B.R.S.M. When all you have is a hammer everything looks like a nail

24Dec/123

Merry Christmas 2012!

Happy Christmas from all of us* at BRSM! Thanks for reading and all your comments and help over the past year!

*it's actually just me.

Filed under: Not Chemistry | 3,613 views | 3 comments 3 Comments
24Dec/128

Synthetic Biology versus Total Synthesis

From a series of paintings by David Cordes at Pacific University, Oregon.

I think most would agree that synthetic chemists can now make just about any non-protein/non-polysaccharide natural product if enough time, resources and manpower are brought to bear.[1] But that's not to say that the field is yet mature, or stagnating, as there still remain so many challenges to make our science more efficient, practical, and free from its current over-dependence on rare metals and petrochemical feedstocks. Recently, synthetic biology has started to emerge as a serious alternative to total synthesis when large amounts of complex natural products are required. Just think how many total synthesis papers start with a desultory line about 'the dearth of natural material', before recounting an arduous one- or two-yearlong quest to make a few more milligrams of the compound in question. Perhaps it sometimes makes more sense to try a different approach and ask 'can't we just improve the natural source?'. We synthetic chemists like to think we're special because we have the ability to make new compounds never seen in Nature, but with an increasing understanding of enzymes and the genes that encode for them, organisms can now be coaxed into producing compounds that have never been seen before. If you're interested in reading further debate over the future of the two fields then you should definitely read this short piece in Nature, in which champions of synthetic chemistry Phil Baran and Abraham Mendoza duke it out with Jay D. Keasling, a strong proponent of synthetic biology.

Reaction Vessels

From Nature, 492, 188.

Etc.

1.  Of course, there still exists the question of 'should we?'. Aside from the importance of total synthesis in structural determination, and ignoring for the moment the oft quoted reason of solving supply problems, the other main justification offered by the practitioners of the art is the development of new methodology. I'd love to find a way to test this claim, but my feeling is that few generally useful reactions are discovered in long synthetic campaigns. Let me know in the comments if I'm wrong about this.

Filed under: Current Literature, Total Synthesis | 9,285 views | 8 comments 8 Comments
16Dec/123

What’s Wrong With This Picture 2: An Intriguing Biosynthetic Proposal

As a synthetic chemist I'm always on the hunt for interesting molecules to disconnect/speculate about, and a couple of  natural products published at the start of this month (Organic Letters ASAP; DOI: 10.1021/ol3028303)  immediately caught my eye:

1

So far so good! Don't start looking for mistakes yet! The problems start when the authors go on to suggest what I'm going to politely call a most intriguing biosynthetic proposal:

2

 

It's not too bad at the start, borrowing heavily from Baldwin and Whitehead's hypothesis for manzamine and related alkaloids. The problems come one the authors need to go from the pyridinium dimer to the natural product itself. How the C4-C5 bond is supposed to form on the middle line is beyond me, and the arrows in the cyclopropane opening seem to go in entirely the wrong direction, but all that stuff seems entirely sensible compared to the madness on the top line. I know that people often play a bit fast and loose with steps in proposed biosyntheses; it's easy to shrug and go "there's probably an enzyme that does that", but this just shows no understanding whatsoever of arrow pushing. I can't believe this got into an ACS journal, or am I missing something?

Filed under: Ask the audience, Current Literature, WWWTP | 6,801 views | 3 comments 3 Comments
15Dec/127

Resource Page and Blogroll: 2012 Update

I've got a few emails lately pointing me in the direction of good resources such as the much discussed How To Chemdraw video and the beautiful new name-reaction.com. I've also just recently become aware of great new(ish) blogs like Not The Lab, Doctor Galactic, The Chemistry Cascade, Chemistry Tips and Techniques, and The Organic Solution. However, I am sure that for every useful resource (blog, tutorial, reference...) that I've read, I've missed many more! Below are the links on my resource page at present, and you can see my blogroll on the right. I've just noticed that the former hasn't been updated in over a year. So, what should I be reading or linking to? Drop me a comment or email (N.B. new address on about page)!

Incidentally, if your bookmark/RSS feed to this site points to my old eristocracy.co.uk domain, you should change it as I'm losing that tomorrow.

Filed under: Ask the audience | 8,365 views | 7 comments Continue reading
15Dec/128

Non-Thermal Microwave Effects: Probably Bollocks

Update 1900: This was blogged earlier today by Tom Phillips over at A Chemical Education. Whoops!

For a related post on things to check before publishing your controversial results to avoid potential humiliation, see my old piece on 'metal-free' reactions.

mcontent

From Angew. Chem. Int. Ed. 2012, 51, 2.

It seems to me that people still talk a great deal about so-called 'non-thermal' effects in microwave reactions; i.e. some kind of mysterious rate acceleration that occurs from excitation (or even stabilisation) of particular bonds or intermediates directly, in a fashion distinct from simple macroscopic heating of the reaction mixture. One of the most prominent critics of those who claim to observe these phenomena is Austrian chemist Oliver Kappe, who's been debunking claims of non-thermal effects for at least a decade and he's just written an excellent Essay in Angewandte Chemie on the subject. Now, few people would argue that a lot of reactions work better in the microwave, but this can often be explained by rapid internal heating or increased pressure; that is, by thermal effects, however dramatic. An example from Kappe's essay illustrates the incredible magnitude of rate improvement that's sometimes observed:[1]

From Angew. Chem. Int. Ed. 2012, 51, 2.

Filed under: Current Literature, Serious | 17,202 views | 9 comments Continue reading
2Dec/124

Mulvember 3: Lycoflexine

I'd originally planned to do four of these posts, but it looks like I've run out of time so I'll be getting back to more cutting edge work (as soon as something exciting is published). Maybe I'll post the last one in March Mulch. Check out Mulvember 1: Penfulvin A and Mulvember 2: Echinopines A and B!

Okay, I suppose I should start off by acknowledging that Mulzer isn't the corresponding author on this one (instead it's Mulzer group postdoc Jürgen Ramharter), but it's still a nice piece of work so I'm including it anyway. The target itself is one of the perennially popular lycopodium alkaloids whose first member - lycopodium itself - was isolated way back in 1881. A number of classic syntheses of members of this family in the 1970s and 80s by famous alkaloid chemists such as Stork, Heathcock, Wiesner and Wenkert have set the bar pretty high, but work towards these targets continues to this day.[1] Particularly, the fawcettimine-type members of this family, to which lycoflexine belongs, have proved very popular in recent years with a new synthesis seemingly out every few months.

 

 

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1Dec/124

Superlatives 3: The Longest Polyene

Update 02-12-12: If anyone wants/needs a copy of the original image without the text and arrow added, you can find it here.

 

Some of you may remember this synthesis of the world's longest polyene from a few months ago, covered by See Arr Oh here. I'm not going to say much about the the chemistry of this synthesis (Wittigs. Shedloads of 'em), or its significance, but I'd like to post a little addendum to the work here.

From Org. Lett., 2012, 14, 5496

I just got an email from a friend of mine who, upon reading the paper, asked the obvious question 'but what colour is it?'. Lycopene, of course, is famously red:

Image partly from wikipedia.org

Unable to find a answer to the question in the paper itself, or the Supporting Information he contacted the authors. After a few days, they sent a short reply and a beautiful image:

'the longest polyene is best represented by the vial on 7th from the left'

Now, how often do organic chemists get colours like that?

Filed under: Uncategorized | 15,019 views | 4 comments 4 Comments
18Nov/125

Mulvember 2: Echinopines A and B

Although there have been a couple of interesting syntheses this week, I'm still very busy so I'm going to write about another Mulzer synthesis from my talk. See my previous post for the background to this tribute.

 

Since their fairly recent isolation in 2008 the echinopine sesquiterpenes have proved quite popular targets for total synthesis. In fact, four rather different total syntheses have been reported since their unusual and compact molecular architectures first graced the literature. The first of these was that of Johann Mulzer, published just a year after their isolation, in which both natural products were synthesised in near enantiopure form (starting from cyclooctadiene!) and their absolute configurations were confirmed for the first time.[1]

Filed under: Literature, Mulvember, Total Synthesis | 9,217 views | 5 comments Continue reading
5Nov/126

Mulvember 1: Introduction and Penifulvin A

Like many research groups, the one I’m in does weekly literature talks so people get a bit of practice with powerpoint and public speaking. Because excessive freedom can be a bit daunting, although people are free to choose the topic of their own talk it has to fit in with a particular theme, which, at the moment, is living Germanic chemists. In this vein, last month I wrote and gave a talk on the life and work of Johann Mulzer. Now, as I've been a bit busy lately, and the literature has been a bit lacking in interesting total syntheses, I've decided to rehash my talk as a series of blog posts. On the upside, this should mean more posts for you guys and less hassle for me (as I've already drawn everything in ChemDraw). Also, although I didn't know this when I wrote the talk, it seems that Mulzer is finally winding down and I think he deserves a bit of send-off. I, for one, have learnt a lot from reading his papers over the past few years.

From a recent Angewandte paper.

Unfortunately, most of the syntheses that I covered in my talk are already pretty well known, and many of them have also already been covered on Totally Synthetic at one time or other. Still, if you missed somehow missed reading about them there or prefer my more rambling style then read on!

Incidentally, if you’re wondering what the German text on the slide is all about, it’s taken from the group website and is usually rendered (non-literally) in English as ‘no battle plan survives contact with the enemy’, something all chemists who have worked in total synthesis know well![1]

Filed under: Literature, Mulvember, Total Synthesis | 11,866 views | 6 comments Continue reading
24Oct/120

Chem Coach Carnival: I’m A Postdoc and I Love It

Hi all, we* interrupt our* scheduled** programming to bring you an exciting** Chemistry Carnival entry! See Arr Oh recently had the brilliant idea of a Chem Coach Carnival, where people in different chemical careers describe their working lives to give others an idea of what it's like to be in their shoes. Here's my entry, which unfortunately seems to have turned out a bit too long:

What do you do?
As you might have guessed, I'm currently a 'postdoc' or post-doctoral research associate at a UK university. If you're not familiar with the academic hierarchy you can see where this fits in the academic food chain here, thanks to Karl Collins.

What does a typical day involve?
I'm one of three postdocs in a research group of around twenty people engaged in diverse projects across the spectrum of organic chemistry. When I was at school The RSC ran a campaign to tell people that 'not all chemists wear white coats', but I'm proud to do so for 90% of a normal day. At the moment I'm mostly working on a short-ish biomimetic alkaloid synthesis but in addition to my own project(s), I also get to field questions from PhD and MSci students, show people how to do stuff in the lab, write papers, work on my own crazy ideas, manage an MSci student and worry about what I'm doing with my life. I also do some teaching in the form of undergraduate tutorials, which is great fun. My job is essentially to solve an increasingly varied and intricate series of puzzles, and it's good.

How did you get where you are?
It sometimes feels like I've spent my whole life in full time education as I started university straight after school and my PhD a few months after I finished my undergrad. As it happens, I'm currently still at the same institution from which I obtained my PhD a few months back. Staying in one place like this is usually inadvisable, but it's not a bad university, there's a good climbing wall nearby, and my current position is really just a short term filler until I move to the US next year for a 'real' postdoc. Goodness knows what I'll do after that. Fortunately, thanks to the shorter British PhD, I've only just turned 26.

How does chemistry inform what you do?
I really can't know enough chemistry as it pervades everything I do at work. The deeper my knowledge, the better I'll be at my current job, and the greater the chance I'll have of getting another.

Pros and Cons?
It seems that this job combines most of the good bits of being an academic and a PhD student; on the one hand I get almost total freedom to do what I like, I still spend most of my time in the lab, I get to teach and I get to be familiar with all the stuff that other people in the group work on but I don't have to write grant proposals or a thesis, take exams, or attend many meetings. It's pretty much how I think being a chemist should be. The main problems with the job are that it doesn't pay that well; although money is rarely a problem for me, I couldn't start a family or buy a house; the hours are pretty long, and are only going to get worse when I cross the Atlantic; and it isn't a long term career, as doing more than a couple of one or two year postdocs is widely considered a bad idea. It can also be stressful and frustrating.

A funny story?
Reading through what I've just written I guess I come across as pretty keen on chemistry, but it hasn't been a lifelong interest of mine. I wanted to study physics at university but sucked at math so I ended up studying materials science. That turned out to be a little too last-but-one century for me; the amount of time we spent learning about steel and concrete really put me off. After a year I switched to chemistry, but was a mediocre undergrad as I spent most of my time running the university mountaineering club and planned to get a job in the outdoor industry when I graduated. It wasn't until my final year masters project that things changed for me. Although I usually did much better in inorganic chemistry, I chose to join an organic research group that looked interesting on paper, but to my surprise it turned out to consist only of one mostly retired emeritus professor and a young - but extremely talented - postdoc. To hear those two talk about chemistry was amazing; it was like listening to a conversation in another language, and as they swapped stories about this academic or that, discussed the latest Nicolaou paper or just stood around cracking jokes I realised that the world of organic chemistry was much more interesting than I'd ever realised. I loved the history, the in-jokes and the community. I wasn't a great masters student, but I doubt anyone else in my year learned as much as I did during their project. Four years later I'm still a chemist. And I'm not ready to stop learning yet.

 

*Majestic plural.

** This is not true.

Filed under: Ask the audience, Serious | 7,038 views | no comments No Comments