Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Justin M. Lopchuk, Ph.D.

Co-Major Professor

James Leahy, Ph.D.

Committee Member

Jianfeng Cai, Ph.D.

Committee Member

Uwe Rix, Ph.D.

Keywords

Electrophilic amination, Methodology development, Peptidomimetics

Abstract

Synthetic organic chemistry has long served as a driver of innovation in the drug discovery and development process. Given the prevalence of the nitrogen atom in small molecule drugs, improved methods for C–N bond installation are in high demand. Heteroatom transfer reagents such as oxaziridines and diazirines can be used to selectively deliver nitrogen atom(s) to organic compounds. Herein, I’ll describe my work utilizing Armstrong’s oxaziridine (TBDOT) in peptide backbone modification, and diazirines (TPD) in the development of a hydroamination reaction.

Peptide backbone N-amination has emerged as an attractive peptidomimetic strategy in the design of amyloid aggregation inhibitors. In addition to maintaining sidechain functionality, critical for biomolecular recognition, the incorporation of α-hydrazino acid residues to the backbone of a peptide conserves key hydrogen-bonding interactions, important not only for peptide folding, but target binding. The work detailed below describes the synthesis of chiral α-hydrazino acids using TBDOT as a nitrogen transfer reagent. These N-aminated monomers were used in the synthesis of N-aminated hexapeptide mimics modeled after the core hydrophobic sequence of amyloid beta (Aβ42). A key design feature was the incorporation of N-amino substituents at alternating backbone amides, allowing for an intact hydrogen-bonding edge and an N-aminated inhibitor blocking edge. Thioflavin T fluorescence assays, circular dichroism measurements, and transmission electron microscopy were used to evaluate the inhibition potential of these mimics, and one di-aminated analog emerged from this study as an effective inhibitor of Aβ42 aggregation.

Historically, diazirines have been used in chemical biology as carbene precursors, however, Krespan and Barton showed, over 30 years ago, that diazirines can also be used as electrophilic sources of nitrogen. In both reports, however, only a single nitrogen atom was retained in the imine products. In addition, either an excess of substrate or reagent was necessary for the transformation to occur in an efficient manner. Our group has demonstrated that diazirines can be used in an efficient decarboxylative amination reaction where both nitrogen atoms are retained in the highly diversifiable diaziridine products. In addition, we showed applications of this work to fluorous phase synthesis, and demonstrated our method’s utility in the synthesis of a wide array of heterocycles.

In an attempt to further expand the diazirine chemical space, we sought to develop a hydroamination reaction, employing diazirines as nitrogen transfer reagents. We began the method development process by reacting TPD with unsymmetrical olefins under manganese catalysis. Although this transformation was very robust, no regioselectivity was observed. Both the Markovnikov and anti-Markovnikov products were isolated in a 1:1 ratio, nevertheless, this method worked well in the hydroamination of symmetrical olefins. After a series of additional optimization experiments, we were able to develop a completely regioselective hydroamination reaction. When the model substrate was reacted under cobalt catalysis, the Markovnikov addition product was isolated in excellent yield. With optimized conditions in hand, we next set out to examine the functional group tolerance of the reaction conditions, the utility of our method in the synthesis of pharmaceutically relevant compounds, and applications of our method to the 15N stable isotopic labeling of pharmaceutical compounds.

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