Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer–Villiger Oxidation

Abascal, Nadia C.; Miller, Scott J.

doi:10.1021/acs.orglett.6b02282

Cited by 20 publications

(17 citation statements)

References 21 publications

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“…14 In the case of 2 -catalyzed BVO, a favorable interaction of the amido group with catalyst 2 is consistent with our recent observations (Figure 2b). This hypothesis was stimulated by analysis of an experimentally derived (ROESY) solution structure of 2 , 26 along with our study of catalyst analogues. 15 A critical role for the lysine side chain, along with the schematic secondary structure shown, contributes to a view of competing hydrogen bonding networks as catalyst ent - 2 operates on substrate 14 - trans (Figure 2c).…”

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2016

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“…In general, α-peptides of small or medium size (3–20 residues) are conformationally flexible and able to adopt several conformers that are in rapid equilibrium unless constraints are implemented . Recent studies by Miller as well as Thiele and Schreiner showed that even peptidic catalysts with rigidifying turn motifs adopt more than one structure but can be highly stereoselective. − Despite these examples, there is still little knowledge about the conformational features that are ideal to achieve highly reactive and stereoselective peptidic catalysts.…”

Section: Introductionmentioning

confidence: 99%

Conformational Properties of a Peptidic Catalyst: Insights from NMR Spectroscopic Studies

et al. 2018

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Peptides have become valuable as catalysts for a variety of different reactions, but little is known about the conformational properties of peptidic catalysts. We investigated the conformation of the peptide H-dPro-Pro-Glu-NH, a highly reactive and stereoselective catalyst for conjugate addition reactions, and the corresponding enamine intermediate in solution by NMR spectroscopy and computational methods. The combination of nuclear Overhauser effects (NOEs), residual dipolar couplings (RDCs), J-couplings, and temperature coefficients revealed that the tripeptide adopts a single predominant conformation in its ground state. The structure is a type I β-turn, which gains stabilization from three hydrogen bonds that are cooperatively formed between all functional groups (secondary amine, carboxylic acid, amides) within the tripeptide. In contrast, the conformation of the enamine intermediate is significantly more flexible. The conformational ensemble of the enamine is still dominated by the β-turn, but the backbone and the side chain of the glutamic acid residue are more dynamic. The key to the switch between rigidity and flexibility of the peptidic catalyst is the COH group in the side chain of the glutamic acid residue, which acts as a lid that can open and close. As a result, the peptidic catalyst is able to adapt to the structural requirements of the intermediates and transition states of the catalytic cycle. These insights might explain the robustness and high reactivity of the peptidic catalyst, which exceeds that of other secondary amine-based organocatalysts. The data suggest that a balance between rigidity and flexibility, which is reminiscent of the dynamic nature of enzymes, is beneficial for peptidic catalysts and other synthetic catalysts.

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“…Recent findings by Jacobsen and co-workers also underscore that a small-molecule catalyst may interact with multiple states along a complex reaction coordinate. 15,16…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination

et al. 2018

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It is widely accepted that structural rigidity is required to achieve high levels of asymmetric induction in catalytic, enantioselective reactions. This fundamental design principle often does not apply to highly selective catalytic peptides that often exhibit conformational heterogeneity. As a result, these complex systems are particularly challenging to study both experimentally and computationally. Herein, we utilize molecular dynamics simulations to investigate the role of conformational mobility on the reactivity and selectivity exhibited by a catalytic, β-turn-biased peptide in an atroposelective bromination reaction. By means of cluster analysis, multiple distinct conformers of the peptide and a catalyst-substrate complex were identified in the simulations, all of which were corroborated by experimental NMR measurements. The simulations also revealed that a shift in the conformational equilibrium of the peptidic catalyst occurs upon addition of substrate, and the degree of change varies among different substrates. On the basis of these data, we propose a correlation between the composition of the peptide conformational ensemble and its catalytic properties. Moreover, these findings highlight the importance of conformational dynamics in catalytic, asymmetric reactions mediated by oligopeptides, unveiled through high-level, state-of-the-art computational modeling.

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Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer–Villiger Oxidation

Cited by 20 publications

References 21 publications

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

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

Conformational Properties of a Peptidic Catalyst: Insights from NMR Spectroscopic Studies

Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination

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