Preparation of Thioaminals in Water

Cavaca, Lídia A. S.; Gomes, Rafael F. A.; Afonso, Carlos A. M.

doi:10.3390/molecules27051673

Cited by 6 publications

(5 citation statements)

References 38 publications

(45 reference statements)

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“…42 We confirmed the highly symmetrical structure of H 1 by 1 H NMR spectroscopy that contained a single set of well-defined ligand signals (Figures 2c and S2). When benzaldehyde 1a (model substrate; 20 mM) and morpholine 1b (amine donor; 80 mM) were mixed, the intermediate 4,4′-(phenylmethylene) dimorpholine was formed by a reaction path, 43 from the adduct morpholino(phenyl)methanol, then the imine intermediate, 4-benzylidenemorpholinium (1c). Upon the addition of the aforementioned mixture solution into the H 1 (4.0 mM) solution, we observed changes consistent with substrate engagement (e.g., the broadening of resonances and downfield shifting and the splitting of the active H-atom (H 7 ) of the NADH mimetic moiety and the upfield shifting of the resonances originating from the tyrosine-mimicking group) (Figures 2c and S3).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Enzyme Grafting with a Cofactor-Decorated Metal-Organic Capsule for Solar-to-Chemical Conversion

et al. 2023

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Semi-artificial approaches to solar-to-chemical conversion can achieve chemical transformations that are beyond the capability of natural enzymes, but face marked challenges to facilitate in vivo cascades, due to their inevitable need for cofactor shuttling and regeneration. Here, we report on an enzyme grafting strategy to build a metal-organic capsule-docking artificial enzyme (metal-organic-enzyme, MOE) that comprised the self-assembly of a cofactordecorated capsule and the supramolecular enzyme-recognition features between the enzyme scaffold and the capsule to bypass cofactor shuttling and regeneration. The incorporated NADH mimics within the metal-organic capsule interacted with the imine intermediate that formed from the condensation of the amines and the dehydrogenation of alcohol substrates in the microenvironment to form complexes within the capsule and subsequently served as an in situ-generated photoresponsive cofactor. Upon illumination, the photoresponsive cofactor facilitates efficient proton/electron transport between the inner space (supramolecular hydrogenation) and outer space (enzymatic dehydrogenation) of the capsule to dehydrogenize the alcohols and hydrogenize the imine intermediates, respectively, circumventing the conventionally complex multistep cofactor shuttling and regeneration. The semi-artificial enzyme endows the conversion of diverse types of alcohol to amine products in both aqueous/organic solutions and Escherichia coli with high efficiency, offering a wide range of opportunities for sustainable and environmentally friendly biomanufacturing of commodity and fine chemicals.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Enzyme Grafting with a Cofactor-Decorated Metal-Organic Capsule for Solar-to-Chemical Conversion

et al. 2023

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“…Conjugation to thiols was expected based on previous reports. 38,43 While partially stable under LC/MS conditions, the N,S-thioaminal product was not stable under stronger acidic conditions (0.1 M HCl) and is readily reversible (see below). 43 The tryptophan mimic, 3-methyl indole, reacts with 1 to form multiple products, likely a mixture of N-substitution and C2/C3-Mannich-or Pictet Spangler-type additions.…”

Section: Resultsmentioning

confidence: 99%

“…Thiol addition to the imine is reversible, 38,43 yet this reaction may limit the desired reactivity of imines to tyrosines in cellular contexts where glutathione concentrations can be 1-10 mM. 51,52 To evaluate this reversibility, the pre-formed thioaminal product of 1 with N-acetyl-cysteine methyl amide was treated with either glutathione (1 M) or Ac-Tyr-NHMe (100 mM).…”

Section: Resultsmentioning

confidence: 99%

Covalent Protein Inhibitors via Tyrosine Conjugation with Cyclic Imine Mannich Electrophiles

Wang

Hadisurya

Tao

et al. 2022

Preprint

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Targeted covalent inhibitors (TCIs) have increased in popularity among drug candidates and chemical probes. Among current TCIs, the chemistry employed is largely limited to labeling cysteine and lysine side chains. Tyrosine is an attractive residue for TCIs due to its enrichment at protein-protein interfaces. Here, we investigate the utility of cyclic imine Mannich electrophiles as covalent warheads to specifically target a pro-tein tyrosine adjacent to an inhibitor binding pocket. We characterized the intrinsic reaction rates of several cyclic imines to tyrosine and identified the iminolactone to be suitable for a covalent inhibitor (second order rate constant of 0.0029 M-1 s-1). We appended the cyclic imine warheads to a CBX8 chromodomain inhibitor to label a non-conserved tyrosine, which markedly improves both the potency and selectivity of the inhibitor for CBX8 in vitro and in cells. These results indicate that Mannich electrophiles are promising and robust chemical warheads for tyrosine bioconjugation and covalent inhibitors.

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“…This is in accordance to our previous findings where Cu(OTf)2 promote the formation of aminals and thioaminals. 27,28 Furthermore, the use of 10 mol% Sc(OTf)3 and extension of reaction time from 5 to 8h allowed to access isolated yields of 87% of 11, which could be further improved to 91% by increasing reaction concentration 18-fold (see SInfo, Table S1). This method enables the competitive preparation of 2-…”

Section: Scheme 3 Scope Of Dcp Obtained Under Atmospheric Vs High Pre...mentioning

confidence: 99%

High-Pressure promoted Nazarov-like electrocyclization enables access to trans-4,5-Diamino-Cyclopent-2-enones bearing Electron-Poor Anilines

Afonso

Cavaca

Ravasco

et al. 2022

Preprint

Self Cite

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Unlike secondary alkyl amines and electron-rich anilines, secondary electron-poor anilines are challenging amine sources to explore the chemical space of Lewis acid-catalyzed condensation-based transformations with furfural. In this work is reported the efficient synthesis of trans-4,5--diamino cyclopentenones (DCP) using a high-pressure promoted Nazarov-like electrocyclization of Stenhouse salts arising from the Sc(III)-catalyzed condensation of furfural with secondary electron-poor anilines. The reaction enables access to otherwise difficultly accessible DCP and compatibility with a large scope of alkyl and aryl secondary amines. A 2 to 18-fold increase in yields for electron-poor anilines was highlighted by the use of this approach in the synthesis of a pharmacologically active compound.

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Preparation of Thioaminals in Water

Cited by 6 publications

References 38 publications

Enzyme Grafting with a Cofactor-Decorated Metal-Organic Capsule for Solar-to-Chemical Conversion

Enzyme Grafting with a Cofactor-Decorated Metal-Organic Capsule for Solar-to-Chemical Conversion

Covalent Protein Inhibitors via Tyrosine Conjugation with Cyclic Imine Mannich Electrophiles

High-Pressure promoted Nazarov-like electrocyclization enables access to trans-4,5-Diamino-Cyclopent-2-enones bearing Electron-Poor Anilines

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