Month: July 2012

Trip the light fantastic.

Posted on by doctorgalactic

Alert! Alert! Shameless plug for my own chemistry contained within!

I would be totally missing an opportunity if I didn’t blog about some chemistry that is very close to my heart, so here’s a little ode to my PhD work. My thesis a.k.a the bane of my life for three whole months that consumed every single waking hour, until my brain felt like it had been pulverised into the ground…*ahem*  …what was I saying?

Oh yes, my thesis was entitled “The Double [3+2] Photocycloaddition reaction“.

I’m sure some of you will have quickly beaten a retreat when you noticed the prefix “photo-” in that there sentence. Photo-chemistry is an oft maligned area of research because it can be quite a fickle mistress, that behaves in unusual ways compared to your standard thermal chemistry (those high energy states just love to do crazy shit!). There are also the many practical considerations you have to account for: purity of reagents, solvent selection, direct or sensitized irradiation (do you need a sensitizer?), the specialist equipment, quantum yield measurements (which are a pain in the behind I can tell you) and the hazards of high energy UV radiation.

Of course, none of this should put you off, because what you can do with photo-chemistry is pretty darn marvelous. You see, one of synthetic organic chemistry’s greatest challenges is to create step-efficient routes toward compounds with high molecular complexity (i.e. to make something complex as possible in as few a steps possible). Therefore, reactions which provide more than one bond in a single step are of significant importance (see the Diels-Alder reaction).

In my own work we reported an intriguing case of a double [3+2] photocycloaddition reaction that resulted in the formation of a complex cis, cis, cis, trans-[5, 5, 5, 5] fenestrane derivative  from a simple aromatic acetal as shown in scheme 1.

Scheme 1 An example depicting the photochemical  reactions of arenyl-diene photosubstrate, including the double [3+2] photocycloaddition reaction.

During this transformation, four carbon-carbon bonds, five new rings and seven potentially new stereocenters are created in an essentially one-pot process using only UV light (at 254 nm). Here’s an X-ray crystall structure of it, because X-ray crystal structures always make your chemistry 100% more legit:

You can’t dispute this little beauty.

The reaction actually occurs in a sequential manner from the linear meta photocycloadduct (for a detailed review of the meta photocycloaddition reaction click here or here), via a secondary [3+2] addition of the alkene across the cyclopropane of the adduct. In addition, an angular meta photocycloadduct also produced in the initial addition step, undergoes an alternative fragmentation-translocation photoreaction to afford an angular triquinane compound. Scheme 2 gives a little idea of mechanistic stuff.

Scheme 2: A mechanistic summary of the reactions involved in the irradiation of the linear meta photocycloadduct.

We also produced a series of other fenestranes (including my favourite nitrogen containing variant) through the same method which can be found in our follow-up paper in JOC. I think we really only scratched the surface of this chemistry, but due to a set of unfortunate circumstances which I’d rather not recollect, the work has had to cease for the time being. I’d like to go back to it some day because it’s quite a unique area.

Fenestranes are quite rare in nature and their synthetic utility is pretty much untapped, but they’ve got bags of potential as possible agrochemicals, chiral auxiliaries, scaffolds, pharmaceuticals and materials. They compare favorably to the steroid class of compound in that they are both conformationally rigid and chemically robust. The real problem with them is the are hard to make (although not using our method)

A selection of naturally occurring fenestranes. Pretty aren’t they?

Penifulvin A shown above actually has notable insecticidal properties, whereas asperaculin was only recently isolated, but being a fungal metabolite it may also prove useful. Laurenene unfortunately is totally useless, but it certainly looks the part!

If you really wanted to see all the nonsense I got up to in my PhD, I have just discovered that you can buy my thesis on Amazon…which feels a bit weird. It’s still pretty cool that you can even buy a kindle version!

–The Lab Coat Cowboy–

 

Here there be dragons.

Posted on by doctorgalactic

I’m still getting to grips with this whole blogging malarkey so I thought I’d give it yet another go today.

Something massive happened to today.

Yes. That’s right….

I used tertiary butyllithium for the first time at the age of 27, in the second year of my post doc. 

I know, I know, this is heavy. I can see you need a sit down now. I’ll get you some tea/coffee/cider/beer/other in a minute.

Truth be told, I’ve heard enough bad stories about tert-BuLi over the years that I’ve pretty much done my best to avoid it whenever I could. However, seeing as Grignard failed me the other day, I was forced to turn to lithiation and when it was suggested to me that tert-BuLi might do the trick, I thought “why the hell not?”.

So here is my reaction vessel (argon balloon not shown):

The foil is there to potential stop t-BuLi dropping into the acetone/CO2 bath. Not just to make it pretty…

And a handy message on the fumehood:

A comical safety message. Before you jump on me, there was a proper safety notice placed on the fumehood out of shot as well.

To be fair to tert-BuLi (because chemicals have feelings just like people?) when under an inert atmosphere its more happy, and by the point above it had already done its business. However, it’s one of those chemicals that should never be underestimated. Just look at the hazard symbols:

Chemists should all be aware of what these mean. I miss the old orange and black ones personally.

Basically, *deep breathe* it’s highly flammable, spontaneously catches fire in air, liberates flammable gases in contact with water (which will likely ignite), may be fatal if swallowed/inhaled, causes severe burns in contact with the eyes or skin and to top it all it’s very “dead fish, dead tree” (as we call it in the laboratory – aren’t we witty?).

Suffice to say that it’s a chemical you should show great respect and the utmost care in using. There have been a number of high profile laboratory accidents involving tert-butyllithium over the years. In particular the recent (2009) tragic case of Sheharbano Sangji in the lab of Patrick Harran at the UCLA, who died after being severely burned while working with tert-butyllithium when her synthetic sweater caught on fire. I don’t think that there is a chemist who shouldn’t read about what happened in that case and a very detailed explaination can be found here via Chemistry and Engineering news.

Every single university has it’s own safety rules and every single laboratory has its own safety practices and every single researcher has their own way of working. These three aspects do not always mesh very well, especially (as I’ve discovered over the years) if the University tends to talk about safety a lot, but doesn’t have a budget to act upon aforementioned talk.

I asked for advice today on how to use tert-butyllithium, as you’ve probably surmised I’m not a cavalier when it comes to my approach to chemical safety and I’m pretty sure if anything went wrong everyone in the laboratory would have known what to do.

I think the take away message is…Always play it safe with chemicals you’ve never used before. Do your homework. Check your hazards. Take all the necessary precautions.

In other  news….

Oh. The physicsts at CERN might have pretty much found that Higgs Boson thing that they and the whole world has been obsessing over for years. Don’t let it be said that I don’t pay attention to the bigger picture.

-The Lab Coat Cowboy-

That pesky Madonna and her drug peddling…

Posted on by doctorgalactic

First day of the new blog and I found a rather interesting and wholly relevant article in this mornings free Metro, regarding the previous unsavory behavior of pharmaceutical giant GlaxoSmithKline. Obviously, they decided that the banks were stealing all of the morally reprehensible spotlight and wanted to throw their lab coat into the pot for most publicly hated international corporation.

Here is a poor quality photo of the article in question:

Shall we go for generic laboratory picture #12? Nah. Madonna’s all people are going to care about.

The reason I started this blog is due to the encouragement I recieved through a Science Communication Workshop (it’s also somrthing I’ve wanted to try for a while), within which we were shown an Ipsos MORI poll on which were the most trusted professions. You can find the link here.

As you can see, doctors (M.D) come out on top as the single most trusted profession, while MPs are bathing in the shallow end of the dream pool with the journalists (shock! horror!). The general public might, in light of the case shown above, like to readjust their opinion on the trustworthiness of medical practitioners, who are far from above reproach and not immune to the cult of greed that seems to have pervaded almost every corner of our lives.

Pressure on doctors from big pharma for them to prescribe particular drugs is actually nothing new, it happens all the time (big pharma spends more on marketing than research which is a little annoying). The line that’s been crossed here is similar to that crossed by certain high ranking bankers. Taking bribes be it in the form of holidays, pheasant hunts and (of all things) Madonna concert tickets is repugnant.

Returning to the poll, “Scientists” (I love it when we’re all clubbed together) don’t come off too badly in the poll, although it doesn’t show the divide between academia and industry. Sadly, I can’t get hold of the exact information we were shown at the workshop, but suffice to say about 68% of the public trusted scientists in academia/universities compared to about 41% for the chemical industry scientists. The article above being a perfect illustration of why this is so.

The only thing going for GSK is that they pleaded guilty to the illegal practice, which is  known euphemistically as “off-label marketing”.

Just how dangerous was this practice exactly? How morally dubious are we talking about? Well one of the drugs GSK were bribing doctors to prescribe is Paroxetine (aka Aropax, Paxil, Seroxat and Sereupin) – which is drawn below.

Look! Some kind of organic compound! Pretty!

Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) type antidepressant which is widely used to treat major depression, obsessive-compulsive disorder, panic disorder, social anxiety, post traumatic stress and anxiety disorder in adults. GSK (at the time SmithKline Beecham) have been marketing it since 1992, although the patent ran out in 2003, so generic brands have now flooded the market.

You can read more about Paroxetine and SSRI‘s in general on Wikipedia, which has some pretty decent looking entries for both and covers a lot of the controversy that has occurred over the years (although it’s wikipedia, so pinch of salt territory time). Some interesting reading to be sure. Suffice to say GSK had been pushing doctors to give paroxetine to adolescents in whom the drug may increase the risk of suicidal tendencies. They have also in the past consistently marketed the drug as “not habit forming”, which it turns out is complete and utter baloney of the highest order.

GSK’s CEO Sir Andrew Witty (only knighted in the 2012 honours list for services to the economy and the UK pharmaceutical industry – it should be noted that he is not a chemist) gave the following statement on the matter:

“Today brings to resolution difficult, long-standing matters for GSK. Whilst these originate in a different era for the company, they cannot and will not be ignored. On behalf of GSK, I want to express our regret and reiterate that we have learnt from the mistakes that were made.

“We are deeply committed to doing everything we can to live up to and exceed the expectations of those we work with and serve. Since I became CEO, we have had a clear priority to ingrain a culture of putting patients first, acting transparently, respecting people inside and outside the organisation and displaying integrity in everything we do.

“In the US, we have taken action at all levels in the company. We have fundamentally changed our procedures for compliance, marketing and selling. When necessary, we have removed employees who have engaged in misconduct. In the last two years, we have reformed the basis on which we pay our sales representatives and we have enhanced our ability to ‘claw back’ remuneration of our senior management.

“We have a vital role to play in bringing innovative medicines to patients and we understand how important it is that our medicines are appropriately promoted to healthcare professionals and that we adhere to the standards rightly expected by the US Government.”

So I guess that’ll be that. It’s cost them a staggering £2 billion or  $3 billion (the biggest in US history for such a case) at a time when almost all big pharma are struggling to come to terms with the fast approaching patent cliff. “Sailing into troubled waters” doesn’t really cover it.

I love chemistry. I love responsible chemistry even more, so it saddens me a little that GSK thought this kind of behaviour was acceptable in the first place. Hopefully, this sort of thing will be stamped out in the long term and chemistry can continue to enhance and enrich people’s lives as it ought to.

Having now said all the serious stuff, I’d also like to point out the other reason I highlighted this article today and that is…that it’s some slightly sloppy journalism. I think the first rule of good journalism should be to check you’ve spelled your headline correctly. They probably should have stuck to the the official company abbreviation, GSK (which they do later with no problem). The second rule should be to get your mathematics correct. I’m not sure £637 billion goes into £2 billion with much in the way of change.

The third rule should be that, just because a celebrity is mentioned, doesn’t mean a picture of them is AT ALL relevant to the story. Why should it matter that doctors were bribed with Madonna concert tickets? What if it were Coldplay, Justin Bieber or Elton John? Would they have equally adorned this piece? I’m pretty sure most of these artists are not drug peddling fraudsters in their spare time.  Are we so obsessed by celebrity that the only way to sell any other news is to put one in every article?

Surely a generic picture of a laboratory, or GSK’s logo or some brightly coloured drug capsules would have been more appropriate? I just looked up “drugs” on google images and found a whole host of suitable images.…Oh hang on…I take it all back.

Look who I found! Turns out she’s entirely relevant.

The Metro’s logic clearly links back to Madonna’s recent album MDNA, which sounds suspiciously like MDMA (3,4-methylenedioxy-N-methylamphetamine) or “Ecstasy”.

Journalists. Where were they in that “most trusted profession” poll again? Oh yes just above this guy:

David Cameron also turns up when you google image search for drugs. He took some at Eton, dontcha know?

-The Lab Coat Cowboy- 

One small step for a blog…

Posted on by doctorgalactic

So this is it.

My Neil Armstrong moment.

I’ve just set foot in the blogosphere.

Hopefully this little endeavor proves fruitful.

I’ll be updating as much as I can on a variety of topics that I find interesting.

So keep your eyes peeled!

 

-Doctor Galactic & The Lab Coat Cowboy-