So You Think You’re Having A Bad Day?
Another quick update! Still busy!
From Biogr. Mems Fell. R. Soc. 1971, 17, 399-429 (doi:10.1098/rsbm.1971.0015)
Next week I'm starting a new total synthesis project with alkaloids. This is pretty exciting, as some incredibly famous (historic and modern) targets belong to this class, and, well, it's always fun to learn new things. Most of the compounds I've made in the past three years have been bright orange, which has made chromatography a bit of a breeze, and I'll miss that, but it's time to move on. While doing some literature searching and background reading for my new project I noticed the name William Kermack on quite a lot of papers. I knew I'd heard it before, but I struggled to remember where for a while. Eventually I remembered: he was mentioned in a footnote to an article on Sir Robert Robinson and the curly arrow in Chemistry World in 2010. You can read it for free, courtesy of the University of Saint Andrews here.
Born in the small town of Kirriemuir at the end of the 19th century, Kermack studied maths, natural philosophy, and chemistry at the University of Aberdeen, where he enrolled as a student at the age of 16, before heading south to work with William Perkin junior and Sir Robert at the legendary Dyson Perrins laboratoryof the University of Oxford (as a member of the British Dyestuffs Corporation contingent there). Two years later, in 1921, he returned to Scotland to take charge of the Chemical Section of the Royal College of Physicians in Edinburgh where he continued the work on alkaloids he began in Oxford as well collaborating with the medical researchers there. Tragically, his career as a bench chemist came to a violent end one fateful monday evening in 1924, when, while working alone in the lab, a flask exploded showering him in caustic reaction mixture. After two months in hospital he was discharged completely blind at the age of just 26.
Remarkably, this didn't particularly affect his career as chemist. He continued to collaborate and supervise PhD students, and still made he way to the lab each day by public transport. A year later he got married. He continued to research alkaloids, and became interested in carbohydrate chemistry, statistics and epidemiology as well. He obtained a D.Sc. from his alma mater, Aberdeen, for work on carbolines and was elected a Fellow of the Royal Society. Some 25 years after his accident he was appointed the first Professor of Biochemistry at the University of Aberdeen, which surprised many as he was, by training, an organic chemist whose major interest at the time was statistics, and he lacked experience in teaching and administration. An editorial in Nature remarked that ‘to proceed with such an appointment in a laboratory subject has something in it of an act of faith, based not alone on the high scientific attainments but also on the rich mental endowments and sterling qualities of the new professor’
Before accepting the new position, while still in Edinburgh, he commissioned a Plasticine model of his new department to enable him to familiarise himself with its layout, and was indeed able to find his way around without any problems. He lectured, oversaw the expansion of his own department (and others), translated works from German to English, wrote books, worked for the Chemical Abstracts service, collaborated and researched, aided by his students and his remarkable memory, and eventually became Dean of the Faculty of Science. He continued to work until his death at the age of 72, at his desk, while at work on another book on biochemistry. Kermack lead a remarkable life, rising to become a respected and popular academic, in spite of his disability, in an era when few technological aids existed to help the blind. So, next time you have a bad day in the lab, remember that things could be worse, and that Kermack himself only referred to his accident as a minor setback!
References
Biogr. Mems Fell. R. Soc. 1971, 17, 399-429 (doi:10.1098/rsbm.1971.0015)
Chemistry World, 2010, April, 54-57
Hi Everybody!
The amount of traffic that this site has got since Thurday's conditions you'll probably never be desperate enough to try post has been truly unbelievable.[1] Thanks to Derek for featuring this page on In The Pipeline, as well as other readers for submitting it to reddit and getting the word out on twitter. Hell, I somehow even got on the front page of actual news site arstechia.com:
Spot the odd one out!
Despite the fact that I've had this blog up for over 11 months now, I got some 15% of my total traffic ever in the last three days. So, thank you all! More updates later this week!
brsmblog.com daily traffic over the last month!
1. What's funny about this, is that that post took me all of about 30 mins to write. I already had the links saved from when I'd first come across them. I didn't really think it was very good, but wanted to write something that wouldn't take too long. On average, a total synthesis write up can take me 4 or 5 times that long to write, and they don't even get 1/10 of the traffic that post has. Oh, well. The response it got was still incredible!
If Had A Blog Back Then 1: (+/-)Acanthodoral
More updates soon; I'm trying to finish my thesis this week as I have to start work on Monday!
Zhang and Koreeda, Org. Lett., 2004, 6, 537
DOI: 10.1021/ol0363063
Yes, there's been plenty of good stuff in the literature recently, so much so that I'm hoping to soon resurrect my old habit of making 'Top 5 syntheses of the month' lists this week, retrospectively starting with April. However, as I'm a bit busy right now, here's a short post on some slightly older work. A co-worker showed me this paper last week, which he'd found trawling the ACS website looking for good problem session material, but was worried might be 'a bit mental'. I'm not so sure, but then my last few problem sessions have included dodecahedrane and discodermolide. There are quite a few interesting steps, especially for an Org. Lett., but some of the chemistry you'd just never expect to work as it does.
Conditions You’ll Probably Never be Desperate Enough to Try
Or: Somewhat Like Cooking
We all know what it’s like to be desperate for a reaction to work; to need a result so badly, or to have a supervisor breathing down our necks, telling us that something must be possible. I’m sure all bench chemists can remember searching the literature for a procedure to prepare a given compound, only to find one, read it and then discard it for being too dangerous or just plain ridiculous. We can all probably think of a few procedures that we're just not paid enough to follow. For example, before Christmas I wanted to make some of this carboxylic acid.
Easy, right? Surely you just oxidise the 2,5-hexadienol that you can get in one step from allyl bromide, unprotected propargyl alcohol and indium? Nope, there are numerous preparations reported, and they all use either tin, or worse, nickel tetracarbonyl. A thing that myself and Derek Lowe definitely won’t work with.[1]
Yup, chemists love to talk about dangerous procedures. But what about ridiculous ones? I once heard an academic tell a story about his time as postdoc with Steve Ley. In his first few months in the group, another postdoc whom he referred to as ‘Crazy Norman’ had been working out the last few steps in a natural product synthesis. The final reaction was the selective reduction of one of three or four double bonds in the molecule by hydrogenation. Norman performed this reaction once on a small scale, got some NMRs and then left and moved on. After he was gone, Ley set another postdoc the task of making a little bit more of the natural product, by repeating Norman’s final step. But they couldn’t. The particular selectivity that Norman observed (and had the NMR data to prove) was never seen again. His successor tried everything – different catalysts, solvents and temperatures. New glassware, clean stirrer bars, old glassware and dirty stirrer bars. They stirred clockwise and anticlockwise, by the window and in the dark. It was rumoured that someone in the lab might have been doing some sulfur chemistry on the day when Norman did his reduction, so they tried even tried wafting some thiols at the flask full of catalyst and solvent, to maybe poison it just a little bit. Eventually, they rang up Norman to ask if he remembered doing anything – anything at all – unusual when he ran the reaction. He thought for a while and then replied, in total seriousness, “I think I might have washed the glassware with Vimto”.[2]
Image from americansweets.co.uk
Give that man a Tet. Lett.! Here are a few other examples of ridiculous things you’ll never try:
(+)-IKD-8344
Three Rings in One Step: A Quick Approach to IKD-8344
Zou and Wu, Angew. Chemie. Int. Ed., Early View, 2012
It's feels like ages since my last total synthesis post, but I couldn't resist writing something about this unusual looking macrodiolide with its rather unmemorable name and ridiculous number of THF rings. Aesthetic reasons aside, with subnanomolar activity against leukaemia in mice, as well as some antiparasitic effects, this Steptomyces-derived natural product appears to be a more worthy target than many. Wu and single co-author Zou reported a modern yet slightly oldschool synthesis in Angewandte a couple of weeks back and it's been high up my 'to blog' list ever since. The route used is a delightful blend of old and new marrying modern asymmetric aldol chemistry with every first year undergrad's favourite way to make ethers - the trusty SN2 Williamson ether synthesis. This disconnection, leading back to a substrate containing two β-mesyloxyketones (with α-stereogenic centres!), would definitely have worried me, but the methodology, which the group has developed over a number of years, works very well. The synthesis is simplified somewhat by the fact that the natural product is dimeric, as macrodiolides tend to be, and the group are really able to showcase their methodology here, forming all three THF rings in the monomer unit in a single step.
Two Reactions of Hydrazones
I thought I'd quickly share with you a couple of useful transformations involving hydrazones that I read about recently. The first one I found yesterday, reading George Majetich's perovskone full paper in Gilbert Stork's special issue of Tetrahedron. Although it's not the most atom economic thing ever, it struck me as quite a neat, if somewhat oldschool, way to transfer chirality. The second reaction is from Rawal's recent total synthesis of the weltwitindolinones, which I blogged about in detail here, and which I actually saw Rawal himself talk about on Tuesday at Bristol. The reason I've brought it up again is that when I wrote my last post commenter MadForIt asked about the mechanism of this transformation, which at the time I didn't know and didn't get round to looking up. By chance I found out the mechanism a few weeks later (completely by accident) but never got round to posting it up. Rawal's talk reminded me of this, but it didn't seem worth burying the answer in the archives so I thought I'd make a new post out of it here.
So, before I give you some possible answers, have a think about how you might do these and then read on for more information.
The Splenda Effect and Chlorosulfolipids
Acknowledgement: I took the term 'Splenda Effect' from Carreira's talk at the Bristol Synthesis Meeting on Tuesday. It's a useful term to describe the low reactivity of alkyl halides near electron withdrawing groups. This post is mostly sourced from that, wikipedia and the Nature paper cited below.
Anyone eat any primary alkyl chlorides today? My dad had a few spoons in his morning coffee but that's not unusual. I only found out at the start of the week that sucralose, the main ingredient in Splenda and other sweetners, actually contains not one BUT TWO primary alkyl chlorides.[1] That makes it rather indigestable and also about 600 times sweeter than the starting material. In fact, as it contains fewer than 5 calories per serving the FDA allow it to be sold as 'zero calorie'. Because anything below five is basically zero.[2]
But why bring that up? Well, in considering synthetic approaches to the chlorosulfolipids Carreira asked the obvious question, 'can't we just start from a polyol and do a bunch of halogenations?'
"The result of initial synthetic efforts involving model systems led us to conclude that construction of such systems would have to take into account the unique behaviour and properties of a polychlorinated backbone with electron-withdrawing groups. As a relevant benchmark, sucralose, the key ingredient of Splenda, incorporates two 1° and one 2° chlorides on a disaccharide core and is sufficiently stable and safe to be widely used as an artificial sweetener. In a similar fashion, in preliminary investigations we observed that displacement reactions of activated alcohol derivatives to furnish the corresponding alkyl chlorides proved unworkable when the carbinol bears two methine substituents with electron-withdrawing groups, such as chlorides. Additionally, we noted that α- and β-chlorinated aldehydes are fleeting intermediates, which undergo enolization, hydration or elimination too rapidly. Thus, we sought to implement strategic approaches that would circumvent these limitations in crafting a synthesis route to chlorosulpholipid 5." - Carreira in Nature, 2009, 457, 573
The route the group actually used was interesting, and worth a minute's consideration. It's from three years ago, but I didn't have a blog back then so I'll quickly cover it now.
Woodward Wednesday 4: And All That Could Have Been
Woodward was a member of the highly elite few; organic chemists who won Nobel prizes not for a specific reaction, discovery, or work with a particular element but for simple mastery of organic chemistry - theory, synthesis, methodology, structural determination, biochemistry - the list goes on. The elegant citation for his prize summed this up nicely:
"Professor Woodward's research work covers vast and various fields in Organic Chemistry. A leading feature is that the problems have been extremely difficult and that they have been solved with brilliant mastery. He has attacked them with a maximum of theoretical knowledge, a never-failing practical judgement and, not least, a genial intuition. He has, in a conspicuous way, widened the limits for what is practically possible."
I'd be very surprised if we see a Nobel Prize award to a synthetic organic chemist any time soon. The total synthesis/general organic crowd never seem very high up Paul's lists. As we saw in the very first post in this series, Woodward interestingly didn't use the opportunity given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and puzzles were concerned, as well as the willingness to take on daunting challenges. Woodward's chemical legacy was enviable and it's telling that no conversation or book on classic synthesis can fail to cover such masterpieces as his work on reserpine, strychnine, chlorophyll and B12. That aside, I've heard numerous chemists talk about his contributions to other Nobel Prize winning work, so I thought it might be interesting to write a post on this.
Unnatural Products 4: Tetrahedrane
“Why does the tetrahedrane molecule fascinate the organic chemist? Is it the aesthetic appeal of the topology of the tetrahedron or the hope that the unusual bonding properties of this molecule could lead to otherwise inaccessible knowledge of general importance, or is it indeed the synthetic challenge of the highly reactive - if at all capable of existence - tetrahedrane, together with the sporting ambition to reach the goal first?” – Maier, 1988
This bonus Unnatural Products post was written by guest blogger Ckellz from New Reactions, who has worked on far more strained systems than most of us ever will. If anyone else fancies writing a post, get in touch. Enjoy! --BRSM.
When I first found out that BRSM was doing a series on unusual and platonic hydrocarbons, I immediately became really excited and nostalgic. I spent a good part of my undergraduate research career working on strained systems (which culminated in the synthesis of a highly strained bicyclobutane bearing a CF3 group). During my time in Dr. Tilley's lab tetrahedrane 4 often came up as a topic of discussion (Dr. Tilley's goal is ultimately the synthesis of this elusive molecule) and how we thought it was a very interesting molecule that might actually be quite stable. So when I was reading the posts about cubane, I commented that I had a good deal of knowledge about its smaller C4 cousin. The next morning I received a very nice e-mail from BRSM asking me to do a guest post about tetrahedrane and I jumped at the opportunity!
A Little Self Deprecation in Tetrahedron
This caught my eye while reading Tetrahedron this morning. At first I thought it was a mistake, but then I realised that it was also in the PDF as well, presumably okayed by the authors. I think it's pretty funny to see this title in the TOC with 'Orginal Research Article' next to it:
Strangely, the rest of the paper seems quite confident. I guess time will tell.