Divergent Stereoselectivity in  Phosphothreonine (pThr)-Catalyzed Reductive Aminations of 3-Amidocyclohexanones

Shugrue, Christopher R.; Featherston, Aaron L.; Lackner, Rachel M.; Lin, Angela Yu-Chen; Miller, Scott J.

doi:10.1021/acs.joc.8b00207

Cited by 14 publications

(17 citation statements)

References 51 publications

(97 reference statements)

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“…Although a steric effect is possible, the increased enantioselectivity is thought to be associated with changes in the electronic nature of the N -terminal amide that alters the intramolecular hydrogen bonding of the peptide. 13…”

Section: Resultsmentioning

confidence: 99%

Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer–Villiger Oxidations of Cyclobutanones

et al. 2018

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Biologically inspired phosphothreonine (pThr)-embedded peptides that function as chiral Brønsted acid catalysts for enantioselective Baeyer–Villiger oxidations (BV) of cyclobutanones with aqueous H2O2 are reported herein. Complementary to traditional BINOL-derived chiral phosphoric acids (CPAs), the functional diversity of the peptidic scaffold provides the opportunity for multiple points of contact with substrates via hydrogen bonding, and the ease of peptide synthesis facilitates rapid diversification of the catalyst structure, such that numerous unique peptide-based CPA catalysts have been prepared. Utilizing a hypothesis-driven design, we identified a pThr-based catalyst that contains an N-acylated diaminopropionic acid (Dap) residue, which achieves high enantioselectivity with catalyst loadings as low as 0.5 mol%. The power of peptide-based multi-site binding is further exemplified through reversal in the absolute stereochemical outcome upon repositioning of the substrate–directing group (ortho- to meta). Modifications to the i+3 residue (LDap to LPhe) lead to an observed enantiodivergence without inversion of any stereogenic center on the peptide catalyst, due to noncovalent interactions. Structure–selectivity and 1H-1H-ROESY studies revealed that the proposed hydrogen bonding interactions are essential for high levels of enantioinduction. The ability for the phosphopeptides to operate as multifunctional oxidation catalysts expands the scope of pThr catalysts and provides a framework for the future selective diversification of more complex substrates, including natural products.

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Section: Resultsmentioning

confidence: 99%

Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer–Villiger Oxidations of Cyclobutanones

et al. 2018

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“…Although rigidifying elements are generally incorporated within the small molecule catalysts that are used for enantioselective methods in order to increase selectivity, flexible catalysts, like the DAP catalysts described above, may provide unique opportunities to maximize stabilizing NCIs throughout the catalytic cycle and perhaps provide greater substrate generality . For example, tetrapeptidic catalysts 22 , pioneered by the Miller group, can adopt multiple conformations and have been shown to be highly effective for a variety of transformations, including those traditionally catalyzed by BINOL-derived CPAs 23 . − Various mechanistic tools, driven by data science, were employed to directly compare these two disparate catalyst scaffolds in the study of an atroposelective cyclodehydration (Figure A) . It was hoped that further insight into the key features of privileged catalysts could be gained through this comparison, which may enable predictable catalyst design …”

Section: Conformational Dynamics In Catalysismentioning

confidence: 99%

Data Science Meets Physical Organic Chemistry

et al. 2021

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Metrics & MoreArticle Recommendations CONSPECTUS: At the heart of synthetic chemistry is the holy grail of predictable catalyst design. In particular, researchers involved in reaction development in asymmetric catalysis have pursued a variety of strategies toward this goal. This is driven by both the pragmatic need to achieve high selectivities and the inability to readily identify why a certain catalyst is effective for a given reaction.While empiricism and intuition have dominated the field of asymmetric catalysis since its inception, enantioselectivity offers a mechanistically rich platform to interrogate catalyst-structure response patterns that explain the performance of a particular catalyst or substrate.In the early stages of an asymmetric reaction development campaign, the overarching mechanism of the reaction, catalyst speciation, the turnover limiting step, and many other details are unknown or posited based on related reactions. Considering the unclear details leading to a successful reaction, initial enantioselectivity data are often used to intuitively guide the ultimate direction of optimization. However, if the conditions of the Curtin−Hammett principle are satisfied, then measured enantioselectivity can be directly connected to the ensemble of diastereomeric transition states (TSs) that lead to the enantiomeric products, and the associated free energy difference between competing TSs (ΔΔG ⧧ = −RT ln[(S)/(R)], where (S) and (R) represent the concentrations of the enantiomeric products). We, and others, speculated that this important piece of information can be leveraged to guide reaction optimization in a quantitative way.Although traditional linear free energy relationships (LFERs), such as Hammett plots, have been used to illuminate important mechanistic features, we sought to develop data science derived tools to expand the power of LFERs in order to describe complex reactions frequently encountered in modern asymmetric catalysis. Specifically, we investigated whether enantioselectivity data from a reaction can be quantitatively connected to the attributes of reaction components, such as catalyst and substrate structural features, to harness data for asymmetric catalyst design.In this context, we developed a workflow to relate computationally derived features of reaction components to enantioselectivity using data science tools. The mathematical representation of molecules can incorporate many aspects of a transformation, such as molecular features from substrate, product, catalyst, and proposed transition states. Statistical models relating these features to reaction outputs can be used for various tasks, such as performance prediction of untested molecules. Perhaps most importantly, statistical models can guide the generation of mechanistic hypotheses that are embedded within complex patterns of reaction continued...

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“…Peptide P1 was previously synthesized and characterized in a related publication. , Compound trans -2-acetamidocyclohexanol ((±)- 12 ) was synthesized according to the method of Hawkins . For the syntheses and characterizations of catalyst P2 (Boc-Pmh-Val-Val- d Pro-Leu-Val-Val-OMe) and acylated 13 , please see a related publication .…”

Section: Experimental Sectionmentioning

confidence: 99%

“…The approach to assigning specific catalyst–substrate interactions described below uses peptide-based catalysts in a biomimetic manner, building on their analogy to enzymes . Presented herein are reports involving two different families of catalysts: (1) phosphothreonine (pThr)-embedded peptides, − complementary to BINOL-derived chiral phosphoric acid (CPA) catalysts, , are explored for multicatalytic transfer hydrogenations (Figure C); and (2) π-methylhistidine (Pmh)-containing peptides are explored for in situ parallel hydroxyl group transfer reactions (Figure D) …”

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confidence: 99%

Outer-Sphere Control for Divergent Multicatalysis with Common Catalytic Moieties

et al. 2019

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We herein report two examples of one pot, simultaneous reactions, mediated by multiple, orthogonal catalysts with the same catalytic motif. First, BINOL-derived chiral phosphoric acids (CPA) and phosphothreonine (pThr)-embedded peptides were found to be matched for two different steps in double reductions of bisquinolines. Next, two π-methylhistidine (Pmh)containing peptides catalyzed enantio-and chemoselective acylations and phosphorylations of multiple substrates in one pot. The selectivity exhibited by common reactive moieties is adjusted solely by the appended chiral scaffold through outer-sphere interactions.

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Divergent Stereoselectivity in Phosphothreonine (pThr)-Catalyzed Reductive Aminations of 3-Amidocyclohexanones

Cited by 14 publications

References 51 publications

Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer–Villiger Oxidations of Cyclobutanones

Phosphothreonine (pThr)-Based Multifunctional Peptide Catalysis for Asymmetric Baeyer–Villiger Oxidations of Cyclobutanones

Data Science Meets Physical Organic Chemistry

Outer-Sphere Control for Divergent Multicatalysis with Common Catalytic Moieties

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