2-Nitropyrrole cross-coupling enables a second generation synthesis of the heronapyrrole antibiotic natural product family

2016 ◽  
Vol 52 (85) ◽  
pp. 12638-12641 ◽  
Author(s):  
Xiao-Bo Ding ◽  
Daniel P. Furkert ◽  
Margaret A. Brimble
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Second Generation ◽  
Product Family ◽  
Cross Coupling

The heronapyrroles are a family of antibiotic natural products containing the rare 2-nitropyrrole motif.

The Bradshaw/Bonjoch Synthesis of (-)-Anominine

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Aldol Condensation ◽  
Selective Reduction ◽  
Cross Coupling ◽  
Conjugate Addition ◽  
Quaternary Centers ◽  
Selective Protection ◽  
Open Face ◽  
Robinson Annulation

The Hajos-Parrish cyclization was a landmark in the asymmetric construction of polycarbocyclic natural products. Impressive at the time, the proline-mediated intramolecular aldol condensation proceeded with an ee that was low by modern standards. Ben Bradshaw and Josep Bonjoch of the Universitat de Barcelona optimized this protocol, then used it to prepare (J. Am. Chem. Soc. 2010, 132, 5966) the enone 3 en route to the Aspergillus alkaloid (-)-anominine 4. The optimized catalyst for the enantioselective Robinson annulation was the amide 5 . With 2.5 mol % of the catalyst, the reaction proceeded in 97% ee. With only 1 mol % of catalyst, the reaction could be taken to 96% yield while maintaining the ee at 94%. Conjugate addition proceeded across the open face of 3 to give, after selective protection, the monoketal 7. After methylenation and deprotection, oxidation with IBX delivered the enone 9. With the angular quaternary centers of the natural product in place, the molecule became increasingly congested. Attempted direct alkylation of 9 led mainly to O-methylation. A solution to this problem was found in condensation with the Eschenmoser salt, followed by N-oxide formation and elimination to give the tetraene 10. Selective reduction by the Ganem protocol followed by equilibration completed the net methylation. Under anhydrous conditions, the oxide derived from the allylic selenide 12 did not rearrange. On the addition of water, the rearrangement proceeded smoothly. Protection and hydroboration converted 13 into 14. The bulk of the folded molecule protected the exo methylene of 14, so hydrogenation followed by protection and oxidation delivered 15. Conjugate addition of indole to 15 set the stage for oxidation and bis-methylenation to give 17. Selective Ru-mediated cross-coupling with 18 followed by deprotection then completed the synthesis of (-)-anominine 4, which proved to be the enantiomer of the natural product.

Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications

2019 ◽  
Author(s):  
Yu Kawamata ◽  
Julien Vantourout ◽  
David P. Hickey ◽  
Peng Bai ◽  
Longrui Chen ◽  
...  
Keyword(s):  
Natural Products ◽  
Organic Synthesis ◽  
Second Generation ◽  
Cross Coupling ◽  
Aryl Halides ◽  
Catalytic Systems ◽  
Full Disclosure ◽  
Aryl Amination ◽  
Mechanistic Understanding

<div> <div> <div> <p>C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles, including complex examples on oligopeptides, medicinally-relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations as well as procedures for both batch and flow scale-ups (100 gram) are also described. </p> </div> </div> </div>

The Palladium-Mediated Cross Coupling of Bromotropolones With Organostannanes or Arylboronic Acids: Applications to the Synthesis of Natural Products and Natural Product Analogs

1991 ◽  
Vol 44 (5) ◽  
pp. 705 ◽  
Author(s):  
MG Banwell ◽  
JM Cameron ◽  
MP Collis ◽  
GT Crisp ◽  
RW Gable ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Natural Products ◽  
Natural Product ◽  
Cross Coupling ◽  
Binding Activity ◽  
X Ray ◽  
Arylboronic Acids ◽  
Wide Range ◽  
Tubulin Binding

The bromotropolones (4), (5) and (10) undergo palladium-mediated cross coupling with a wide range of organostannanes to produce alkenyl -, alkyl- and aryl-substituted tropolones . The methodology has been applied to the synthesis of the monoterpenes β- dolabrin (11),β- thujaplicin (12), 4-isopropyl-7-methoxytropolone (13) and β- thujaplicinol (14). Cross coupling of bromotropolones (4), (5) and (10) with various aryltrimethylstannanes or arylboronic acids has permitted the preparation of the bicyclic colchicine analogues (30)-(43) which have been tested for tubulin -binding activity. The X-ray crystal structure of the most active of these systems, compound (38), is reported.

Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications

2019 ◽  
Author(s):  
Yu Kawamata ◽  
Julien Vantourout ◽  
David P. Hickey ◽  
Peng Bai ◽  
Longrui Chen ◽  
...  
Keyword(s):  
Natural Products ◽  
Organic Synthesis ◽  
Second Generation ◽  
Cross Coupling ◽  
Aryl Halides ◽  
Catalytic Systems ◽  
Full Disclosure ◽  
Aryl Amination ◽  
Mechanistic Understanding

<div> <div> <div> <p>C–N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles, including complex examples on oligopeptides, medicinally-relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations as well as procedures for both batch and flow scale-ups (100 gram) are also described. </p> </div> </div> </div>

scholarly journals Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

2019 ◽  
Vol 15 ◽  
pp. 577-583 ◽  
Author(s):  
Jan Hendrik Lang ◽  
Thomas Lindel
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Propylene Oxide ◽  
Cross Coupling ◽  
Solution Phase ◽  
Partial Structure ◽  
Open Chain ◽  
Phase Synthesis ◽  
Solution Phase Synthesis ◽  
Ester Enolate

The synthesis of the polyketide section present in the potently cytotoxic marine cyclodepsipeptide jasplakinolide and related natural products, geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxopropyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide. The overall synthesis comprises nine steps with an overall yield of 21%. It proved to be possible to liberate the free 8-hydroxynonenoic acid and to couple it with a protected tripeptide composed of L-alanine, N,O-dimethyl-D-iodotyrosine, and TIPS-protected L-threonine, which occurs as partial structure of seragamide A. The tripeptide section of seragamide A was assembled by solution-phase synthesis and an open-chain analogue of the natural product was obtained.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

2018 ◽  
Author(s):  
Jonathan J. Mills ◽  
Kaylib R. Robinson ◽  
Troy E. Zehnder ◽  
Joshua G. Pierce
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Mechanism Of Action ◽  
Marine Natural Products ◽  
Biological Evaluation ◽  
Lead Compounds ◽  
Follow Up Studies ◽  
Initial Resistance ◽  
Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

Unzipping Natural Products: Improved Natural Product Structure Predictions by Ensemble Modeling and Fingerprint Matching

2018 ◽  
Author(s):  
William A. Shirley ◽  
Brian P. Kelley ◽  
Yohann Potier ◽  
John H. Koschwanez ◽  
Robert Bruccoleri ◽  
...  
Keyword(s):  
Natural Products ◽  
Open Source ◽  
Natural Product ◽  
Gene Cluster ◽  
Public Domain ◽  
Product Structure ◽  
Fingerprint Matching ◽  
Ensemble Modeling ◽  
Chemical Structures ◽  
Source Gene

This pre-print explores ensemble modeling of natural product targets to match chemical structures to precursors found in large open-source gene cluster repository antiSMASH. Commentary on method, effectiveness, and limitations are enclosed. All structures are public domain molecules and have been reviewed for release.

Metal-Free Photoredox-Catalyzed C–H/C–H Coupling of Arenes Enabled by Interrupted Pummerer Activation

2019 ◽  
Author(s):  
Miles Aukland ◽  
Mindaugas Šiaučiulis ◽  
Adam West ◽  
Gregory Perry ◽  
David Procter
Keyword(s):  
Natural Product ◽  
Selective Reduction ◽  
Cross Coupling ◽  
One Pot ◽  
Complex Molecules ◽  
Pummerer Reaction ◽  
Metal Free ◽  
Bond Forming ◽  
Coupling Partner ◽  
Bioactive Natural Product

<p>Aryl–aryl cross-coupling constitutes one of the most widely used procedures for the synthesis of high-value materials, ranging from pharmaceuticals to organic electronics and conducting polymers. The assembly of (hetero)biaryl scaffolds generally requires multiple steps; coupling partners must be functionalized before the key bond-forming event is considered. Thus, the development of selective C–H arylation processes in arenes, that side-step the need for prefunctionalized partners, is crucial for streamlining the construction of these key architectures. Here we report an expedient, one-pot assembly of (hetero)biaryl motifs using photocatalysis and two non-prefunctionalized arene partners. The approach is underpinned by the activation of a C–H bond in an arene coupling partner using the interrupted Pummerer reaction. A unique pairing of the organic photoredox catalyst and the intermediate dibenzothiophenium salts enables highly selective reduction in the presence of sensitive functionalities. The utility of the metal-free, one-pot strategy is exemplified by the synthesis of a bioactive natural product and the modification of complex molecules of societal importance.</p>

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