Hydrofunctionalization is a powerful tool to add fragments across unsaturated building blocks to furnish more complex structures and introduce new stereocenters. My PhD studies have focused on Rh and Cu-catalyzed hydrofunctionalization to build both carbon-carbon and carbon- heteroatom bonds in a stereoselective and regioselective manner. With careful pairing of transition-metals and ligands, we successfully accessed chiral α,α-disubstituted-α-amino acid (α,α- disubstituted-α-AA) precursors, chiral cyclopropyl phosphines and N-arylated pyrazole motifs.

In chapter 1, the study is focused on Rh–H catalyzed hydrofunctionalization of alkynes with α-nitroesters to synthesize α,α-disubstituted-α-AA building blocks. The method generates biologically important precursors bearing two contiguous stereocenters with high enantioselectivity, diastereoselectivity and regioselectivity. The transformation involves the Rh– H catalyzed isomerization of alkynes into Rh-π-allyl electrophiles through an allene intermediate. By trapping with nucleophiles, different allylic compounds can be formed stereoselectively. Mechanistic studies supported the presence of Rh–H and allene intermediates in the catalytic cycle. The allylic α,α-disubstituted-α-nitroester can be readily reduced to the corresponding amino ester with indium powder. Building on this report, I also developed a Rh–H catalyzed nitroalkane addition to alkynes to afford allylic nitro compounds as chiral amine precursors. Although high diastereoselectivity was achieved with the transformation, optimization of enantioselectivity still remains challenging. The initial results of this study are included at the end of chapter 1.

In chapter 2, we developed a Cu-catalyzed hydrophosphination of cyclopropenes to build chiral cyclopropyl phosphines, which are biologically and chemically unique. A range of different cyclopropyl phosphines bearing different stereoelectronics can now be accessed. Supported by both experimental results and computational studies, we propose the transformation generates a Cu-phosphido species, which facilitates migratory insertion followed by protodemetalation to afford the desired products. Density function theory (DFT) calculations suggested migratory insertion is the rate- and stereo-determining step. With NMR studies, we identified a dimeric resting state structure, which can be brought back to the active monomer with addition of DBU. Transition state analysis indicates the stereoselectivity comes from a combination of dispersion and steric interactions. Insights of this study helps future phosphine ligand design and chiral phosphine synthesis.

In chapter 3, a Cu-catalyzed regiodivergent N-arylation of unsymmetric pyrazoles with aryne intermediates is investigated. The method provides a new vector for late-stage functionalization of pyrazole compounds to selectively access both N-arylated regioisomers. We propose pyrazole binds with Cu to form a Cu-pyrazolate which undergoes a 5-centered amino- cupration with an aryne intermediate to afford the desired arylated pyrazoles. By enforcing steric or non-covalent interactions between ligands and the Cu catalyst, we can control the Cu-pyrazolate formation with either more hindered nitrogen atom (Nα) or less hindered nitrogen atom (Nβ). The corresponding 5-centered transition structure undergoes bond formation with the aryne fragment with high Nα- or Nβ- selectivity. The methodology is compatible with a wide scope of pyrazoles bearing different stereoelectronics; we exemplify more than 60 different Nα- and Nβ-arylated pyrazoles with moderate to high regioselectivity. We also performed the transformation with different aryne precursors which demonstrates the generality of this reaction.