Archive for the ‘Chemistry World articles’ Category

Stirring microwave synthesis

It is next to impossible to achieve good mixing with traditional magnetic stir bars in the cylindrical vessels used in microwave synthesis. So scientists in Austria have designed a new stir bar. 

Stirring-up-microwave-synthesis_c3ob40790j_300mMicrowave synthesis is becoming more popular thanks to the dramatically reduced reactions times and improved yields it offers. However, as the majority of these reactions involve a small narrow reaction vessel, traditional horizontal stir bars often result in inefficient mixing which can cause temperature gradients to develop and reduce product yields. 

Magnetic stirring usually involves a polymer coated AlNiCo or ferrite magnet and relies on the establishment of a liquid flow induced by centrifugal forces. These flow patterns involve a downward liquid motion towards the centre and an upward motion at the vessel wall. However, the strength of the magnet decreases rapidly over a period of months when subjected to the high temperatures of microwave synthesis and the limited size of the vessel restricts the establishment of flow patterns. 

‘We noticed that in some instances the agitation of the reaction mixture using a standard magnetic stir bar was very poor. Sometimes the stirrer was not moving at all,’ says Oliver Kappe whose team at the University of Graz used a camera to look at a microwave system before designing the new stir bar. 

Choice of magnetic material and shape were thought to be key to the success of the new stir bar. Vertical blade extensions were added to a more robust Sm2Co17 rare earth magnet. This not only extends the life of the stir bar but also significantly enlarges the cross-sectional area of the stirrer. A gap in the centre of the bar guarantees backflow which enforces flow patterns and extended blades mean that even the upper part of the system receives efficient mixing with the incorporation of additional holes and cut-outs inducing additional turbulence.

Read the full story in Chemistry World 

Design and evaluation of improved magnetic stir bars for single-mode microwave reactor
David Obermayer, Markus Damm and C. Oliver Kappe
Org. Biomol. Chem., 2013, Accepted Manuscript
DOI: 10.1039/C3OB40790J

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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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An end to chasing molecules that were never there?

Imagine finally completing a 30 step total synthesis only to discover that the molecule you were aiming for was the wrong one. The consequences of structural misassignment of complex organic molecules can be costly and time consuming, not to mention frustrating. Now, a new NMR method aims to highlight errors in proposed structures at a much earlier stage, preventing such scenarios.

NMR spectroscopy is a standard tool for elucidating the structure of organic molecules. This may be a straightforward job when confirming the identity of small molecules. However, in the case of complex molecules, the task becomes much more difficult and errors can result in the wrong structure being proposed.

Ariel Sarotti from the Rosario National University, Argentina, has developed a new, computationally inexpensive method combining calculated and experimental 13C NMR data to flag up incorrect structures. This rapid and simple process can determine if a candidate structure is incorrect, using trained artificial neural networks (ANNs) to find patterns in both the calculated and experimental data to do the decision making. A set of 200 molecules with known correct and incorrect NMR assignments was used to create and train the system. The subsequent testing phase correctly identified the incorrect structures of a set of 26 natural products. While some knowledge of computational chemistry is required, Sarotti’s development of an Excel spreadsheet tool will allow chemists to use the method without being experts in ANNs, making it much more accessible.

new-NMR-method_c3ob40843d-ga_630

Read the full story in Chemistry World

Successful combination of computationally inexpensive GIAO 13C NMR calculations and artificial neural network pattern recognition: a new strategy for simple and rapid detection of structural misassignments
DOI: 10.1039/C3OB40843D

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New diagnostic test lights up bacteria

Fluorescent probe before (left) and after (right) addition of S. aureusUK researchers have developed a faster way to detect Staphylococcus aureus bacteria using a fluorescent probe. The method holds promise as the basis for a new rapid diagnosis kit to identify infections in hospital patients.

S. aureus infections, including both methicillin-resistant and methicillin-susceptible strains (named MRSA and MSSA, respectively), persist in hospital wards worldwide. In the UK, controlling outbreaks is a constant challenge for the NHS. Fast diagnosis is as important as thorough treatment in the early stages of an outbreak. However, current screening methods are slow and costly.

‘The problem with existing techniques is that they take time,’ explains Adam Le Gresley, of Kingston University, who lead the team that developed the probe. ‘You either have to amplify the bacteria in culture, or amplify the DNA with PCR. It’s not something that can be done at the point of care.’

To address this, Le Gresley and his colleagues have developed a test that is sensitive to very low levels of bacteria, eliminating the need for culture. The method utilises staphylothrombin, an enzyme complex unique to S. aureus. It employs a test solution comprising a tripeptide chain, which mimicks staphylothrombin’s natural target, that is bound to rhodamine, a fluorescent dye. When S. aureus is present, it releases staphylothrombin which frees the rhodamine from the tripeptide by cleaving an amide bond. This results in a strong colouration in the solution.

Read the full story in Chemistry World

Development of an in situ culture-free screening test for the rapid detection of Staphylococcus aureus within healthcare environments
Alex Sinclair, Lauren E. Mulcahy, Lynsey Geldeard, Samerah Malik, Mark D. Fielder and Adam Le Gresley
DOI: 10.1039/c3ob40150b

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Flow synthesis for anticancer drug

The flow-based route required minimal manual intervention and was achieved despite poor solubility of many reaction components

UK chemists have used a combination of flow chemistry methods with solid-supported scavengers and reagents to synthesise the active pharmaceutical ingredient, imatinib, of the anticancer drug Gleevec. The method avoids the need for any manual handling of intermediates and allows the drug to be synthesised in high purity in less than a day.

Gleevec, developed by Novartis, is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours. The drug molecule represents a particularly challenging target for flow chemistry because of the low solubility of many of the reaction components required for its synthesis. The team devised a new synthesis route that prevents the equipment blockages from product precipitation and avoids many of the labour and time intensive practices of traditional batch-based preparation.

The work proved to be a challenge. Steve Ley, at the University of Cambridge, who led the team, says that along the way, they ‘met some considerable obstacles and dead ends’. He remarks that ‘in order to overcome the need to change solvents between some of the reaction stages, we had to invent a new in-line evaporator, which served us well in this and in later synthesis studies’.

Unlike the conventional industrial synthesis of Gleevec, this newly developed route couples molecular fragments in a modular approach. Thomas Wirth, who works on microreactor technology at Cardiff University, UK, remarks that ‘although not designed to compete with the industrial synthesis, the modular approach allows an easy variation of building blocks for the efficient and rapid generation of Gleevec analogues for screening purposes’.

A total of nine analogues were synthesised using the final equipment set-up, which were then screened for anticancer activity. The findings revealed that the piperazine group in the drug molecule plays a role in receptor binding, rather than simply acting as a solubilising group as previously thought.

Ley’s team is now working to combine the synthesis and screening to provide information on products rapidly, as well as extending their approach to new functional materials.

Read the Organic & Biomolecular Chemistry paper, for free for 4 weeks here:

An expeditious synthesis of imatinib and analogues utilising flow chemistry methods
Mark D. Hopkin, Ian R. Baxendale and Steven V. Ley
Org. Biomol. Chem.
DOI: 10.1039/C2OB27002A

Story first published in Chemistry World.

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Following her passion – an interview with Veronique Gouverneur

Veronique Gouverneur

Veronique Gouverneur is professor of chemistry at the University of Oxford, UK. She investigates fluorine chemistry and is working on developing novel synthetic methodologies for the preparation of fluorinated targets. The OBC team have been fortunate enough to work with Veronique for the past 6 years in her role on our Editorial Board, from which she has recently retired, and as such we are very pleased to bring you this interview with her.

What inspired you to be a scientist?

I’ve always been interested in science. My love for chemistry was perhaps related to my dad’s career. He was an engineer and secured a PhD in theoretical chemistry, but after a few years as an academic, he changed his career path to become a diplomat. He worked for the United Nations Educational, Scientific and Cultural Organization (UNESCO), but was still involved in the science area. That was probably an inspiration to me as I was familiar with chemistry at home.

I found science easier at school than any other subject, but I did hesitate between chemistry and maths; I was so clumsy that I thought chemistry was perhaps not the best way forward. But chemistry was what I enjoyed the most and what I wanted to do. Chemistry is all about creativity and, as such, is somehow related to art: you create a molecule (useful or not!) and can endow it with a function. It’s a unique dimension to one particular subject.

Click here to read the complete interview…

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Stereospecific total synthesis of (+)-myrrhanol C achieved

Spanish chemists have completed the stereospecific total synthesis of (+)-myrrhanol C.

(+)-Myrrhanol C is a natural triterpene isolated from mastic gum (the resin of Pistacia lentiscus), a substance well known for its medicinal properties as well as use in various cuisines. The compound itself was used to embalm corpses in ancient Egypt. More recently, it has been recognised as a promising anti-prostate cancer lead. However, before a molecule can be used to develop drugs, a successful synthesis must be developed.

Mastic gum (from Pistacia lentiscus, pictured) has been used for many applications, from treating snakebites to tooth whiteners. © Science Photo Library

Alejandro Barrero and his group at the University of Granada have done just that. Their synthesis starts with (–)-sclareol, a bicyclic diterpene alcohol isolated from clary sage (Salvia sclarea). It then proceeds through a key C–H oxidation step, which is achieved with cytochrome P450 enzyme catalysis by incubating a reaction intermediate with the fungus Mucor plumbeus.

By cultivating clary sage, Barrero can sustainably produce (–)-sclareol, meaning (+)-myrrhanol C can be made on a large scale that is also environmentally friendly.

Read the full story in Chemistry World

And read the OBC paper, highlighted as being HOT by the referees, for free here:
First synthesis of (+)-myrrhanol C, an anti-prostate cancer lead
Victoriano Domingo, Lidia Lorenzo, José F. Quilez del Moral and Alejandro F. Barrero
DOI: 10.1039/C2OB26947C

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