Herein, we document our recent efforts to expand the scope of Bronsted base-containing peptide catalysis. This body of work has primarily focused on rationally designed peptides that take advantage of well-defined β-turn scaffolds to achieve ambifunctional catalytic mechanisms. The structure of the L-β-dimethylaminoalanine (Dmaa)-containing catalysts has also proven to be a focal point of this research, and attempts are made in each case to better understand the delicate interplay among primary sequence elements, secondary structural attributes, and reaction outcomes (e.g., enantioselectivity). Another aspect of this work is the stereochemical complexity of the reactions that we have investigated; dynamic stereochemistry is a common theme throughout these projects. Mechanistic insights have also been gleaned using both experimental and computational methods, which have contributed to the advancement of our understanding of these complex reaction coordinates.
In Chapter 2, we report the development and optimization of a Dmaa-containing tetrapeptide that catalyzes the methanolytic DKR of oxazol-5(4H)-ones (oxazolones) with high levels of enantioinduction.39 Oxazolones possessing benzylic-type substituents are found to perform better than others, providing methyl ester products in 88:12 to 98:2 er. The mechanism of this peptide-catalyzed process was investigated through truncation studies and competition experiments. High-field 2D-NOESY analysis was performed to elucidate the solution-phase structure of the peptide, and we present a plausible model for catalysis. Preliminary multidimensional analysis of the substrate scope provides additional insights into the factors that contribute to high selectivity.
Chapter 3 describes the study of an N,N-unsymmetrically disubstituted tertiary benzamide that exhibits two axes of stereochemical relevance—one defined through the benzamide substructure, and the other implicit with differentially N,N-disubstituted amides. 38c Following peptide-catalyzed bromination, we observe a kinetically controlled product distribution that is substantially perturbed from equilibrium. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher er value, while enantioerosion occurs in a compensatory manner for the other diastereomeric pair. To the best of our knowledge, these findings represent the first observation of spontaneous enantioenrichment in homogeneous solution. The stereodynamics of these substrates provided an opportunity to observe the curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to partial equilibration.
In Chapter 4, we report the development of a Dmaa-containing β-turn peptide that catalyzes the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin- 4(3H)-ones (quinazolinones) with high levels of enantioinduction over a broad substrate scope.38d The structures of the free catalyst and the peptide-substrate complex were explored using X-ray crystallography and solution-phase 2D-NOESY experiments. Rotational barriers about the chiral anilide axis of a subset of quinazolinones were also computed using DFT and are discussed in light of the high enantioselectivities observed. Mechanistic studies also suggest that the initial bromination event is stereodetermining, and the major monobromide intermediate is an atropisomerically stable, mono-ortho-substituted isomer. An expanded study of this peptide library led to the identification of an improved catalyst, the structure of which was studied and compared to the original hit catalyst. 98 Preliminary results for a related atroposelective bromination reaction of α- methoxytropolones are presented as a future direction.
Chapter 5 discusses the application of X-Ray crystallography to the structural analysis of a series of tetrapeptides that were previously assessed for catalytic activity in the atroposelective quinazolinone bromination reaction. Common to the series is a central Pro-Xaa sequence, where Pro is either L- or D-proline, which was chosen to favor nucleation of canonical β-turn secondary structures. Crystallographic analysis of 35 different peptide sequences revealed a range of conformational states. The observed differences appear not only in cases where the Pro-Xaa loop region is altered, but also when seemingly subtle alterations to the flanking residues are introduced. In many instances, distinct conformers of the same sequence were observed, either as symmetry-independent molecules within the same unit cell or as polymorphs. Computational studies using DFT provided additional insight into the analysis of solid-state structural features. Select X-ray crystal structures were compared to the corresponding solution structures derived from measured proton chemical shifts, 3 J-values, and 2D-NOESY contacts. These findings imply that the conformational space available to simple peptide-based catalysts is more diverse than precedent might suggest. The direct observation of multiple ground state conformations for peptides of this family, as well as the dynamic processes associated with conformational equilibria, underscore not only the challenge of designing peptide-based catalysts, but also the difficulty in predicting their accessible transition states. Moreover, these data perhaps implicate that there are some advantages to low-barrier interconversions between conformations of peptide-based catalysts for multistep, enantioselective reactions.
|Advisor:||Miller, Scott J.|
|School Location:||United States -- Connecticut|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Chemistry, Organic chemistry|
|Keywords:||Atropisomerism, Beta-Turns, Computational Chemistry, Dynamic Kinetic Resolution, Enantioselective Catalysis, Peptides|
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