As much as I've enjoyed my forays into analytical and flavour chemistry, yesterday afternoon I had a relapse and attended the Arthur C. Cope session on organic chemistry in the cathedral-sized ballroom. Actually, the cathedral analogy doesn't seem a bad one, as sometimes it does feel as if there's a certain amount of worshipping going on.

I really enjoyed this session because it had an ecelectic mix of topics. Highlights for me included Kenneth Shea's talk on how to build polyethylene molecules from single-carbon units, in a living polymerization reaction involving ylides and diazoalkanes. In this way, he's made some unusual polymers - such as chains with high steric congestion that can't be prepared using traditional methods for polyolefin preparation.

I also liked Leonard MacGillivray's presentation on solid-phase organic reactions. He co-crystallizes pairs of organic compounds to form lattices in which hydrogen-bonding aligns the molecules in a perfect orientation for reaction - specifically, photodimerization reactions between alkenes to form cyclobutanes. Because the lattice holds the molecules in very specific orientations, the stereochemistry of the process is precisely controlled.

But my favourites were Dave Macmillan and Andre Charette. Charette described his work on the preparation of chiral amines by adding organozinc reagents to N-phosphinoylimines. Now I've always been a bit dubious about dialkylzinc compounds, because they're a pain to make. But Charette has thought of this, and has developed a relatively simple way to make them from zinc methoxide - so top marks for thinking of the practicalities.

MacMillan discussed his work on SOMO-activation reactions using organocatalysis. I liked the way that he gave much of the credit for this idea to his co-worker, Teresa Beeson. His group are currently developing new reactions using SOMO-activation, so expect to see enantioselective alpha-halogenation of aldehydes, vinylation reactions, and the enentioselective alkylation of cyclic ketones (which apparently requires a completely different catalyst to the one currently published).

All in all it was a top session. The only down-side was the way that people in the audience would get up and leave as soon as the speaker they were interested in had finished. I know that people have to focus on lectures in their own fields to get the most out of these meetings, but if they'd stuck around for the whole session I think they'd have found the variety of topics refreshing and stimulating.

Andy

Andrew Mitchinson (Associate editor, Nature)

Posted by amitchinson at 08:45 AM | Permalink | Comments (0) | TrackBacks (0)

Like Catherine, I'm a bit behind on scientific posts - so here's a quick recap of some of the talks I attended earlier in the week.

My Sunday morning started with an excellent session on malaria/anti-malarials - Solomon Nwaka from the World Health Organization's Special Programme for Research and Training in Tropical Diseases 'kicked off' the session with a broad overview that really drove home why malaria is (still) such an important disease: every 30 seconds a child dies from malaria, and the disease is responsible for more that one million deaths each year. Anti-malarial drug resistance is a huge problem (and there aren't that many new drug candidates in the pipeline), so the session focused on several academic scientists who are searching for new drug candidates. This is often done as a collaboration with Medicines for Malaria Venture, a non-profit organization created to “discover, develop and deliver new antimalarial drugs through public-private partnerships.” (For more information on public-private partnerships, click here and here).

I was only able to stay for the first half of the session, but I heard Jonathan Vennerstrom talk about synthetic peroxide anti-malarials (including this simplified analog of artemisinin) and Paul O'Neill talk about analogs of amodiaquine that were active against drug-resistant strains of malaria (click here for a recent review on 4-aminoquinoline anti-malarials).

The debate about whether or not academic scientists should try to get involved in drug discovery can get quite heated (see Derek Lowe's take on it here; you might also be interested in this NRDD 'Outlook'). Though I understand why some scientists think that academics should avoid this area of research, many pharmaceutical companies aren't willing (or able) to pursue a drug discovery program that focuses on malaria or other important, yet neglected, infectious diseases that disproportionately affect developing countries. (NITD and GSK are important exceptions to this general rule...)

So my question is if many pharmaceutical companies aren't willing/able to tackle these problems, why shouldn't academic groups give it a try?

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 08:26 AM | Permalink | Comments (1) | TrackBacks (0)

This is my final blog from the RSC symposium on synthesis in organic chemistry, and it’s been great. The undoubted highlight came last night, when Ian Fleming (now an emeritus professor) gave a brilliant overview of his career, describing all the influences that culminated in his famous work on the use of silyl groups in organic synthesis.

Starting from his work as grad student, he presented the highs (and occasional lows) of his career with wit and candour. He began his working life in the 1950s, at a time when state-of-the-art spectroscopy meant IR and combustion analysis was often the linchpin of your analytical data. NMR had only just been invented and was only to be used “if you were desperate”, as he put it. And if you did get an NMR, you needed good eyesight, because the resulting spectra were smaller than dollar bills. Even a couple of decades later, 10 g of sample were still required for a carbon-13 NMR experiment.

It was a fascinating story, peppered with amusing anecdotes – for example, as a grad student, he had to cover all his samples with watch glasses, to stop his PhD supervisor from absent-mindedly tipping ash into them from his pipe. And it was fascinating to get the inside story of some of the historic achievements in organic chemistry – such as Woodward’s synthesis of vitamin B12.

Fleming spoke for 90 minutes and was rewarded with a standing ovation – not something that I’ve ever seen before at a chemistry conference. It was an evocative description of a bygone era, delivered by one of the last remaining gentleman chemists, and I felt privileged to witness it.

So, thumbs up to Cambridge. The next meeting in this series will be in two years time – I heartily recommend it, and I hope I’ll see you all there!

Andy

Andrew Mitchinson (Associate Editor, Nature)

Posted by amitchinson at 08:24 AM | Permalink | Comments (0) | TrackBacks (0)

WARNING! This blog entry contains a joke with chemical content! Those of a nervous disposition may want to look away.

For those who didn’t read my last entry, I’m currently at an RSC symposium on organic chemistry, held in Cambridge (UK, not MA). It’s traditional for UK conferences to be held at universities, apparently so the delegates can be shocked at the quality of the food. Last night was particularly cruel, because all the tables were laid out with wine glasses, creating an expectation of alcohol. Sadly, no wine was actually forthcoming, so the delegates had to face the evening lecture unfortified.

Still, we’ve had some cracking talks. Today, Varinder Aggarwal presented some powerful chemistry for homologating boronic esters; this allows carbon chains to be ‘grown’ with control over the relative and absolute stereochemistry. This work has yet to be published, but he reckons the paper will be ready later this year - so keep your eyes peeled.

Shu Kobayashi discussed various topics in catalysis, ranging from scandium complexes that enable carbon-carbon bond formations to be performed in water (click here for an example), to lab-on-a-chip hydrogenations that are performed in channels coated with polymer-encapsulated palladium. And Dean Toste gave an overview of his work on gold catalysis – a truly amazing lecture, delivered with such aplomb and rapidity that it was difficult to tell when he drew breath.

So who told the chemistry joke? It was Amos B. Smith III, at the evening lecture last night. Dithiane groups feature heavily in his work, and he was questioned about the best way of removing them. This prompted the following gag:

Why are there 32 methods for removing dithianes?
Because none of them work…

Andy

Andrew Mitchinson (Associate Editor, Nature)

Posted by amitchinson at 12:37 PM | Permalink | Comments (0) | TrackBacks (0)

I don’t seem to be having much luck at conferences recently. At the ACS meeting in Chicago earlier this year, I was given a hotel room without a bed. Yesterday, I turned up for an RSC symposium on organic synthesis and there wasn't even a room for me. At this rate, I’m assuming that when I arrive in Boston for the autumn ACS meeting I’ll discover that my hotel doesn’t exist.

Anyway, once the small issue of my accommodation was sorted out, I had a fun evening catching up with some familiar faces until very late in the night. I’m now experiencing that familiar conference feeling of being very tired but totally wired on coffee.

The lectures this morning kicked off in fine style with Steve Davies. You could hear the scratching of pens on paper coming from all around as he described lots of useful synthetic organic chemistry reactions (including an amazingly stereoselective variant of the Horner-Wadsworth-Emmons reaction – I’ll post the details of the paper once it gets published). Incidentally, I’ve commented before that chemists often seem to have splendid hair, but Steve’s must surely win all the prizes…

Another highlight was Ben List’s talk on new strategies in organocatalysis, including some very neat ideas on chiral Bronsted acid cataysis using phosphoric acid derivatives – see this paper for an example. Contributing to the truly international flavour of the symposium, Goverdhan Mehta from the Indian Institute of Science presented some of his total syntheses of biologically active natural products. Worryingly, he began by defending total synthesis, which he thinks is being marginalized – does anyone agree with him?

OK, that’s plenty for now, but I’ll update you on other interesting stuff tomorrow.

Andy

Andrew Mitchinson (Associate Editor, Nature)

Posted by amitchinson at 10:26 AM | Permalink | Comments (3) | TrackBacks (0)

One thing that really irritates me is badly drawn ChemDraw structures (maybe I should get out more...).

Anyway, there is no excuse for a benzene ring not being a perfect hexagon - unless of course you’re showing perspective or drawing a fullerene or nanotube. Double and triple bonds should be well separated so that they don’t just look like thick bonds. And as for angles... unless there’s a really good reason for it not to be 120 or 180 degrees (depending on the hybridisation flavour of your [carbon] atoms), then there is likely something wrong; in flatland, even your sp3 centres should be 120 degrees unless you're showing the stereochemistry and need to draw all four bonds. Atom labels should be in a consistent font (preferably Helvetica) and should be of a size that does not require one to use some kind of electron microscope to read them.

Simple really... so why do a lot of ChemDraw structures that appear in papers or on slides at conferences look like a six-year old has drawn them with a crayon (and I mean a particularly untalented six-year old at that - one that probably wouldn't even win a Blue Peter drawing competition)? I think it’s just people being lazy...

I’ve been to a couple of conferences in the last month and gasped in horror (that may be a slight exaggeration) at some of the representations of C60 I’ve seen. Somewhat annoying is when the double bonds are drawn inside the pentagonal rings - please, can everyone just agree from now on to put them in the six-membered rings (surely it makes more sense that way?) . When I confronted one speaker about the ChemDraw crimes they had perpetrated, I was told that they’d just used the template... - and yes, it turns out that some of the C60 structures in the template library have dubious patterns of bonding...

Even worse, I see the occasional 5- and 6-bonded carbon atoms in fullerenes (and pyrene seems to fall into that trap as well). Maybe it shouldn’t get under my skin as much as it does, but this is how organic chemists communicate - and wrong is wrong. You wouldn’t use ‘2’ in an equation if it called for the square root of 2, so let’s be a bit more careful about our structures.

Right, soap-box carefully stowed away now for another day...

Stuart

Stuart Cantrill (Associate Editor, Nature Nanotechnology)

Posted by Stuart Cantrill at 06:26 AM | Permalink | Comments (9) | TrackBacks (0)

In this week's issue of Nature, there's an Insight - a special collection of six or seven related review articles - on Glycochemistry & Glycobiology. In this particular Insight, there are seven review articles:

Chemical glycosylation in the synthesis of glycoconjugate antitumour vaccines from Galonic & Gin

Unusual sugar biosynthesis and natural product glycodiversification from Thibodeaux, Melancon, & Liu

Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins from Hart, Housley, & Slawson

Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins from Varki

Heparan sulphate proteoglycans fine-tune mammalian physiology from Bishop, Schuksz, & Esko

Exploiting the defensive sugars of HIV-1 for drug and vaccine design from Scanlan, Offer, Zitzmann, & Dwek

Synthesis and medical applications of oligosaccharides from Seeberger & Werz

There's also a paper from van Kasteren et al. (with a News & Views from Grotenbreg & Ploegh) describing a new chemical tagging approach that can be used to add multiple sugars to bare protein scaffolds (i.e., proteins that were over-expressed and purified from bacteria). (You may have also noticed Wang et al's paper in last week's Nature, so it looks like April may be the sweetest - and not the cruelest - month after all...)

As I wrote in the editorial that accompanies the Insight, scientists generally shy away from carbohydrates - I barely remember learning about them in my undergraduate years and spent little time thinking about them during graduate school. But now it seems like the field is exploding: everywhere you look there's an interesting paper about carbohydrate chemistry and biology.

So with that in mind, we've put together this collection of review articles to celebrate chemists and biologists working with carbohydrates... We hope you enjoy them!

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 01:54 PM | Permalink | Comments (2) | TrackBacks (0)

Having bravely explored the wilds of inorganic chemistry, I decided to meander back to the more familiar territory of organic synthesis, by way of some organometallic chemistry. Braving the overly effective air-conditioning, I shivered through a terrific session in honour of David Milstein. I enjoyed listening to Ilan Marek, who gave a beautifully clear account of some pretty hardcore asymmetric organic synthesis, involving lots of zinc, copper and lithium species. Milstein himself gave a historical overview of his work, including his cool stuff on carbon-carbon bond activation.

But my favourite speaker was Bob Bergman, who wowed the crowd with his latest research on reactions mediated by nanovessels (or cavitands). I love this work - Nature covered some of it in a News & Views article by Julius Rebek last year. Bergman described unpublished results showing that uncharged organic bases (tertiary amines) are actually trapped by cavitands as protonated ammonium cations. This means that acid-catalysed reactions can be perfomed in basic solution! Very nice indeed. Don't forget that we have a News & Views feature article on C-H activation by Bergman in the March 22nd issue of Nature.

It was, all in all, a brilliant day, which ended with that traditional conference activity, a long night in the bar. As a result I'm now feeling a bit like a run-down battery, but that's also traditional after a few days. Time to stoke myself up with coffee, I think...

Andy

Andrew Mitchinson (Associate Editor, Nature).

Posted by amitchinson at 01:15 PM | Permalink | Comments (0) | TrackBacks (0)

Though Lake Michigan is quite beautiful, it's pretty tough to appreciate the view when you're in the back of a stalled bus in the middle of Lakeshore Drive. Luckily, it only took 15 minutes for a replacement bus to arrive...

Despite this minor setback, I made it to the conference center in time to see most of the symposium in honor of Dave Evans. Evans talked about a few recent total syntheses from his group, including Oasomycin A, which was recently completed (see also these two papers). He's a great speaker who really holds your attention for the whole talk: he only discusses the most interesting reactions/transformations (and not every single step of the synthesis) and he uses some color (but not too much) to draw your attention to key atoms and/or newly formed bonds.

Later on in the afternoon, I made my way over to see Regan Thomson's talk on his recent synthesis of (+)-symbioimine. I really enjoyed his talk - I've known Regan for years and it's always exciting to see people you know publish interesting work... But the chair of the session really didn't bring her 'A' game today - she had trouble pronouncing his name (calling him 'Dr. Thomas' twice), fumbled through the word 'osteoclastogenesis,' and completely mis-pronounced the name of the molecule. OK - I agree that 'osteoclastogenesis' isn't a very common word, but I think it's pretty important to get the names of the people in your session correct. (Maybe I'm just overly sensitive about names, as so many people have trouble pronouncing mine...)

Well I'm bushed and it's not even 10 PM - it's amazing how exhausted you can get by running around from session to session... For those of you who are here in Chicago, how's your meeting going? What session/talk/event has been the most enjoyable for you? What are you looking forward to seeing tomorrow?

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 09:48 PM | Permalink | Comments (0) | TrackBacks (1)

I made it in to Chicago late last night (only two hours late, which for isn't that bad for O'Hare...) There must have been a few chemists on my flight, as I wasn't the only person who chuckled when they announced that our pilot's name was Dave Evans...

I got up early this morning to check email, plan my day at the conference, and make a few last minute adjustments to an iPod playlist (it's a 20-25 minute bus ride from my hotel to the convention center). When traveling for work, I usually create a playlist to 'match' the location of the conference: Radiohead works well if you're heading off to an RSC conference, but a meeting in Chicago really calls for some Robert Johnson and Muddy Waters... (This isn't always easy - I'm not sure what I'm going to do for the 2009 ACS meeting in Salt Lake City. Any suggestions?)

Anyways, this morning I saw a great talk from Dennis Dougherty - most of the talk focused on cation-pi interactions in ligand-gated ion channels (for example, the Cys-loop superfamily) and how his laboratory has used unnatural amino acid mutagenesis to dissect how nicotinic acetylcholine receptors work (click here for his Nature paper from 2005 - I think it's a great demonstration of how organic/physical organic chemistry can be used to reveal how a biological system works...)

After grabbing a quick (and remarkably expensive) bite to eat, I went to Linda Hsieh-Wilson's and Jotham Coe's talks, both of which were great. Coe talked about Varenicline/Chantix, which looks like it'll really be able to help people who want to quit smoking.

If you're blogging from the conference, please let us know/please feel free to mention it in the comments section - so far, I know that

Richard from Chemistry World

Egon from chem-bla-ics

Kyle from The Chem Blog

are here (I'm not sure if all of them are blogging, though...) As Katharine mentioned, her news@nature blog posts can be found here.

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 06:13 PM | Permalink | Comments (2) | TrackBacks (0)

Just a quick post about a couple of papers I saw while surfing through Angewandte Chemie earlier today.

The best porphyrin structure I've seen for a while is right there in Early View - Harry Anderson and cohorts in Oxford have used a porphyrin to template the formation of a conjugated octaporphyrin ring (thought I'd mention this before carbon-based curiosities get a hold of it... I'll see about getting our blogroll updated as ChemBark needs a direct link as well...).

Other than that, there's an essay about Mendeleev that will keep me occupied on the train this evening, 100 years since he died apparently...

Stuart

Stuart Cantrill (Associate Editor, Nature Nanotechnology)

Posted by Stuart Cantrill at 10:27 AM | Permalink | Comments (1) | TrackBacks (0)

Looking for something to read while you're waiting for the rotovap to free up or the PAGE gel to finish running? You might want to take a look at yesterday's issue of Nature, which has a number of chemistry/chemical papers. In addition to the paper by Serreli et al. that Katharine and Stuart mentioned, there's a News & Views piece from Steven Nolan on Craig Forsyth's recent ACIE paper and a paper from Stern et al. that describes miniature, ultra-sensitive sensors that can detect unlabeled antibodies at concentrations below 100 femtomolar (and can monitor the cellular immune response in 'real-time').

There's also a cool paper involving the TRPA1 channel - TRP channels respond to "temperature, touch, pain, osmolarity, pheromones, taste, and other stimuli," and the TRPA1 channel specifically responds to a range of structurally-diverse compounds, including mustard oil, acrolein, and icilin.

In Macpherson et al., the authors used 'click chemistry' to show that derivatives of mustard oil and cinnamaldehyde covalently bound to the TRPA1 channel. They used mass spectrometry to identify fourteen TRPA1 cysteine residues that reacted with iodoacetamide, three of which were required for normal channel function. From a chemical standpoint, this might not seem all that surprising, but this is apparently the first ion channel known to be activated by this mechanism, and I think it's interesting to see how "tuning TRPA1 to respond to covalent modification by reactive compounds ... [enables the nervous system to] directly assess the noxious environment of sensory neurons." For those of you teaching biological/bio-organic chemistry courses, this might make a good test question - it's a nice 'real world' example of how understanding basic organic chemistry can be used to explore how an enzyme works...

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 02:57 PM | Permalink | Comments (0) | TrackBacks (0)

I saw an amazing BBC documentary a few years ago called "Bad Medicine" - the documentary focused on Dora Akunyili, the Director General of Nigeria's National Agency for Food and Drug Administration and Control (NAFDAC), and her efforts to eradicate fake pharmaceuticals/counterfeit drugs in Nigeria.

Before Akunyili took over her post in 2001, a staggering 80% of the medications sold there were deficient in one way or another. Some contained less of the active ingredient than was specified on the label. Others were past their expiration date. Some were filled with inert lactose or powdered chalk.

The stories she told were astonishing: after cracking down on the counterfeiters, they "fought back ... [burning] down Nafdac's offices and threaten[ing] to kill her and her children"; "snipers opened fire on her car ... [and] a bullet pierced through [her] head scarf and grazed [her] scalp"; when the International Children's Heart Foundation visited Nigeria to perform heart surgery on children, four died because someone had replaced the adrenaline with water. It was a heart-wrenching documentary about how far some people will go to make money, and how hard it is to stop them: the World Health Organization "estimates up to 25% of medicines consumed in developing nations are counterfeit or substandard" and this problem isn't restricted to countries in the developing world.

So I was excited to read a recent news@nature.com story by Katharine Sanderson about a paper that just came out on Analytical Chemistry's ASAP. The authors used spatially offset Raman spectroscopy (SORS) to examine ibuprofen and paracetamol (acetaminophen), without removing them from their blister packs/bottles - the hope is that existing handheld Raman spectrometers could be turned into portable SORS detectors and that these devices could be used by people like Dora Akunyili to quickly determine whether or not a drug is counterfeit...

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 03:52 PM | Permalink | Comments (1) | TrackBacks (0)

Hi everyone - sorry it's been such a long time since I've posted. December and January are pretty crazy months around here... (There's usually a huge spike in submissions at the end of each year and it often takes a few weeks to work our way through the long backlog... Now that things have quieted down a bit, I hope to post more regularly...)

Anyways, a comment from yesterday's In the Pipeline caught my eye:

You never seem to discuss the current absymal [sic] state of employment for chemists. What reality are you living in? Maybe you should stick to the 'chemistry is fun talk'? You do your field a disservice by constantly ignoring reality.

Now I certainly don't want to trivialize how difficult it can be to find a job in the pharma/biotech sector, but those of you who aren't happy with your current position/are looking for another job might want to read this 'Careers and Recruitment' piece that was recently published in Nature Reviews Drug Discovery. The article focuses on two "biopharma company founders" - Alice Huxley (President and Chief Executive Officer, Speedel) and Dominic Behan (Chief Scientific Officer and Senior Vice President, Arena Pharmaceuticals) - who "discuss their experiences and highlight factors that have been important for success."

Huxley was a global project manager working on renin inhibitors, and after the merger of Sandoz and Ciba–Geigy (to create Novartis) it looked like that project was in jeopardy - Huxley "believed strongly in the potential" of the lead renin inhibitor in the program and was able to convince the management to "let me take on the project within Speedel and prove that it would work." The outcome? That compound - Aliskiren - is now in Phase III clinical trials. Behan founded Arena Pharmaceuticals with two colleagues in 1997 and has helped it grow to 300 employees. They now have a drug candidate - Lorcaserin - in Phase III trials for obesity and several other compounds in clinical and preclinical development.

So let's say you have a great idea and want to start your own company - what's the next step? How do you turn those late-night conversations at the pub with your coworkers into a real company? (And I don't mean a garden in your backyard that you call a 'massive pharmaceutical factory.') Though I know a few people who have started their own biotech companies (and though there's lots of information about venture capital companies on the web), I don't have any personal experience in this area... Maybe some of our readers have been through this process and know what to do next/who to approach with your ideas?

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 11:59 AM | Permalink | Comments (2) | TrackBacks (0)

Banert et al. recently published the first synthesis of tetraazidomethane (and some of its "exciting chemistry"). Like it's cousin triazidomethane, this compound is highly reactive/explosive:

Safety Precautions: Tetraazidomethane (1) is extremely dangerous as a pure substance. It can explode at any time - without a recognizable cause. Less than a drop ... is able to destroy completely not only the glass trap but also the vacuum Dewar flask of the cooling bath.

It looks like it's a lot easier to make than octanitrocubane, so we'll just have to hope that there aren't any terrorists out there who subscribe to ACIE... (As an aside, I don't think there are any official policies for papers that contain explosive chemical reagents, but when it comes to biological papers that contain information that could be exploited by terrorists, many journals "have a policy in which editors will screen and, if necessary, reject manuscripts submitted for publication if 'an editor ... conclude(s) that the potential harm of publication outweighs the potential societal benefits.'")

Though this study sounds somewhat esoteric at first, when tetraazidomethane was reacted with norbornene, the authors isolated two unexpected 5-aminotetrazole derivatives (see Scheme 2). The authors haven't done a detailed mechanistic analysis yet, so a bit more work is needed to learn exactly what's going on - in the meantime, I think this would be a great question to test your students' (or friends') arrow-pushing skills...

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 11:09 AM | Permalink | Comments (5) | TrackBacks (0)

If you live in the Boston area and you're an organic chemist, you've probably heard about the upcoming Novartis Symposium on Advances in Organic Synthesis to honor Professor Dave Evans. (Thanks to Paul Bracher for this info.) It's on Tuesday (December 5th) at MIT's Kresge Auditorium and there's an excellent lineup of speakers. I think you can still sign up (and it's free...)

Kresge Auditorium is a stone's throw away from the Miracle of Science Bar & Grill, so if I don't bump into you during one of the breaks, keep an eye out for me at the end of the day - maybe we can grab a post-symposium pint...

Hope to see you there,

Joshua

Joshua Finkelstein (Senior Editor, Nature)

Posted by Joshua Finkelstein at 12:33 PM | Permalink | Comments (0) | TrackBacks (0)

J.J. La Clair, the controversial chemist (for background, see http://www.nature.com/news/2006/060731/full/442492c.html) in the mutton chop sideburns, gave a talk today to a packed room. It was hot, stuffy, and young in there, as he talked us, mic-less, through what he called "an approach used in a number of labs that I've developed, optimized and made easier to use." As far as I could tell as a layman, the approach had to do with designing synthesis of natural products with florescent labeling and biological tests in mind. I'll leave an evaluation of the technical content to others more synthesis (or biology)-savvy than I. I'll just mention that his first slide talked about his Xenobe Research Institute (which is pronounced "zen-OH-bee"). His slide said that the company was working on 80 studies with academe, industry and government. He must be a pretty busy man.

He acknowledged the contretemps over his claimed synthesis of hexacyclinol—and even included on his acknowledgement page a shot of the T-shirt being sold which memorializes the controversy, saying that he salutes creativity in all forms. And yes, that was my headline on the shirt, but I didn't write it. Reporters very rarely write our own headlines—but we do get to write our own blog post titles. So I decree that the title of this post shall be: "butternut squash soup", since that is what I am eating right now.

Posted by Emma Marris at 08:57 PM | Permalink | Comments (0) | TrackBacks (0)

I went to a talk on by UCSB's Robert Vestberg, on "Synthesis of hydrogels with well defined network structure using Click chemistry", because I have been hearing this buzzword floating around – "click chemistry"—and I wanted to figure out what it was.

But first, hydrogels. Hydrogels are polymers all cross-linked together and stuffed with water. They can be useful in medicine, for example, as soft contact lenses. They are biocompatible, key molecules can diffuse through them, and they are tough. Often the crosslinks are induced by a blast of radiation—like UV light, for example.

Vestberg and his colleagues are using "click chemistry" to do their linking. The click concept was described quickly as a reaction catalyzed by copper (I) that seems to be a one-size-fits-all room temp process that organizes your molecules into a regular structure. Functional groups can be knitted right in.

At least that was the impression I got. The meeting room in the Marriot was next to some sort of noisy kitchen or workroom, and it was hard to concentrate. It sounded like they were banging the lumps out of large cookie sheets on the other side of the wall. The "backing up" beep of some kind of vehicle was also intermittently heard.

Anyway, the hydrogels are made in little Teflon molds. You can make them with other fluids besides water, too. "We've done it in crappy Australian wine that I got from my boss," says Vestberg, who is pleased with his gels, which can be stretched to 1500% their original length before they break, much more than UV crosslinked hydrogels.

After the talk, I did some reading on click chemistry, which was invented by Barry Sharpless. It seems like a kind of Lego chemistry to me. You may be interested to know that searching the program of abstracts for this meeting with the term "click" yields 42 hits.

Posted by Emma Marris at 01:18 PM | Permalink | Comments (2) | TrackBacks (0)

I went to the carbohydrate-protein interactions and glycolipids session this morning (I'm at the ACS, in case you forgot). It was a great session! Even with the best efforts from the session chair, there were so many questions that we got way behind (which unfortunately meant that I missed George Wang's talk due to a previous engagement). One particularly interesting part of the morning was yet another tribute to Emil Fischer, who seems to have done more work in his life than occurs in a year at most universities. In this particular story, Jacqueline Gervay-Hague was discussing the troubles with substituting sugars at the alpha position, and had tried to use trimethylsilyl iodine in combination with an alcohol to activate the center and incorporate the alcohol as a substituent. To her amazement, her student didn't form the ester, but instead purified the iodated sugar. They looked back in the literature for any precedent of stable iodo-substituted sugars, and found that Fischer not only made them, but crystallized them back in 1910. The secret? The alpha-substituted sugar is stable, whereas the beta-functionalized position reacts right away. They have since used this insight to couple unprotected lipids to TMS-protected sugars; with the right purification conditions, they get the unprotected final product in one step.

Catherine Goodman (Assistant Editor, Nature Chemical Biology)

Posted by Catherine Goodman at 05:41 PM | Permalink | Comments (0) | TrackBacks (0)

The morning session of the Arthur C. Cope Award and Arthur C. Cope Scholar Awards just finished - I was really impressed with F. Dean Toste's talk, which was a whirlwind tour of some of the work his group has done involving gold(I)-catalyzed reactions.

There are now a number of groups exploring the chemistry of gold(I) and gold(III) complexes - Toste's group has focused on gold(I) complexes, which are air-/moisture-tolerant and able to catalyze a number of reactions, including the stereoselective cyclopropanation of olefins and intramolecular acetylenic Schmidt reactions (making substituted pyrroles). They've also shown that these reactions can be used to make natural products, recently demonstrating that the gold(I)-catalyzed cyclization of a silyl enol ether onto an alkyne enabled them to rapidly synthesize (+)-lycopladine A (in eight steps with 17% overall yield from the starting enone).

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 03:17 PM | Permalink | Comments (0) | TrackBacks (0)

In yesterday's issue of Nature, we published a paper from Amir Hoveyda's and Mark Snapper's groups at Boston College. The paper describes a simple metal-free catalyst that can perform enantioselective catalytic silylations on a variety of meso 1,2-diols, obtaining mono-protected chiral diols.

In the accompanying News & Views article, Scott Denmark wrote

The chemical yields and enantiomeric selectivities of the reactions are very good - in some cases, excellent - although the reaction times are long (2-3 days). Relatively large amounts of the catalyst are required, but this is not a problem as the catalyst is simple to prepare from inexpensive starting materials. Clearly this is just the beginning of a development process and more active catalysts will be forthcoming.

These kinds of catalysts could shave several steps off synthetic routes to prostaglandin analogues, unnatural nucleosides, and neocarzinostatin analogues, which currently require a number of chemical transformations and an enzymatic de-acylation to obtain a key building block. By shortening the synthetic route, the amount of chemical waste produced can be minimized and the amount of time needed to make the molecule can be dramatically reduced. Denmark concludes the News & Views article by saying that

this procedure is likely to have a significant impact on the efficiency and cost of constructing single-enantiomer products. Most importantly, however, this report demonstrates the creative power of synthetic chemistry to build simple organic catalysts that mimic and ultimately surpass, biological catalysts - especially for non-biological transformations.

Collaborations between two well-known organic chemistry labs aren't extremely common, and Hoveyda talked about this phenomenon on our 'Authors' page:

Hoveyda says the synthetic organic chemistry field has traditionally been wary of two principal investigators sharing credit on single papers. "The culture almost discourages it," he says. Early on, colleagues warned Snapper that working with a more senior researcher could hurt his career. But their partnership has been fruitful; the two have received joint grants from the National Institutes of Health since 1997 and have published about 20 papers together. "The reason this collaboration has been so successful is that neither of us cares who gets the credit," Hoveyda adds.

If you’d like to learn more about the research, Hoveyda was interviewed on this week’s Nature Podcast (he also appears on the recent chemistry podcast). And if you're in San Francisco at the Fall ACS Meeting next week, you can see Yu Zhao talk about the work on Monday afternoon.

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 04:04 PM | Permalink | Comments (1) | TrackBacks (0)

For some reason, many non-scientists (and even some scientists) see chemists as "nefarious creators of toxic pollutants ... [or] mad scientists brewing up Love Potion #9 in ... [a] cluttered and archaic laboratory." Or worse yet, they think chemistry is boring and/or useless...

The editorial in the September 7th issue of Nature tries to capture why organic chemistry is interesting and attempts to explain some of the things that excite the 'average' organic chemist. (Though the editorial is mainly about organic chemistry, I think many of the statements in the editorial are true for other areas of chemistry...)

Many organic chemists spend their days searching for creative solutions to real-world problems, yet the media pays them just a fraction of the attention devoted to physicists or biologists. Even fellow scientists think organic chemistry is esoteric ... [But a]sk a group of organic chemists why they love their work ... and most will tell you that it enables them to make things that no one else has made before ... [C]hemists are frequently drawn to the field because there is not just one way to solve the problem, and the search can reveal a bit more about how the world works.

When people ask me why I like being an editor, I often tell them that it's like being a first year graduate student again: every day I get to read exciting chemistry papers and often feel like that "child in a sweetshop" - there are so many interesting discoveries out there, and countless problems that still need to be solved. The excitement peaks when I'm at a meeting - I love going to sessions and hearing people talk about their unpublished/newly published work, meeting students and post-docs at the poster sessions, and chatting with speakers after the talks about their future plans...

With that in mind, I hope to bump into you at the ACS meeting next week - keep an eye out for Catherine Goodman (from Nature Chemical Biology), Mirella Bucci (from Nature Chemical Biology), and Emma Marris (from the Nature news team) who are also in town for the meeting. And don't forget to check back here regularly, as we'll be blogging throughout the meeting...

Hope to see you there,

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 02:01 PM | Permalink | Comments (2) | TrackBacks (0)

In the September issue of Nature Chemical Biology, John Silvius wrote about McGill University's interdepartmental graduate program in chemical biology, which was established in 2002 and now has "roughly 30 graduate students, 10 postdoctoral fellows and 30 faculty mentors."

The program involves scientists from the Department of Biochemistry, the Department of Chemistry, and the Department of Pharmacology and Therapeutics, and a "key objective of the program is to maximize opportunities for students with chemistry and life science backgrounds to share and appreciate their sometimes distinct perspectives on the field of chemical biology." Silvius wrote that this is accomplished via seminar discussion meetings, workshops, and an "annual research symposium at which students present their work to other students and faculty mentors."

There are other interdepartmental and multi-institutional graduate programs in chemical biology: for example, there is the Cornell/Rockefeller/Sloan-Kettering Tri-Institutional Training Program in Chemical Biology in New York City (which involves Cornell University, The Rockefeller University, Memorial Sloan-Kettering Cancer Center, and the Weill Medical College of Cornell). Graduate students in the Tri-Institutional Training Program can rotate in (and join) laboratories at any of the institutions and they do not have to teach classes, "enabling them to take an accelerated course schedule (four courses per semester during the first year)." (Although I understand that the program was designed so the students could take a large number of classes, I really enjoyed teaching during graduate school and think it's an important experience for all graduate students. But I'll save that topic for another blog post...)

There's obviously more than one way to train the next generation of chemical biologists, but Silvius believes that

An effective training program in chemical biology must produce graduates who have a distinct sense of intellectual identity yet can work effectively with researchers that are more conventionally trained either in chemistry or in the life sciences alone... Moreover, by promoting constant intermixing of individuals trained in the cultures of chemistry and biology, such a program allows students to be participants in the very type of stimulating, creative ferment that drives the field of chemical biology itself.

If you are a graduate student in (or a recent graduate of) an interdepartmental or multi-institutional graduate program in chemical biology, I'd be interested in hearing your thoughts about your program/your experiences. Why did you choose an interdepartmental or multi-institutional graduate program, instead of a Department of Chemistry & Chemical Biology? (And for those of you who did their graduate work in a Department of Chemistry & Chemical Biology, why didn't you choose an interdepartmental or multi-institutional graduate program?) For those of you working on the interface of other disciplines (for example, biophysics, chemical physics, bionanotechnology, etc.) did your graduate program meet your (scientific) needs/expectations? If not, what could they have done to make it easier for you to pursue interdisciplinary research?

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 10:31 AM | Permalink | Comments (4) | TrackBacks (0)

You might remember endosymbiotic theory from your high school or college biology classes: it's the idea that some organelles (for example, mitochondria and chloroplasts) were originally separate prokaryotic organisms that were engulfed by eukaryotic cells. Although it's not clear how or why this occurred, this became a mutually beneficial relationship for both cells (i.e., a symbiotic relationship), resulting in the organelle-containing cells that appear in biology textbooks (and in our bodies...)

But why - you might ask - would a chemist care about endosymbionts (organisms that live inside other organisms)? Well I think they're interesting because "[b]acterial symbionts have long been suspected to be the true producers of many drug candidates" isolated from natural sources. For example, there is some evidence that the antitumor polyketides of the pederin family are produced by an uncultured bacterial symbiont of Paederus beetles, which can cause dermatitis.

Late last year, Partida-Martinez & Hertweck discovered that another natural product (rhizoxin) is not biosynthesized by the fungus Rhizopus microsporus itself, but by a bacteria that lives inside the fungus. In a follow-up paper in JACS, these authors were able to isolate a rhizoxin-producing bacterial strain from the fungus ("Burkholderia rhizoxina") and could grow it in liquid culture. They lysed the cells, and found (quite surprisingly) that "about 40% of the crude extract is composed of rhizoxin derivatives" - in addition to rhizoxin, Burkholderia rhizoxina produces a number of related structures.

The authors determined that some of these natural products were 1,000 to 10,000 times more active than rhizoxin in cell-based assays (the assay was looking at antiproliferative activity). Rhizoxin went through extensive clinical trials in the 1990s and showed some promise as an anti-cancer drug, though it was not taken into Phase III clinical trials because it was not active enough in vivo. These authors hope that, since the derivatives they isolated are more active in vitro, they might more successful in the clinic. And since the natural products can be harvested from bacterial cultures, it may be possible to rapidly produce a large amount of these complex natural products without having to resort to chemical synthesis.

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 11:30 AM | Permalink | Comments (0) | TrackBacks (0)

The collection, preparation, and analysis of chemical compounds using miniaturized devices are appealing for many reasons: the use of smaller reagent volumes can reduce the time needed to synthesize and analyze a product, the amount of chemical waste produced and the overall costs can be reduced by performing chemical reactions in these 'lab-on-a-chip' devices, and compact devices also allow samples to be analyzed at the point of need rather than at a centralized laboratory. For these reasons, chemists are now using these devices to create new molecules and materials, and biologists are employing these devices to study complex biological problems. Furthermore, labs on chips offer ‘point-of-care’ diagnostic abilities that could revolutionize medicine.

To highlight our interest in this exciting field, the July 27th issue of Nature contains an Insight (a collection of topical articles and reviews) which discuss the history, design, current applications, and the promising future of these 'lab-on-a-chip' devices:

The origins and the future of microfluidics (Whitesides)
Scaling and the design of miniaturized chemical-analysis systems (Janasek et al.)
Developing optofluidic technology through the fusion of microfluidics and optics (Psaltis et al.)
Future lab-on-a-chip technologies for interrogating individual molecules (Craighead)
Control and detection of chemical reactions in microfluidic systems (deMello)
Cells on chips (El-Ali et al.)
Microfluidic diagnostic technologies for global public health (Yager et al.)

There’s also a news story from Jenny Hogan on microreactors. (And you may want to check out 'Clicks and chips’ and Haswell’s recent News & Views article on Belder et al.)

For a complete list of Insights, click here - we hope you enjoy these reviews!

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 10:11 AM | Permalink | Comments (1) | TrackBacks (0)

When it comes to marine natural products, there's certainly no shortage of chemically-interesting, highly toxic molecules: for example, there's saxitoxin ("Exposure to saxitoxin might cause ... muscle weakness, vertigo, and cranial nerve dysfunction. Respiratory failure and death might occur from paralysis.") and brevetoxin ("Gastrointestinal symptoms include abdominal pain, vomiting, and diarrhea. Neurologic symptoms include paresthesias, reversal of hot and cold temperature sensation, vertigo, and ataxia. Inhalational exposure to brevetoxin results in cough, dyspnea, and bronchospasm.").

So ciguatoxin may seem quite mild by comparison: "symptoms include nausea, vomiting, diarrhea, cramps, excessive sweating, headache, and muscle aches. The sensation of burning or "pins-and-needles," weakness, itching, and dizziness can occur. Patients may experience reversal of temperature sensation in their mouth, ... unusual taste sensations, nightmares, or hallucinations. Ciguatera poisoning is rarely fatal."

It can be extremely challenging to isolate these molecules (for example, only "0.35 mg of ciguatoxin [was] extracted from 4000 kg of moray eels") and many of these molecules (and other marine toxins) have complex molecular architectures that have fascinated synthetic chemists for years.

Although maitotoxin (one of the largest and most toxic marine natural products) has not been synthesised (yet), many other marine toxins have been made in the lab: the synthesis of (+)-saxitoxin was described earlier this year (Fleming & Du Bois), brevetoxin A and B were synthesized years ago (brevetoxin A; brevetoxin B), and earlier this month, the syntheses of the two most toxic ciguatoxins (ciguatoxin and 51-hydroxyCTX3C) were reported in JACS (Inoue et al.). One highlight of the ciguatoxin synthesis involved a radical cyclization reaction which stereospecifically formed a key seven-membered ring in the middle of the molecule (the 'G' ring)...

But have no fear, not every natural product made by a marine organism is ultra toxic: Fuwa et al. just reported the synthesis of the proposed structure of brevenal, a pentacyclic polyether natural product. For some reason, this molecule actually "displaces tritiated dihydrobrevetoxin-B ... from voltage-sensitive sodium channels in a dose-dependent manner and acts as a natural brevetoxin antagonist in vivo."

After making the proposed structure, the authors noticed that "[u]nfortunately, 1H and 13C NMR data ... were not identical to those reported for the natural sample ... On the basis of these NMR variations, along with the proposed biosynthetic pathway for marine polycyclic ethers, we think that the correct structure of brevenal is most likely represented by the C26 epimer of the [molecule we synthesized]." But keep your eyes peeled for their next paper, as they say that "efforts toward structural determination and total synthesis of brevenal are underway and will be reported in due course."

Joshua

Joshua Finkelstein (Associate Editor, Nature)

Posted by Joshua Finkelstein at 04:20 PM | Permalink | Comments (2) | TrackBacks (0)

I'm sure many of you know that Bruce Merrifield passed away a few weeks ago. In today's issue of Nature, Stephen Kent wrote an obituary describing Merrifield and his accomplishments.

If your institution subscribes to the ACS archives, you can download "Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide" (you should be able to download the first page for free). According to C&EN, this was the "fifth most cited paper in the journal’s 125-year history."

You may also want to take a look at Gutte's & Merrifield's classic 1971 JACS paper, in which they reported the synthesis of ribonuclease A (124 amino acids long: this "required 369 chemical reactions and 11,931 steps of the automated peptide synthesis machine without any intermediate isola