations with well-confined reactivity and selectivity. Nevertheless, the applications of donor-, donor/donor- and alkyl diazo compounds have been largely underdeveloped. This dissertation mainly focuses on how the chemistry of these types of diazo compounds was initiated by using commonly available aldehyde-derived sulfonylhydrazones as diazo surrogates. In the context of Co(II)-MRC, in situ-generated diazo compounds can be effectively activated for various asymmetric radical transformations, including intermolecular radical cyclopropanation of alkenes and intramolecular radical alkylation of C–H bonds. First, as a proof of concept, we have demonstrated the feasibility of using aryl aldehyde-derived sulfonylhydrazones as new radical precursors for diastereo- and enantioselective radical cyclopropanation of alkenes, and proven that the diazo in situ-generation protocol is well compatible with the catalytic radical process. Second, we have expanded the application of Co(II)-based MRC to a new territory by employing aliphatic diazo compounds for asymmetric cyclopropanation. The system is highlighted by the excellent enantioselectivity together with remarkable cis-selectivity. Finally, with the utilization of linear aliphatic aldehyde sulfonylhydrazones as diazo precursors, we have presented a new radical cyclization mode, involving hydrogen atom abstraction and radical substitution, for enantioselective synthesis of common five-membered rings via radical C–H alkylation. The system would offer a new retrosynthetic paradigm for construction of ring structures, where C–C bond can be disconnected as common C=O and C–H units of linear aldehydes. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: X. Peter Zhang / Thesis advisor: James P. Morken / Chapter 1. Stereoselective Cyclopropanation of Alkenes with Alkynyl- and Vinyl-Substituted Diazo Compounds Alkynyl- and vinyl-substituted cyclopropanes are ubiquitous structural motifs in drug molecules and bioactive compounds. In addition, alkynyl- and vinyl-substituted cyclopropanes may serve as useful intermediates for stereoselective organic synthesis. Metal-catalyzed cyclopropanation of alkenes with alkynyl- and vinyl-substituted diazo compounds offers a potentially general approach for stereoselective construction of these valuable three-membered ring structures. This chapter summarizes the development of stereoselective olefin cyclopropanation with alkynyl- and vinyl-substituted diazo compounds. Chapter 2. Metalloradical Activation of In Situ-Generated α-Alkynyldiazomethanes for Asymmetric Radical Cyclopropanation of Alkenes We have developed a Co(II)-based metalloradical system that is highly effective for asymmetric radical cyclopropanation of alkenes with in situ-generated α-alkynyldiazomethanes. Through fine-tuning the cavity-like environments of D₂-symmetric chiral amidoporphyrins as the supporting ligand, the optimized Co(II)-based metalloradical system is broadly applicable to different alkynyldiazomethanes for asymmetric cyclopropanation of a broad range of alkenes, providing general access to valuable chiral alkynyl cyclopropanes in high yields with excellent diastereoselectivities and enantioselectivities. Chapter 3. Asymmetric Radical Process for Cyclopropanation of Alkenes with In Situ-Generated α-Vinyldiazomethanes We have demonstrated the feasibility of using vinyl aldehyde-derived sulfonylhydrazones as new metalloradicophiles for the generation of allylic radicals. Through fine-tuning the cavity-like environments of D₂-symmetric chiral amidoporphyrins as supporting ligands, the key α-Co(III)-allylic radical intermediates are exclusively engaged in the highly asymmetric cyclopropanation with wide-ranging alkenes in the optimized Co(II)-based metalloradical system, as shown broadly applicable to activate different α-vinyldiazomethanes. Chapter 4. Asymmetric Synthesis of Vinyl-Substituted Cyclopropanes by Radical C-H Alkylation from Alkynes and In Situ-Generated Alkyldiazomethanes via Co(II)-Based Metalloradical Catalysis We have successfully expanded the application of Co(II)-based MRC by applying in-situ generated alkyldiazomethanes as new radical precursors for stereoselective synthesis of vinyl-substituted cyclopropanes by radical cascade C-H alkylation of alkynes. Through fine-tuning of D₂-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of vinyl-substituted cyclopropanes in high yields with excellent diastereoselectivities and good enantioselectivities. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Xiaoxiang Peter Zhang / Thesis advisor: James P. Morken / Diazomalonates have been demonstrated, for the first time, as effective radical precursors for asymmetric radical cyclopropanation of alkenes via Co(II)-based metalloradical catalysis (MRC). With an optimized D2-symmetric chiral amidoporphyrin as the supporting ligand, the Co(II)-based metalloradical system can efficiently activate unsymmetrical methyl phenyl diazomalonate (MPDM) for the asymmetric cyclopropanation of alkenes, enabling stereoselective construction of 1,1-cyclopropanediesters bearing two contiguous chiral centers, including at least one all-carbon quaternary stereogenic center. The Co(II)-catalyzed asymmetric cyclopropanation, which operates at room temperature without slow addition of the diazo compound, is generally applicable to a broad range of olefin substrates and tolerates various functionalities, providing a streamlined synthesis of chiral 1,1-cyclopropanediesters in high yields with high level of control in both diastereoselectivity and enantioselectivity. Mechanistic studies on the cyclopropanation reactions, including the use of (E)- and (Z)-b-deuterostyrenes, support the underlying stepwise radical pathway for the Co(II)-catalyzed cyclopropanation. In addition to functioning as effective 1,3-dipoles for stereospecific formation of five-membered ring structures, the resulting enantioenriched methyl phenyl (E)-1,1-cyclopropanediesters serve as useful building blocks for the synthesis of different 1,1-cyclopropanediesters, 1,1-cyclopropaneestercarboxylic acids and 1,1-cyclopropaneesteramides while maintaining the original stereochemistry. Additionally, the enantioenriched (E)-1,1-cyclopropanediesters can be converted to (Z)-diastereomers without affecting the high enantiopurity. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.