Archive for the ‘Hot articles’ Category

HOT – Novel copper-mediated cyclisations leading to diverse heterocyclic structures

copper-mediated oxidative coupling
In this HOT paper, Peter Kündig’s research team have developed a new mode of copper-mediated oxidative coupling allowing access to racemic (aza)oxindole structure in an efficient and atom-economic fashion.

Oxindoles are useful structures in organic chemistry as they are found ubiquitously in nature. Molecules bearing this motif have a range of interesting biological properties and new methods of their construction are always useful to the organic chemist.

Peter Kündig and his team at the University of Geneva have been looking into the asymmetric synthesis of these structures, employing palladium-catalysed intramolecular α-arylations of amide substrates.[1] During these studies, they discovered a novel and efficient route to access racemic 3,3,-disubstituted oxindoles which employed a copper-mediated radical reaction.[2] This reaction has also been applied to the racemic synthesis of aza-oxindoles.[3]

In this excellent account from Prof. Kündig, this methodology has been further explored. The substrate scope has been expanded leading to a range of oxindoles bearing a variety of aromatic, hetero- aromatic, allyl and heteroatom substituents in the 3-position. The reaction was also successfully performed on a large scale, with excellent yield and regioselectivity. In addition to this, some nifty DFT and computational studies confirm the proposed mechanism and regioselectivity.

Read the full article here.

Copper(II) chloride mediated (aza)oxindole synthesis by oxidative coupling of Csp2–H and Csp3–H centers: substrate scope and DFT study
Chandan Dey, Evgeny Larionov and E. Peter Kündig
Org. Biomol. Chem., 2013,  DOI: 10.1039/c3ob41254g


[1] E. P. Kündig, T. M. Seidel, Y. X. Jia and G. Bernardinelli, Angew. Chem., Int. Ed., 2007, 46, 8484; Y. X. Jia, J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Kündig, Chem. Commun., 2008, 4040.

[2] Y. X. Jia and E. P. Kündig, Angew. Chem., Int. Ed., 2009, 48, 1636.

[3] C. Dey and E. P. Kündig, Chem. Commun., 2012, 48, 3064.

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HOT Organic & Biomolecular Chemistry articles for August

Pd(0)-catalyzed benzylic arylation–oxidation of 4-methylquinazolines via sp3 C–H activation under air conditions
Dan Zhao, Min-Xue Zhu, Yue Wang, Qi Shen and Jian-Xin Li
Org. Biomol. Chem., 2013,11, 6246-6249
DOI: 10.1039/C3OB41488D, Communication 

  


Major mechanistic differences between the reactions of hydroxylamine with phosphate di- and tri-esters
Michelle Medeiros, Eduardo H. Wanderlind, José R. Mora, Raphaell Moreira, Anthony J. Kirby and Faruk Nome
Org. Biomol. Chem., 2013,11, 6272-6284
DOI: 10.1039/C3OB40988K, Paper
From themed collection In Celebration of Andrew D. Hamilton’s Career in Chemistry  

 


Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a Vapreotide analogue containing (S)-α-methyllysine
Souvik Banerjee, Walker J. Wiggins, Jessie L. Geoghegan, Catherine T. Anthony, Eugene A. Woltering and Douglas S. Masterson
Org. Biomol. Chem., 2013,11, 6307-6319
DOI: 10.1039/C3OB41282B, Paper


Synthesis of novel pyrazole-based heterocycles via a copper(II)-catalysed domino annulation
Márió Gyuris, László G. Puskás, Gábor K. Tóth and Iván Kanizsai
Org. Biomol. Chem., 2013,11, 6320-6327
DOI: 10.1039/C3OB41146J, Paper


Structure–activity studies of 4-phenyl-substituted 2′-benzoylpyridine thiosemicarbazones with potent and selective anti-tumour activity
Adeline Y. Lukmantara, Danuta S. Kalinowski, Naresh Kumar and Des R. Richardson
Org. Biomol. Chem., 2013,11, 6414-6425
DOI: 10.1039/C3OB41109E, Paper

 


Transport of macrocyclic compounds across phospholipid bilayers by umbrella-rotaxanes
Christine Chhun, Josée Richard-Daniel, Julie Kempf and Andreea R. Schmitzer
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB41209A, Paper

 


Bifunctional building blocks in the Ugi-azide condensation reaction: a general strategy toward exploration of new molecular diversity
Steven Gunawan and Christopher Hulme
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB40900G, Paper 

 


Comparative in vitro studies of MR imaging probes for metabotropic glutamate subtype-5 receptor targeting
Sven Gottschalk, Jörn Engelmann, Gabriele A. Rolla, Mauro Botta, David Parker and Anurag Mishra
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB41297K, Paper 

 


Synthesis and biological evaluation of non-isomerizable analogues of Ala-tRNAAla
Denia Mellal, Matthieu Fonvielle, Marco Santarem, Maryline Chemama, Yoann Schneider, Laura Iannazzo, Emmanuelle Braud, Michel Arthur and Mélanie Etheve-Quelquejeu
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB41206G, Paper 

 


First synthesis of antitumoral dasyscyphin B
Ali Akhaouzan, Antonio Fernández, Ahmed I. Mansour, Esteban Alvarez, Ali Haidöur, Ramón Alvarez-Manzaneda, Rachid Chahboun and Enrique Alvarez-Manzaneda
Org. Biomol. Chem., 2013, Advance Article
DOI: 10.1039/C3OB41290C, Paper                                          

Open Access  

 

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Tethered aldo/keto-acids/esters unlock new bis-hetrocyclic tetrazolo scaffolds

The classical Ugi multi-component reaction can be used to generate a peptidic-like molecule, with 4 points of diversification, from an aldehyde, an amine, an isocyanide and a carboxylic acid. In the Ugi-azide reaction, the carboxylic acid is replaced with trimethylsilyl azide, providing a convenient route to 1,5-disubstituted tetrazoles. This scaffold is a bioisostere for the cis-amide bond.

In the HOT article, Gunawan and Hulme report the use of Ugi-azide reactions to generate a series of different bis-hetrocyclic tetrazolo scaffolds, facilitated by variation of the linker group in the aldo/keto-acids/esters. These scaffolds may aid the development of new molecular probes for the investigation of peptidergic biological systems.

Bifunctional building blocks in the Ugi-azide condensation reaction: a general strategy toward exploration of new molecular diversity

Bifunctional building blocks in the Ugi-azide condensation reaction: a general strategy toward exploration of new molecular diversity
Steven Gunawan and Christopher Hulme
DOI: 10.1039/C3OB40900G

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Don’t underestimate the power of the dark side

Electrophilicity - the dark side of indole reactivity

In this PERSPECTIVE article, Marco Bandini presents an overview of indole electrophilicity, illustrated with a range of pertinent examples of this “dark-side” of indole reactivity.

Indoles are one of the most common heterocyclic motifs found in nature. These bicyclic arenes have had a profound impact on drug discovery, materials science, catalysis and many other areas of chemistry.

Professor Marco Bandini and his research group at the Università di Bologna specialise in indole “decoration” and the development of new methodology for the chemical manipulation of this functional group.

The indolyl core is, as Bandini explains, “spectacularly nucleophilic” and this accounts for a large proportion of the literature contributions. There is, however, also a relatively undeveloped side of their reactivity: “electrophilic” indoles.

While there are many examples of this type of reactivity, some of which date back to the 1960s, it remains in the shadow of the well-understood and established chemistry that explores the indole core’s innate nucleophilicity. The opportunities to expand the chemical portfolio of indole decoration, via nucleophilic substitutions and additions, are still largely unexplored.

The ubiquity of this core means that new ways to functionalise and manipulate indoles will always be a welcome addition to the organic chemist’s toolbox. As Bandini discusses, exploitation of the umpolung chemistry of these functional groups provides access to a wide diversity of chemical structures.

This Perspective article elegantly documents the electrophilic nature of indoles, and highlights some of the important discoveries and developments in this field. It is a must-read for anyone interested in these intriguing molecules.

Give yourself to the dark side and check out the article here.

Electrophilicity: the “dark-side” of indole chemistry
Marco Bandini
DOI: 10.1039/C3OB40735G

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Thalidomide teams-up with turmeric to kill myeloma cells

Cancer researchers in the US and China have combined the turmeric spice pigment curcumin and the drug thalidomide to create hybrid compounds that can kill multiple myeloma cells.

curcumin-thalidomide-hybrid-structure_300Multiple myeloma is the second most common type of blood cancer, killing 20% of affected patients each year. The drug thalidomide, banned after causing birth defects when given during pregnancy in the 1950s, was recently rediscovered and approved for the treatment of multiple myeloma. Thalidomide works by disturbing the microenvironment of tumour cells in bone marrow. However, it disintegrates in the body. Curcumin, a yellow pigment from the common spice turmeric, is also active against cancers, including myeloma, but is limited by its poor water solubility.

Shijun Zhang at Virginia Commonwealth University, US, and colleagues, have synthesised compounds combining structural features from both thalidomide and curcumin. ‘The hybrids have enhanced solubility, and higher toxicity against myeloma cells than curcumin, thalidomide, or a mixture of both,’ explains Zhang, ‘so our design rational is going in the right direction.’ Zhang says the hybrids kill myeloma cells through combined mechanisms of action that include the generation of reactive oxygen species and cell cycle inhibition.

Read the full story on Chemistry World.

K Liu et al, Org. Biomol. Chem., 2013, DOI: 10.1039/c3ob40595h

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Carboxylate-isostere analogs of daptomycin: synthesizing the next generation of antibiotics

The emergence of multi-drug resistant bacterial infections has created a pressing need for the identification of new drugs. This HOT article describes the chemical modification of daptomycin, an antibiotic used to treat Gram-positive bacterial infections.  Because of its anionic character daptomycin has a high affinity to pulmonary surfactants, but this limits its use in the treatment of pulmonary infections.

Scott Miller and co-workers hypothesized that reducing surfactant interactions may increase the antibiotic activity of daptomycin. Consequently, they set out to convert the daptomycin carboxylic acid moieties to carboxylate isosteres. This paper reports a direct and efficient procedure to produce isostere analogues of daptomycin, suppressing backbone-cyclization side reactions. The use of a high resolution UPLC-MS/MS technique to characterise the synthetic products by fragmentation analysis is also described.

carboxylate-isostere analogs of daptomycin

An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin
Sabesan Yoganathan, Ning Yin, Yong He, Michael F. Mesleh, Yu Gui Gu and Scott J. Miller
DOI:
10.1039/C3OB40924D

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Latest HOT articles in OBC

Promiscuity of a modular polyketide synthase towards natural and non-natural extender units
Irina Koryakina, John B. McArthur, Matthew M. Draelos and Gavin J. Williams
DOI: 10.1039/c3ob40633d

Promiscuity of a modular polyketide synthase towards natural and non-natural extender units

Synthesis of bis-α,α′-amino acids through diastereoselective bis-alkylations of chiral Ni(II)-complexes of glycine
Jiang Wang, Hong Liu, José Luis Aceña, Daniel Houck, Ryosuke Takeda, Hiroki Moriwaki, Tatsunori Sato and Vadim A. Soloshonok
DOI: 10.1039/c3ob40594j

Synthesis of bis-α,α′-amino acids through diastereoselective bis-alkylations of chiral Ni(II)-complexes of glycine

Aerobic C–H amination of tetrahydrocarbazole derivatives via photochemically generated hydroperoxides
Naeem Gulzar and Martin Klussmann
DOI: 10.1039/c3ob40919h

Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym corannulenes
Martin Mattarella, Jaime Garcia-Hartjes, Tom Wennekes, Han Zuilhof and Jay S. Siegel
DOI: 10.1039/c3ob40438b

Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym corannulenes

Chemical-genetic identification of the biochemical targets of polyalkyl guanidinium biocides
Drew Bowie, Paria Parvizi, Dustin Duncan, Christopher J. Nelson and Thomas M. Fyles
DOI: 10.1039/c3ob40593a

Chemical-genetic identification of the biochemical targets of polyalkyl guanidinium biocides

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Switching chirality in amino acids

An international team of scientists has developed a purely chemical approach to interconvert L- and D-amino acids. This method could rival enzymatic routes used in industry, and enable cheaper production of some pharmaceuticals. interconversion-of-amino-acids_c3ob40541a_300m

 While L-amino acids are an inexpensive and renewable source of chiral molecules, used by all cells to synthesise proteins, D-amino acids are scarce in nature and consequently more expensive. Despite their rarity in biological systems, D-amino acids are widely used in the pharmaceutical industry, occurring in many drugs, including antibiotics such as penicillin and anticancer agents such as goserelin.

Currently, D-amino acids are prepared industrially by enzymatically resolving racemic mixtures of amino acids. A readily available source of D-amino acids would obviate the need for resolution, simplifying synthetic routes to many pharmaceuticals.

Vadim Soloshonok, Ikerbasque Research Professor at the University of the Basque Country, Spain, and his colleagues, used inexpensive nickel(II) acetate and a modularly designed chiral ligand derived from α-(phenyl)ethylamine to transform natural amino acids into their unnatural enantiomers. A Ni(II) amino acid Schiff base complex with three stereogenic centres, including a stereogenic nitrogen, was formed under mild and operationally simple reaction conditions. The complex enables the stereocontrolled deprotonation of the α-carbon of amino acids to invert their stereochemistry.

Soloshonok says that this methodology could have a potentially huge impact on the multi-billion dollar amino acid market. ‘D-amino acids are starting materials in the synthesis of pharmaceutical drugs and if we can reduce the price of the starting materials we can make the pharmaceuticals more affordable to people.’

Read the full story in Chemistry World

Chemical approach for interconversion of (S)- and (R)-α-amino acids
Alexander E. Sorochinsky, Hisanori Ueki, José Luis Aceña, Trevor K. Ellis, Hiroki Moriwaki, Tatsunori Sato and Vadim A. Soloshonok
DOI: 10.1039/c3ob40541a

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New neuraminidase inhibitors to combat bird flu

Avian influenza is an RNA virus, with subtypes classified by hemagglutanin and neuraminidase (NA) viral surface membrane glycoproteins. There are 9 NA serotypes of influenza A circulating within the avian population (N1-N9). At present, there are two commercially available NA inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza) and the threat of drug-resistant viruses is driving the development of new NA inhibitors.

The X-ray crystal structure of zanamivir-bound N1 show the C-4 guanidino group of zanamivir  located near the 150-loop adjacent to the active site of NA.  In this HOT article, Tsu-An Hsu, Chun-Cheng Lin and co-workers report the synthesis and inhibitory activity of a series of zanamivir derivatives with modified C-4 guanidino groups. The new, structurally modified zanamivir analogues retained inhibitory activity against H1N1 and H3N3 avian influenza viruses.

Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities

Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities
Chien-Hung Lin, Tsung-Che Chang, Anindya Das, Ming-Yu Fang, Hui-Chen Hung, Kai-Cheng Hsu, Jinn-Moon Yang, Mark von Itzstein, Kwok Kong T. Mong, Tsu-An Hsu and Chun-Cheng Lin
DOI: 10.1039/c3ob40624e

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HOT – Taxol analogues offer promising new anti-cancer leads

In this HOT paper, K. C. Nicolaou and co-workers have developed a series of taxol analogues which show potent activity against several cancerous cell lines.

The fight against cancer is one of the hottest areas of drug discovery. Despite this, there is still a shortfall in treatment options and the disease is on the rise. The development of safer and more selective drugs is therefore required.

Paclitaxel (taxol) and docetaxel are two of the most highly successful anti-cancer drugs and much research has been performed focused on their synthesis and structure. K C Nicolaou and his group at Scripps are well-versed in the construction of paclitaxel; the group published one of the first total syntheses of this complex molecule in 1994.

10-Deacetylbaccatin III is an advanced synthetic precursor to paclitaxel and shares many its core structural features. Thanks to the synthetic efforts of recent years, it’s also readily accessible and therefore it provides an interesting starting point for further structure-activity relationship studies. Nicolaou and Valiulin have found that, upon treatment with diethylaminosulfur trifluoride (DAST), 10-deacetylbaccatin III undergoes a nifty vinylogous pinacolpinacolone rearrangement leading to a new enone structure and its fluorinated analogue.

Nicolaou and Valiulin have capitalised on this discovery and have prepared an small library of structurally analogous taxoids using this reaction. The library of analogues was submitted to screening program run by the National Cancer Institute (NCI) where the compounds were evaluated against 60 different cancerous cells lines. Several of the taxoids showed significant potency against numerous tumour cell lines. This study has revealed important information regarding the structure-activity relationship of the taxoid family of molecules. It has also produced some promising potential leads for new anti-cancer drugs.

Synthesis and Biological Evaluation of New Paclitaxel Analogs and Discovery of Potent Antitumor Agents

Synthesis and Biological Evaluation of New Paclitaxel Analogs and Discovery of Potent Antitumor Agents
Kyriacos C. Nicolaou and Roman A. Valiulin
DOI: 10.1039/C3OB40654G

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