Bifunctional Chiral Dehydroalanines for Peptide Coupling and Stereoselective <i>S</i>-Michael Addition

Gutiérrez-Jiménez, Marta I.; Aydillo, Carlos; Navo, Claudio D.; Avenoza, Alberto; Corzana, Francisco; Jiménez‐Osés, Gonzalo; Zurbano, Marı́a M.; Busto, Jesús H.; Peregrina, Jesús M.

doi:10.1021/acs.orglett.6b00840

Cited by 32 publications

(31 citation statements)

References 57 publications

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“…The high diastereoselectivity obtained can be explained by the pyramidalization of the enolate intermediate, as we previously demonstrated by theoretical calculations in the case of its enantiomer Dha ent‐2 . The absolute configuration of the new stereocenter created in the Michael addition (C3) was determined by NOESY NMR experiments (see the Supporting Information).…”

Section: Resultssupporting

confidence: 68%

Cell‐Penetrating Peptides Containing Fluorescent d‐Cysteines

Navo

Asín

Gómez-Orte

et al. 2018

Chemistry A European J

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A series of fluorescent d-cysteines (Cys) has been synthesized and their optical properties were studied. The key synthetic step is the highly diastereoselective 1,4-conjugate addition of aryl thiols to a chiral bicyclic dehydroalanine recently developed by our group. This reaction is fast at room temperature and proceeds with total chemo- and stereoselectivity. The Michael adducts were easily transformed into the corresponding amino acids to study their optical properties and, in some selected cases, into the corresponding N-Fmoc-d-cysteine derivatives to be used in solid-phase peptide synthesis (SPPS). To further demonstrate the utility of these non-natural Cys-derived fluorescent amino acids, the coumaryl and dansyl derivatives were incorporated into cell-penetrating peptide sequences through standard SPPS and their optical properties were studied in different cell lines. The internalization of these fluorescent peptides was monitored by fluorescence microscopy.

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Section: Resultssupporting

confidence: 68%

Cell‐Penetrating Peptides Containing Fluorescent d‐Cysteines

Navo

Asín

Gómez-Orte

et al. 2018

Chemistry A European J

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“…Since partial conversion of Cys into cystine occurs during the process, whose properties are similar to the Lan to be purified, purification is challenging. Synthesis from Dha or Dhb needs a chiral oxazolidinone scaffolds to achieve high diastereoselectivity but a protected cysteine and chromatography were used . The aziridine in an aqueous alkaline medium gives a product mixture in which nor ‐Lan prevails.…”

Section: Resultsmentioning

confidence: 99%

“…The hydrolysis of the Michael adducts has been optimized with a thiogalactopyranose oxazolidinone . Complete hydrolysis occurred at 40 °C with aqueous HCl (4 m ) after 16 h. These new reaction conditions are less harsh than the reflux used in Scheme .…”

Section: Chemical Synthesis Of Unprotected Lanthioninementioning

confidence: 99%

Progress in Lanthionine and Protected Lanthionine Synthesis

Denoël

Lemaire

Luxen

2018

Chemistry A European J

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Lanthionine (Lan), a non‐proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and β‐methyllanthionine are also key constituents in lantibiotics, a prevalent class of peptide antibiotics. The development of those new antibacterial drugs with enhanced properties is the focus of recent research. Since multiple isomers of Lan are possible, a regio‐ and diastereoselective synthesis is challenging. This comprehensive review summarizes the known chemical syntheses of lanthionine from various precursors (e.g., β‐chloroalanine, cystine, dehydroalanine, β‐iodoalanine, aziridine, serine lactone, sulfamidate) since 1941. Methods for preparation of unprotected, protected, orthogonally protected, and mutually orthogonally protected lanthionine with relevant experimental details and perspectives on their usefulness are provided. The potential of these Lan derivatives is illustrated by one recent application.

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“…More recently, we developed an improved version of these chiral Dha/Dhb derivatives through lactonisation of the first‐generation scaffolds, yielding chiral bicyclic structures with reduced conformational flexibility and superior reactivity and diastereoinducing properties with thiols as nucleophiles . This methodology allowed the synthesis of cell‐penetrating peptides containing fluorescent d ‐cysteine components .…”

Section: Figurementioning

confidence: 99%

Elusive Dehydroalanine Derivatives with Enhanced Reactivity

et al. 2019

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For the first time, a simple methodology for the chemical synthesis and use of highly reactive 4‐methylenoxazol‐5(4H)‐ones from serine is presented. These dehydroalanine derivatives, which resemble the natural 4‐methylidenimidazole‐5‐one (MIO) cofactor present in lyases and aminomutases, undergo rapid reaction with carbon nucleophiles such as silyl enol ethers, as well as cycloaddition reactions with diazo compounds and reactive dienes, under very mild conditions and without any need for metal catalysts or ring‐strain activation, offering potential for bioconjugation.

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Bifunctional Chiral Dehydroalanines for Peptide Coupling and Stereoselective S-Michael Addition

Cited by 32 publications

References 57 publications

Cell‐Penetrating Peptides Containing Fluorescent d‐Cysteines

Cell‐Penetrating Peptides Containing Fluorescent d‐Cysteines

Progress in Lanthionine and Protected Lanthionine Synthesis

Elusive Dehydroalanine Derivatives with Enhanced Reactivity

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