Synthetic and Mechanistic Studies with Biologically Active Macrocyclic Peptides

10.33540/1100 ◽  
2021 ◽  
Author(s):  
◽  
Thomas Melvin Wood
Keyword(s):  
Biologically Active ◽  
Mechanistic Studies ◽  
Macrocyclic Peptides

Rongalite-Induced Transition-Metal and Hydride-Free Reductive Aldol Reaction: A Rapid access to 3,3´- Disubstituted Oxindoles and Its Mechanistic Studies

2022 ◽  
Author(s):  
Sivaparwathi Golla ◽  
Naveenkumar Anugu ◽  
Swathi Jalagam ◽  
Hari Prasad Kokatla
Keyword(s):  
Transition Metal ◽  
Aldol Reaction ◽  
Dual Role ◽  
Biologically Active ◽  
Mechanistic Studies ◽  
Rapid Access ◽  
Reductive Aldol ◽  
Isatin Derivatives

A transition-metal and hydride-free reductive aldol reaction has been developed for the synthesis of biologically active 3,3´-disubstituted oxindoles from isatin-derivatives using rongalite. In this protocol, rongalite plays the dual role...

scholarly journals Palladium-catalyzed α-arylation for the addition of small rings to aromatic compounds

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhi-Tao He ◽  
John F. Hartwig
Keyword(s):  
Electronic Properties ◽  
Aromatic Compounds ◽  
Ring Opening ◽  
Biologically Active ◽  
High Yield ◽  
Protecting Group ◽  
Mechanistic Studies ◽  
Claisen Condensation ◽  
Wide Range ◽  
Palladium Catalyzed

Abstract Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The α-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).

scholarly journals Efficient Copper Catalyzed Multi-component Synthesis of N-acyl amidines via Acyl Nitrenes

2019 ◽  
Author(s):  
K.M. van Vliet ◽  
Lara H. Polak ◽  
Maxime A. Siegler ◽  
J.I. van der Vlugt ◽  
Célia Fonseca Guerra ◽  
...  
Keyword(s):  
Direct Synthesis ◽  
Bond Formation ◽  
Organometallic Complexes ◽  
Biologically Active ◽  
Mechanistic Studies ◽  
Copper Acetylide ◽  
Substrate Conversion ◽  
Cu Catalyst ◽  
New Type ◽  
Synthetic Routes

Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a fast and practical copper catalyzed 3-component reaction of aryl acetylenes, amines and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO<sub>2</sub> as the only by-product. Transformation of the dioxazolones on the Cu-catalyst generates acyl nitrenes that rapidly insert into the copper acetylide Cu-C bond rather than undergoing an undesired Curtius rearrangement. For non-aromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 minutes. For the direct synthesis of N-benzoyl amidine derivatives from aromatic dioxazolones, [Cu(OAc)(Xantphos)] proved to be inactive, but moderate to good yields were obtained when using simple CuI as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol%. The herein reported procedure does not only provide a new, practical and direct route to N-acyl amidines, but also represents a new type of<br>C-N bond formation.

scholarly journals Electrochemical Synthesis of Allylic Amines from Alkenes and Amines

2021 ◽  
Author(s):  
Diana Wang ◽  
Karina Targos ◽  
Zachary Wickens
Keyword(s):  
Aliphatic Amine ◽  
Reactive Intermediates ◽  
Building Blocks ◽  
Electrochemical Process ◽  
Biologically Active ◽  
Secondary Amines ◽  
High Yield ◽  
Mechanistic Studies ◽  
Allylic Amines ◽  
Synthetic Strategy

Allylic amines are valuable synthetic targets en route to diverse biologically active amine products. Current allylic C–H amination strate-gies remain limited with respect to the viable N-substituents. Herein we disclose a new electrochemical process to prepare aliphatic allylic amines by coupling two abundant starting materials: secondary amines and unactivated alkenes. This oxidative transformation proceeds via electrochemical generation of an electrophilic adduct between thianthrene and the alkene substrates. Treatment of these adducts with aliphatic amine nucleophiles and base provides allylic amine products in high yield. This synthetic strategy is also amenable to functionali-zation of feedstock gaseous alkenes at 1 atmosphere. In the case of 1-butene, remarkable Z-selective crotylation is observed. This strategy, however, is not limited to the synthesis of simple building blocks; complex biologically active molecules are suitable as both alkene and amine coupling partners. Preliminary mechanistic studies implicate vinylthianthrenium salts as key reactive intermediates.

scholarly journals Development of a 1,3a,6a-triazapentalene derivative as a compact and thiol-specific fluorescent labeling reagent

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Atsushi Nakayama ◽  
Akira Otani ◽  
Tsubasa Inokuma ◽  
Daisuke Tsuji ◽  
Haruka Mukaiyama ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Fluorescence Intensity ◽  
Fluorescent Labeling ◽  
Biologically Active ◽  
Thiol Groups ◽  
Mechanistic Studies ◽  
Emission Maximum ◽  
Aliphatic Thiols ◽  
High Yields

AbstractFor the fluorescence imaging of biologically active small compounds, the development of compact fluorophores that do not perturb bioactivity is required. Here we report a compact derivative of fluorescent 1,3a,6a-triazapentalenes, 2-isobutenylcarbonyl-1,3a,6a-triazapentalene (TAP-VK1), as a fluorescent labeling reagent. The reaction of TAP-VK1 with various aliphatic thiols proceeds smoothly to afford the corresponding 1,4-adducts in high yields, and nucleophiles other than thiols do not react. After the addition of thiol groups in dichloromethane, the emission maximum of TAP-VK1 shifts to a shorter wavelength and the fluorescence intensity is substantially increased. The utility of TAP-VK1 as a compact fluorescent labeling reagent is clearly demonstrated by the labeling of Captopril, which is a small molecular drug for hypertension. The successful imaging of Captopril, one of the most compact drugs, in this study demonstrates the usefulness of compact fluorophores for mechanistic studies.

scholarly journals Biologically active [Pd2L4]4+ quadruply-stranded helicates: stability and cytotoxicity

2015 ◽  
Vol 44 (24) ◽  
pp. 11129-11136 ◽  
Author(s):  
Samantha M. McNeill ◽  
Dan Preston ◽  
James E. M. Lewis ◽  
Anja Robert ◽  
Katrin Knerr-Rupp ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Membrane ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Biologically Active ◽  
Mechanistic Studies

A quadruply-stranded dipalladium(ii) helicate exhibits low micromolar IC50 values against a range of different cancer cell lines. Preliminary mechanistic studies indicate that the helicate induces cell death by disrupting the cell membrane.

scholarly journals Single-chain tandem macrocyclic peptides as a scaffold for growth factor and cytokine mimetics

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Kenichiro Ito ◽  
Yoshihiko Matsuda ◽  
Ayako Mine ◽  
Natsuki Shikida ◽  
Kazutoshi Takahashi ◽  
...  
Keyword(s):  
Cell Culture ◽  
Growth Factors ◽  
Growth Factor ◽  
Regenerative Medicine ◽  
Corynebacterium Glutamicum ◽  
Disulfide Bonds ◽  
Biologically Active ◽  
Single Chain ◽  
Large Numbers ◽  
Macrocyclic Peptides

AbstractMimetics of growth factors and cytokines are promising tools for culturing large numbers of cells and manufacturing regenerative medicine products. In this study, we report single-chain tandem macrocyclic peptides (STaMPtides) as mimetics in a new multivalent peptide format. STaMPtides, which contain two or more macrocyclic peptides with a disulfide-closed backbone and peptide linkers, are successfully secreted into the supernatant by Corynebacterium glutamicum-based secretion technology. Without post-secretion modification steps, such as macrocyclization or enzymatic treatment, bacterially secreted STaMPtides form disulfide bonds, as designed; are biologically active; and show agonistic activities against respective target receptors. We also demonstrate, by cell-based assays, the potential of STaMPtides, which mimic growth factors and cytokines, in cell culture. The STaMPtide technology can be applied to the design, screening, and production of growth factor and cytokine mimetics.

scholarly journals Asymmetric construction of acyclic quaternary stereocenters via direct enantioselective additions of α-alkynyl ketones to allenamides

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiawen Wang ◽  
Faqian He ◽  
Xiaoyu Yang
Keyword(s):  
Biologically Active ◽  
Mechanistic Studies ◽  
Asymmetric Catalytic ◽  
Chiral Phosphoric Acid ◽  
Plausible Mechanism ◽  
Acid Catalyzed ◽  
Quaternary Stereocenters ◽  
Acyclic Ketones ◽  
In Virtue Of ◽  
Active Natural

AbstractAcyclic quaternary stereocenters are widely present in a series of biologically active natural products and pharmaceuticals. However, development of highly efficient asymmetric catalytic methods for the construction of these privileged motifs represents a longstanding challenge in organic synthesis. Herein, an efficient chiral phosphoric acid catalyzed direct asymmetric addition of α-alkynyl acyclic ketones with allenamides has been developed, furnishing the acyclic all-carbon quaternary stereocenters with excellent regioselectivities and high enantioselectivities. Extensive and detailed experimental mechanistic studies were performed to investigate the mechanism of this reaction. Despite a novel covalent allyl phosphate intermediate was found in these reactions, further studies indicated that a SN2-type mechanism with the ketone nucleophiles is not very possible. Instead, a more plausible mechanism involving the elimination of the allyl phosphate to give the α,β-unsaturated iminium intermediate, which underwent the asymmetric conjugate addition with the enol form of ketone nucleophiles under chiral anion catalysis, was proposed. In virtue of the fruitful functional groups bearing in the chiral products, the diverse derivatizations of the chiral products provided access to a wide array of chiral scaffolds with quaternary stereocenters.

Catalyst- and Silane- Controlled Enantioselective Hydrofunctionalization of Alkenes by TM-HAT and RPC Mechanism

2019 ◽  
Author(s):  
Kousuke Ebisawa ◽  
Kana Izumi ◽  
Yuka Ooka ◽  
Hiroaki Kato ◽  
Sayori Kanazawa ◽  
...  
Keyword(s):  
Hydrogen Atom ◽  
Dft Calculations ◽  
Cobalt Catalyst ◽  
Critical Factor ◽  
Hydrogen Atom Transfer ◽  
Enantioselective Synthesis ◽  
Biologically Active ◽  
Mechanistic Studies ◽  
Metal Catalyzed ◽  
Active Natural

The catalytic enantioselective synthesis of tetrahydrofurans, found in the structures of many biologically active natural products, via a transition-metal-catalyzed hydrogen atom transfer (TM-HAT) and radical-polar crossover (RPC) mechanism is described. Hydroalkoxylation of non-conjugated alkenes proceeded efficiently with excellent enantioselectivity (up to 97:3 er) using a suitable chiral cobalt catalyst, <i>N</i>-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, and a diethylsilane. Surprisingly, absolute configuration of the product was highly dependent on the bulkiness of the silane. Mechanistic studies suggested a HAT mechanism and multiple enantiodetermining steps via an organocobalt(III) intermediate. DFT calculations suggested the presence of a cationic organocobalt intermediate, and that a critical factor of the enantioselectivity is the thermodynamic stability of the organocobalt(III) intermediate.

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