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!
Biogr. Mems Fell. R. Soc. 1971, 17, 399-429 (doi:10.1098/rsbm.1971.0015)
Chemistry World, 2010, April, 54-57
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. 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!
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!
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.
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”.
Image from americansweets.co.uk
Give that man a Tet. Lett.! Here are a few other examples of ridiculous things you’ll never try:
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.