Aspartyl Oxidation Catalysts That Dial In Functional Group Selectivity, along with Regio- and Stereoselectivity

Abstract

A remarkable aspect of enzyme evolution is the portability of catalytic mechanisms for fundamentally different chemical reactions. For example, aspartyl proteases, which contain two active site carboxylic acid groups, catalyze the hydrolysis of amide bonds, while glycosyltransferases (and glycosyl hydrolases), which often also contain two active site carboxylates, have evolved to form (or break) glycosidic bonds. However, neither catalyst exhibits cross-reactivity in the intracellular environment. The large, macromolecular architectures of these biocatalysts tailor their active sites to their precise, divergent functions. The analogous portability of a small-molecule catalyst for truly orthogonal chemical reactivity is rare. Herein, we report aspartic acid containing peptides that can be directed to different sectors of a substrate for which the danger of cross-reactivity looms large. A transiently formed aspartyl peracid catalyst can participate either as an electrophilic oxidant to catalyze alkene epoxidation or as a nucleophilic oxidant to mediate the Baeyer–Villiger oxidation (BVO) of ketones. We show in this study that an appended peptide sequence can dictate the mode of reactivity for this conserved catalytic functional group within a substrate that has the potential to undergo both alkene epoxidation and BVO; in both cases the additional aspects of chemical selectivity (regio- and stereoselectivity) are high. This sequence-dependent tuning of a common catalytic moiety for functional group selective reactions constitutes a biomimetic strategy that may impact late-stage diversification of complex polyfunctional molecules.

Parameterization and Analysis of Peptide-Based Catalysts for the Atroposelective Bromination of 3-Arylquinazolin-4(3H)-ones

“…The N–H i +2 intensity suggests that an inter- or intramolecular hydrogen bond with this amide is important for catalysis. 9 The statistical significance of the individual models suggests that both conformers could be catalytically relevant, albeit the calculated type II′ conformers are consistently lower in ground state energy (0.9–6 kcal/mol) than the corresponding type I′ structures with the basis set that we employed. Notably, although the NBO charge of O i +1 is included in both models, the parameter values derived from both conformers are not intercorrelated (Figure 3a).…”

“…The reaction we chose to study is the atroposelective bromination of 3-arylquinazolin-4( 3H )-ones (quinazolinones, e.g., 1 ) catalyzed by tertiary amine-containing peptide catalysts with the general structure type of 3 (Figure 1b). 9 Under the optimized conditions, these catalysts have been shown to provide access to atropisomerically enriched products (e.g., 2 ) with high levels of enantioinduction (up to 99:1 er). Moreover, seemingly subtle structural permutations of the catalyst led to non-intuitive changes in enantioselectivity.…”

“…On the basis of X-ray crystallographic and NMR experiments, one key structural feature that was incorporated into our strategy from the start is the observed hydrogen bond between N–H i +3 and O i , as well as between the carbonyl of the substrate and N–H i +2 (Figure 1a). 8, 9, 11 Within this motif, several conformations are accessible, as the prototypical peptide catalyst 3 has been shown to adopt as many as five distinct states in the solid state, more broadly characterized as either a type II′ β-hairpin or type I′ pre-helical β-turn (Figure 1b). In solution, NMR analysis of peptide 3a was also consistent with populated states that map onto pre-helical or nonhairpin β-turn conformers.…”

Harnessing non-covalent interactions to exert control over regioselectivity and site-selectivity in catalytic reactions

“…This approach to peptide peracid catalysis has recently be expanded by the group where they are now able to control regio-, chemo- and diastereoselectivity through use of carefully chosen peptide catalysts. 60 …”

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products

“…These challenges include diastereoselectivity, regioselectivity, site-selectivity, chemoselectivity, and even functional group selectivity. 269 Perhaps these are terms whose specific meanings will also undergo refinement in the future.…”