Revitalizing palladium-catalyzed α-arylation of enolates to generate diverse isoquinoline-based compounds

Posted on behalf of Victoria Corless, guest web writer for Organic & Biomolecular Chemistry

Research efforts carried out by Professor Timothy Donohoe of Oxford University have been focussed on connecting new methodologies in organic synthesis and catalysis with impactful applications to the fields of medicinal chemistry and natural product synthesis.

One of the group’s most recent endeavors includes the development of a generalized strategy to access highly functionalized and diverse isoquinoline cores without the use of expensive and highly-specialized starting materials.

The isoquinoline motif and its derivatives are ubiquitous in a number of natural products, pharmaceutical agents, and chiral catalyst ligands. However, classical syntheses are often centered on electrophilic aromatic substitution of electron-rich systems, resulting in limited chemical diversity in accessible products. New routes are still highly desirable and a resurgence in synthetic efforts has resulted in a number of notable contributions using modern synthetic methodology.

In 2012, Prof. Donohoe and coworkers reported a sequential palladium-catalyzed α-arylation of enolates and cyclization to access isoquinolines based on chemistry originally and independently reported by Buckwald, Hartwig and Miura in 1997. Though a powerful reaction, it remained underutilized in the assembly of complex aromatic compounds. Using clever reaction engineering, Donohoe and coworkers envisioned synthesizing a psuedo-1,5-dicarbonyl accessible through α-arylation of enolizable ketones with aryl halides possessing a protected aldehyde or ketone in the ortho-position. In addition, trapping with reactive electrophiles resulted in functionalization at the C4 position. This methodology can be carried out in one pot, tolerates a wide range of substituents and most notably, provides a route to synthetically challenging electron-deficient isoquinoline scaffolds.

Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines

Their current study presents significant extensions of this earlier work and further demonstrates the innovation possible through transition metal catalysis in enabling the construction of complex architectures in interesting ways. The three- and four-component coupling procedures involve multiple bond formations in one pot from largely commercially available starting materials. Reaction versatility is demonstrated through the use of ketone, ester or nitrile enolates as well as electron-rich, electron-deficient or even sterically hindered aryl halides and in situ functionalization of intermediates to directly access a number of highly functionalized isoquinoline based compounds.

In addition to rejuvenating interesting and underexplored chemistry, Prof. Donohoe and coworkers have appreciably impacted the areas of natural product synthesis and medicinal chemistry through their innovative and streamlined synthesis of isoquinoline-based compounds and it will be interesting to see where their future endeavours will lead.


To find out more see:

Palladium-catalyzed enolate arylation as a key C–C bond-forming reaction for the synthesis of isoquinolines
Ben S. Pilgrim, Alice E. Gatland, Carlos H. A. Esteves, Charlie T. McTernan, Geraint R. Jones, Matthew R. Tatton, Panayiotis A. Procopiou and Timothy J. Donohoe
DOI: 10.1039/C5OB02320C


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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E-WiSPOC 16

European-Winter School on Physical Organic Chemistry (E-WiSPOC)

31st January – 5th February 2016, Bressanone, Italy


OBC is pleased to support the European-Winter School on Physical Organic Chemistry (E-WiSPOC) 2016.

The topic for 2016 is – Functional Surfaces in Chemistry and Biology.

Lectures will be speaking on a variety of subjects, including:

  • Francesco Zerbetto – Theoretical and computational chemistry (University of Bologna)
  • Maria Ramos – Computational biochemistry (University of Porto)
  • Maria Minunni – Surface plasmon resonance (University of Firenze)
  • Chris Hunter – Physical organic chemistry and biomolecular interactions (University of Cambridge)
  • Bart Ravoo – Biological and supramolecular system (University of Muenster )
  • Jurrian Huskens – Biomolecular adhesion and tissue engineering (University of Twente)
  • Alessandro Casnati – Bioorganic and supramolecular chemistry (University of Parma)
  • Zoltan Takats – Ambient mass spectrometry (Imperial College London)

The school,which is part of the cultural initiatives of the Organic Division of the Italian Chemical Society, is open to PhD students and post-docs.

For information visit the e-wispoc website: www.chimica.unipd.it/wispoc or write to: wispoc.chimica@unipd.it

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Applying old tricks to new problems: Acyl Fluorides in Sterically Hindered Amide Coupling

Posted on behalf of Victoria Corless, guest web writer for Organic & Biomolecular Chemistry

It comes as no surprise to those with a background in organic or medicinal chemistry that one of the most important and often-overlooked synthetic transformations is the formation of amide bonds.

Amide linkages are one of the most prolific moieties in the synthesis of pharmaceuticals and biologically active molecules. However, despite their prevalence there remain synthetic challenges, as even the simplest amides can be difficult to make.

A group at the University of Southern Denmark led by Prof. Trond Ulven has developed a protocol for amide coupling through in situ formation of acyl fluorides.

Initially, the researchers were working toward the synthesis of a molecular inhibitor for the free fatty acid receptor 2 (FFA2/GPR43), which has recently generated some interest as a target for treating various metabolic disorders.

While attempting the synthesis of an intermediate, coupling between their sterically hindered and sensitive carboxylic acid with an electron deficient and hindered amide understandably led to unsatisfactory results using standard coupling procedures.

Given the multiple steps required to generate both intermediates, the group decided to explore alternative methods to solve their problem. Indeed, acyl fluorides proved to be ideal as they behave like activated esters due to the unique nature of the carbonyl-fluoride bond while also minimizing steric hindrance between the two coupling partners.

Literature protocols are available for the generation of acyl fluorides and there are disadvantages associated with some. In recent years however, a number of alternative fluorinating agents have been reported that are capable of generating the acyl fluoride in situ under mild reaction conditions.

Prof. Ulven’s group was able to further improve the efficiency of this methodology by utilizing an alternative fluorinating agent, BTFFH, which is normally used in solid-phase peptide synthesis. This reagent reduces byproduct formation observed with reagents such as DAST, Deoxo-Fluor and XtalFluor-E. High conversions and isolated yields were obtained as a result and Ulven’s method was also successfully applied to amide coupling reactions previously reported as low yielding.

There is still a need for chemists to develop better ways to synthesize complex amide-containing structures without the need for external reagents. In the meantime, solutions such as these overcome synthetic challenges and are critical to further development and understanding in organic reaction design.


To find out more see:

A protocol for amide bond formation with electron deficient amines and sterically hindered substrates
Maria E. Due-Hansen, Sunil K. Pandey, Elisabeth Christiansen, Rikke Andersen, Steffen V. F. Hansen and Trond Ulven
DOI: 10.1039/C5OB02129D


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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Heterocyclic and Synthesis Group postgraduate meeting prize winners

Congratulations to all the  prize winners at the Heterocyclic and Synthesis Group Postgraduate Meeting.

The symposium took place on the 10th September 2015. It provides an opportunity for final year PhD students to present talks and posters.

The winners were:

Patrick Brown (Best talk prize) – Biomimetic Synthesis of Dimeric Phenylethanoids

Lee Eccleshare (Best flash presentation prize) – A Novel, One-Pot, Multi-Component Synthesis of Fused 8-Membered Carbocycles

Catherine Holden (Best poster prize) - TheBenzyne Smiles Reaction: A Transition Metal Free Biaryl Synthesis

Patrick Brown

Lee Eccleshare

Catherine Holden

The prizes were presented by Dr Andrew Williams of Eli Lilly.

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Poster Prize winners at RSC Organic Division Poster Symposium 2015

Congratulations to all the Poster Prize winners at the RSC Organic Division Poster Symposium 2015.

©Royal Society of Chemistry / MPP Image Creation

We are pleased to present the prize to these winners:

First Prize – Hiroki Wada
(University of Nottingham)

Second Prize – Keith Andrews & Giacomo Crisenza
(University of Nottingham & University of Bristol)

Industry Prize – Joanna Sadler
(University of Strathclyde)

Participants Prize – Jorge Gonzalez
(University of Edinburgh)

Organised by the Royal Society of Chemistry, the symposium took place in London on the 30th November 2015.

The symposium provides a fantastic opportunity for final year organic chemistry PhD students to showcase their research and network with their peers, leading academics, and industrial chemists.

In the words of the winner:  “This event provided me a great opportunity not only to learn cutting edge organic chemistry and biochemistry, but also to network with academics and industrial researchers. I feel that the event showcases the shift from traditional small molecule medicinal chemistry to biologically and nature orientated chemistry, and it was really interesting to observe this and also to contribute to it.  It was an invaluable experience meeting and discussing my work and theirs with many world leading scientists.”  (Hiroki Wada)

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Dr Keith Stubbs joins Advisory Board

New OBC Advisory Board memberWe are pleased to announce that Dr Keith Stubbs, University of Western Australia, has recently joined the Organic & Biomolecular Chemistry Advisory Board.

Dr Keith Stubbs completed his undergraduate and PhD studies at UWA, followed by a two year post-doctoral position at Simon Fraser University in Vancouver, Canada. He currently is an ARC Future Fellow.

His research group mainly focusses on carbohydrate research ranging from new therapeutic targets against antibiotic and herbicide resistance to tools to study carbohydrate-processing enzymes, as well as on microfluidics as a new technique in organic synthesis.


Selection of his most recent publications:

Gaining insight into the catalysis by GH20 lacto-N-biosidase using small molecule inhibitors and structural analysis (Open Access)
Chem. Commun., 2015, 51, 15008-15011. DOI: 10.1039/C5CC05494J, Communication

An interactive database to explore herbicide physicochemical properties
Org. Biomol. Chem., 2015, 13, 5586-5590. DOI: 10.1039/C5OB00469A, Communication

A simple and robust preparation of N-acetylindoxyls: precursors for indigogenic substrates
Org. Biomol. Chem., 2015, 13, 905,-908. DOI: 10.1039/C4OB02248C, Paper

Photoredox catalysis under shear using thin film vortex microfluidics
Chem. Commun., 2015, 51, 11041-11044. DOI: 10.1039/C5CC02153G, Communication

Thin film microfluidic synthesis of fluorescent highly substituted pyridines
Green Chem., 2014, 16, 3450-3453. DOI: 10.1039/C4GC00881B, Communication

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Tagetitoxin – real structure finally revealed?

Posted on behalf of Victoria Corless, guest web writer for Organic & Biomolecular Chemistry

For centuries, natural products have been linked to medicine through traditional remedies and since played an important role in drug discovery.

New structure of tagetitoxin

New tagetitoxin structure based on 2D NMR correlations

Despite competition from other drug discovery methods, natural products have provided their fair share of clinical candidates and commercial drugs. Furthermore, the isolation, synthesis and biological evaluation of natural products often lead to lasting impressions in science.

In a recent study lead by Dr Abil Aleiv of the University College London, the structure of the known natural product tagetitoxin has been revised based on a detailed analysis of newly acquired NMR and MS data. The group employed 2D 1H–13C HMBC correlations and long-range JCH couplings in conjunction with computational analysis to correlate JCH couplings with predicted values.

For several years, the structure of tagetitoxin remained a mystery. First identified in 1981 by Mitchell, the structure was only partially characterized by MS and was proposed to be an 8-membered heteroatomic ring.  Revised structures have since been published by Mitchel (1989), Vassylyev (2005) and Gronwald (2005). Despite all these efforts, conflicting results and incomplete analyses resulted in the absolute configuration remaining undetermined.

Structures of tagetitoxin previously published by Mitchel (1989), Vassylyev (2005) and Gronwald (2005)

Early analysis of complex structures was generally difficult as spectrometers were relatively insensitive and experiments were performed at low-fields strengths. Through the increasing prevalence and utility of modern 2D NMR experiments in the past decade, NMR has become a powerful and enabling tool for structure elucidation and confirmation.

In addition, the key to Dr Aliev’s findings lies in confirming the purity of the tagetitoxin sample the group had acquired. They noted that the compound gradually decomposed in aqueous solutions if left for prolonged periods of time, which they suspect led to additional peaks being observed in previously reported NMR spectra.

This exciting work showcases the importance of technical advances in determining the structure of biologically active natural products with greater ease and confidence. As a result, advances in lead development and the identification of important families of pharmacophores for drug discovery can be attained with greater efficiency, which may contribute to a revival of interest in natural products for drug discovery purposes.

To find out more see:

The structure of tagetitoxin
Abil E. Aliev, Kersti Karu, Robin E. Mitchell and Michael J. Porter
DOI: 10.1039/c5ob02076j


Victoria Corless is currently completing her Ph.D. in organic chemistry with Prof. Andrei Yudin at The University of Toronto. Her research is centred on the synthesis of kinetically amphoteric molecules, which offer a versatile platform for the development of chemoselective transformations with particular emphasis on creating novel biologically active molecules.

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OBC Call for Papers – Selective Chemistry with Peptides and Proteins Themed Issue

Organic & Biomolecular Chemistry is delighted to announce a call for paper for its latest themed issue on: Selective Chemistry with Peptides and Proteins

Guest Editor: Philip Dawson (The Scripps Research Institute, San Diego, USA)

Deadline for Submission: 11 April 2016

OBC offers fast decisions and publication (average time from receipt to first decision for peer reviewed articles is 12 days for communications and 19 days for papers). Colour publication is free and all articles are indexed in MEDLINE. You can choose for your article to be handled by the Cambridge office or one of our Associate Editors: Christian Hackenberger, Lei Liu, Margaret Brimble or Jin-Quan Yu.

Scope

This issue will cover topics including native chemical ligation and other chemical reactions to prepare proteins and peptides, and selective protein modification. We would welcome either a primary research article or a review.

Research in OBC is published as communications (for urgent work – up to 5 pages in length) or full papers. There is also the opportunity to write a Perspective or Review article for the issue, and if you would be interested in this please let us know. All submissions will be subject to rigorous peer review to meet the usual high standards of OBC. Guidelines are available at rsc.li/1K0EgYx and rsc.li/1OoQWQh.

If you are interested in taking part in this issue, please email OBC: obc-rsc@rsc.org

Manuscripts can be submitted using the Royal Society of Chemistry’s online article submission service. Please clearly state that the manuscript is submitted for the themed issue on Selective Chemistry with Peptides and Proteins.

To view recent articles or find out more about OBC, please visit the journal’s homepage:

Organic & Biomolecular ChemistryRapid publication of high quality organic chemistry research



Please note that articles will be published online as soon as ready to ensure no delay in dissemination of your work. Articles for the web theme will be published in regular issues of the journal. The themed issue will then be published online once all articles have been published. Click here for an example of a previous web theme issue in OBC.

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What are your colleagues reading in Organic & Biomolecular Chemistry?

The articles below are the most read Organic & Biomolecular Chemistry articles in July, August and September 2015.

Linear and star-shaped pyrazine-containing acene dicarboximides with high electron-affinity
Jinjun Shao, Jingjing Chang and Chunyan Chi
DOI: 10.1039/C2OB25680K, Paper

Recent synthetic additions to the visible light photoredox catalysis toolbox
Ricardo A. Angnes, Zhou Li, Carlos Roque D. Correia and Gerald B. Hammond
DOI: 10.1039/C5OB01349F, Review Article

Biomineralization-inspired synthesis of functional organic/inorganic hybrid materials: organic molecular control of self-organization of hybrids
Atsushi Arakaki, Katsuhiko Shimizu, Mayumi Oda, Takeshi Sakamoto, Tatsuya Nishimura and Takashi Kato
DOI: 10.1039/C4OB01796J, Review Article

Decarboxylative functionalization of cinnamic acids
Arun Jyoti Borah and Guobing Yan
DOI: 10.1039/C5OB00727E, Review Article

Design and synthesis of analogues of natural products
Martin E. Maier
DOI: 10.1039/C5OB00169B, Review Article

Anatomy of gold catalysts: facts and myths
Beatrice Ranieri, Imma Escofet and Antonio M. Echavarren
DOI: 10.1039/C5OB00736D, Review Article

Copper-catalyzed trifluoromethylation of alkenes: synthesis of trifluoromethylated benzoxazines
Sadhan Jana, Athira Ashokan, Shailesh Kumar, Ajay Verma and Sangit Kumar
DOI: 10.1039/C5OB01196E, Communication

Synthesis of substituted pyrenes by indirect methods
Juan M. Casas-Solvas, Joshua D. Howgego and Anthony P. Davis
DOI: 10.1039/C3OB41993B, Review Article

Enantioselective cooperative catalysis
Suleman M. Inamdar, Valmik S. Shinde and Nitin T. Patil
DOI: 10.1039/C5OB00986C, Review Article

Organic synthetic transformations using organic dyes as photoredox catalysts
Shunichi Fukuzumi and Kei Ohkubo
DOI: 10.1039/C4OB00843J, Review Article

Read more »

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2016 RSC Prizes and Awards in Organic Chemistry & Chemical Biology now open for nomination

Nominate someone you know who is an exceptional talent in chemical sciences

The 2016 RSC Prizes and Awards are now open for nomination!

Nominations will close on 15 January 2016.


For more than 140 years, our Prizes and Awards programme has been acknowledging and celebrating exceptional talent in the chemical sciences, and with your support we are hoping that 2016 will even more successful!

Last year’s winners include Chemists such as Prof. Wilfred van der Donk (University of Illinois), Prof. Tim Donohoe (University of Oxford), Prof. Shuli You (Shanghai Institute of Organic Chemistry), Prof. Philip Gale (University of Southampton), Prof. Herman Overkleeft (Leiden University), Prof. Alison Ashcroft and Prof. Sheena Radford (University of Leeds).

This year we have 63 prizes and awards open for nominations of individuals, teams and organisations covering the breadth of the chemical sciences across academia, education and industry.

This year’s prizes in the field of Organic Chemistry & Chemical Biology include:

CBID (Chemistry Biology Interface Division) awards –

Organic Awards –

For 2016 our Longstaff Prize is also open – since 1881 we have awarded this prize once every three years to one of our members who has achieved the most to advance the science of chemistry.

Submit your suggestions now!

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