Chemical Science Blog

US scientists have synthesised by a new route a key intermediate for the production of synthetic analogues of natural antibiotic tetracyclines that could be used as potential new drugs to combat the growing ranks of antibiotic resistant bacteria.

Andrew Myers and coworkers from Harvard University, Massachusetts, have developed a scalable five step route to an enone intermediate, which can be converted to a range of tetracyclines in three steps. The products are also crystalline at many stages, so there’s no need for purification by chromatography.

The team made the enone by coupling a cyclohexenone with an ester – two inexpensive starting materials made in a few steps from simple precursors. ‘We’ve reduced the problem of tetracycline synthesis to the synthesis of the enone, because from that molecule, you can make completely new tetracyclines,’ says Myers. ‘All tetracyclines that have been approved as drugs in the last 60 years have been made by semi-synthesis – in which fermentation products are used as starting materials – and chemists’ ability to modify these natural products has been limited. We wanted to see if we could develop a completely synthetic route.’

The enone intermediate, a precursor to tetracyclines, was made in five steps by coupling a cyclohexenone with an ester

Myers can now make tetracyclines with modifications all around the structure’s periphery and even in the interior portion. The reaction that transforms the enone into thousands of antibiotics is a Michael-Claisen cyclisation on the left side of the enone, he explains. But it’s also possible to use a similar transformation to modify the right side. ‘Because we’ve got a de novo construction of the enone, we can modify portions of the enone and greatly expand the number of new tetracyclines we can make. In fact, if you think about it, you realise it’s a multiplicative expansion because the expansions on the right side can be coupled with those on the left,’ explains Myers…

To read more, please visit the Chemistry World website or download the Chemical Science Edge Article, which is free to access until the end of 2011! 

The basic components of cells can operate within the bounds of inorganic membranes made from nanoparticles, a new study shows. The authors say such membranes provide an alternative model for explaining how the first cells evolved from simple, inorganic molecules.

Chemists created silicon-based membranes with hydrophilic and hydrophobic properties akin to those of lipid bilayers in natural cells. Nanoparticles self-assembled in oil to form ‘protocells’, enclosing drops of water inside porous silicon shells. ‘What was really interesting was that not only could we stabilise the droplets – which had been shown before – but that the nanoparticle-based shell could be considered as a primitive, semi-permeable inorganic membrane,’ says Stephen Mann, one of the researchers based at the University of Bristol, UK.

A simple reaction to functionalise the surface of the nanoparticle-stabilised droplets prevents entrapped biomolecules escaping into the water around them

To produce the desired water-loving/hating membrane, the researchers functionalised the surface of hydrophilic silica nanoparticles with silanol and dimethylsilane groups. Shaking the nanoparticles in oil and water made them pack together at the oil-water interface. According to Mann, the approach is simpler than chemical syntheses required to make artificial phospholipids, which are often used in artificial cell membranes…

To read more please visit the Chemistry World website, or you can download the Chemical Science Edge Article, which is free to access until the end of 2011!

Some Alzheimer’s drugs work by blocking the activity of acetylcholinesterase, an enzyme that degrades the neurotransmitter acetylcholine to choline. To find new enzyme inhibitors, researchers need to identify choline formation, or the loss of acetylcholine, so they can tell whether the enzymatic reaction has stopped. But, acetylcholine and choline are both quaternary ammonium ions with very similar structures, making it difficult to distinguish between them.

To overcome this problem, teams led by Werner Nau at Jacobs University Bremen, Germany, and Yu Liu at Nankai University, China, have combined two sequential enzymatic reactions with a calixarene macrocycle that binds to a fluorescent dye to make a tandem assay that can screen for new inhibitors. The enzymes are highly specific and only work on one substrate.

The tandem reaction involves a fluorescence ''switch-on'' displacement assay as a sensor for specific analytes

In their assay, they use acetylcholinesterase to turn acetylcholine to choline. A second enzyme – choline oxidase – turns the choline into betaine. While choline and betaine are similar, they have different affinities for binding within the calixarene. Because of this difference, the dye can replace the betaine inside the calixarene. This turns off the dye’s fluorescence, which is easy to detect. If the enzymatic reactions are inhibited, no betaine will be produced and so the dye’s fluorescence stays on……

To read the full story, please visit the Chemistry World website or download the Chemical Science Edge Article, which is free to access until the end of 2011!

Spanning a vast field of chemistry and biology, it is hard not to notice the flurry of activity and excitement surrounding chemical biology research at the moment. We are seeing chemistry being cleverly applied to biology, in an attempt to understand and answer important biological questions, by directly probing living systems at the chemical level. Areas such as proteomics, glycobiology, combinatorial chemistry, RNA/DNA, microarrays, proteins, peptides (and many, many more!) are becoming prominent topics in the general chemistry literature.   

Here at Chemical Science, we have two fantastic Associate Editors, who handle all submissions in the chemical biology and bioorganic fields; Professor Thomas Carell (Ludwig-Maximilians-Universtät München, Germany) and Professor Benjamin F Cravatt (Scripps, USA). We also have the full support from our dynamic team of chemical biology experts on the Chemical Science Advisory Board; Ben Davis, Linda Hsieh-Wilson, Scott Miller, Paul Reider, Oliver Seitz, Weihong Tan and Jason Chin. 

Chemical Science Associate Editor, Professor Benjamin Cravatt

Why not submit your own exciting chemical biology research to Chemical Science today? Our Associate Editors, Professors Thomas Carell and Benjamin Cravatt, handle all submissions within the chemical biology field and eagerly await your next exciting, high impact submission!

Chemical Science Associate Editor, Professor Thomas Carell

We’ve already published some excellent articles in the field of chemical biology and below we’ve given you a little taster. As a reminder, all articles published in Chemical Science are free to access until the end of 2011, so go ahead and enjoy the free content!

One last thing, you may also be interested to know that the following ISACS5 conference is coming up soon too:-

– Call for posters – deadline 27 May 2011
– Early bird registration – deadline 27 May 2011
– Registration – deadline 24 June 2011

Many congratulations to Professor David MacMillan from the Chemical Science team, who has won the ACS award for creative work in Synthetic Organic Chemistry.

We are delighted to learn that Professor MacMillan, Editor-in-Chief for the Royal Society of Chemistry’s new flagship journal Chemical Science, has been recognised for his contributions to organic chemistry, especially for his ground breaking research in organocatalysis.  

Professor MacMillan sporting a Chemical Science hat at the Pacifichem meeting back in December (2010)

Professor MacMillan has published a couple of Edge Articles in Chemical Science, which are freely available for you to download:-  The organocatalytic three-step total synthesis of (+)-frondosin B  Maud Reiter, Staffan Torssell, Sandra Lee and David W. C. MacMillan Chem. Sci., 2010, 1, 37–42   Total synthesis of diazonamide A Robert R. Knowles, Joseph Carpenter, Simon B. Blakey, Akio Kayano, Ian K. Mangion, Christopher J. Sinz and David W. C. MacMillan Chem. Sci., 2011, 2, 308-311

Professor MacMillan will receive his prize at the 241st ACS national meeting in Anaheim, CA, in the spring. Dr Robert Eagling, Chemical Science Managing Editor, will also be attending this meeting and if you would like to arrange a meeting with Robert, then please contact the Chemical Science Editorial Office. 

Strychnine, best known as a poison but also used medicinally as a stimulant, can now be synthesised in just six steps, say US scientists.

Christopher Vanderwal and his team from the University of California, Irvine created four new carbon-carbon bonds and a carbon-oxygen bond in four steps on the way to making strychnine.

‘Until recently, the fastest synthesis was completed by Viresh Rawal [from The Ohio State University, US] in 14 steps,’ says David MacMillan, an expert in organocatalysis from Princeton University in the US. ‘For a molecule of this complexity, 14 steps is an amazing accomplishment. To be able to complete this in just six steps is simply incredible and something I didn’t necessarily think would ever be possible.’

Defining the shortest route to complex, useful molecules is an important step in uncovering the most efficient way to produce these targets, says Vanderwal. ‘While the overall efficiency of our route isn’t any better than previous routes, the number of chemical operations needed is less than any predecessor,’ he says.

The synthesis began with a pyridinium ring opening reaction to form donor-acceptor dienes known as Zincke aldehydes

The team began with a century-old pyridinium ring opening reaction called the Zincke reaction – named after German chemist Theodor Zincke – in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitrochlorobenzene and a primary amine. This led to the formation of donor-acceptor dienes known as Zincke aldehydes. The next steps involved an intramolecular Diels-Alder reaction, a ruthenium catalysed hydrosilylation and a rearrangement-intramolecular conjugate addition leading to an aldehyde that was then converted to strychnine   

‘Strychnine is the oldest and perhaps most famous “celebrity molecule”,’ remarks MacMillan. ‘Total syntheses of this molecule are among the most famous of all completed to date. As such, the field of total synthesis uses strychnine synthesis as a molecular benchmark.’ 

‘Its first synthesis by Robert Burns Woodward, reported in 1954, stands as an absolute classic,’ adds Vanderwal. ‘Woodward’s pioneering achievement and the numerous syntheses since then have taught us about synthesis strategy, biosynthesis, reaction design, asymmetric catalysis, and more.’ 

Vanderwal sees the ability to build up complex molecular scaffolds in very few steps using their predictable reactivity pattern as the way forward. ‘It need not be a Zincke aldehyde, and the targets need not be indole alkaloids,’ he says. ‘The onus is on organic chemists to increase our ability to make molecules in the most efficient way possible.’   

Elinor Richards

Link to Chemical Science article:-

A synthesis of strychnine by a longest linear sequence of six steps
David B. C. Martin and Christopher D. Vanderwal, Chem. Sci., 2011
DOI: 10.1039/c1sc00009h