Christmas decorations for chemists

As I was decorating the Christmas tree today I found some of my chemistry contributions to the festive season. First up is my carbohydrate paper cone that I received as a gift some years ago:
And then there's this very old distillation receiving flask that looks great on the Christmas tree: Notice how they have marked each of the receiving arms with small blue coloured glass bumps. Okay that really is it until next year. Merry Christmas and Happy New Year. D!

+PLoS+

Some time ago when I was ranting about papers, authors and so on I promised a post on open access journals, more specifically PLoS: Public Library of Science. I'll leave the Open Access issue for another day, suffice to say it's something I like very much. Anyway, the PLoS journals have several neat features:

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(1) Upon submission of a paper to a PLoS journal each author receives an email from the journal where (in detail) they have to justify why their names are on the paper. Until this process has been completed the paper will not be considered for publication.

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(2) If the paper gets published it will contain an account of what each author has contributed to the paper.

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This is all about transparency and not getting on the paper for doing routine work or just as a favour to a buddy. Obviously, the system still isn't perfect but it applies some pressure on the authors. It makes them think about the whole process and I bet that it gets rid of most of the crap you get in ordinary journals.

And there's more:

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(3) PLoS journals have good to high impact factors. In other words people contribute good work to these journals.

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(4) Readers can post comments and questions on the paper and the authors can respond. Just like a blog.

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(5) If the authors make an important discovery relating to the paper they can add more data to the original publication. How cool is that? I wish I could do that with some of my publications. The extra data still has to go through peer review which makes it even better.

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So why am I not publishing all my papers in open access journals. Well chemistry still hasn't caught up with things in this area. There are things happening but compared to what's going on in biology we have a long way to go. However, this is the way of the future and the journals know it so they will have to adapt. Recently, a bill that required all NIH funded research to be published in open access journals was vetoed at a late stage by President Bush so things are certainly bubbling away in this area.

Merry Christmas and Happy New Year people. No more posting this year. See you in 2008 and thanks for all the interesting and very encouraging emails. D!

Colourful Chemistry

I'm doing lots of new chemistry in my new job which is great. Since I started my career as an organic chemist more or less everything has been supposed to be colourless or white.
What makes the chemistry I'm doing now even greater is that it has colour whilst still being organic chemistry.

Here's some recent pretty pictures. Check out my beautiful green reaction.
And how about this product from another reaction? Initially I assumed that the product was impure but what do you know it's supposed to like like this.
In your face inorganic chemists! Can anyone guess what I made? It is a classic reaction taught in first year university organic chemistry. It's nice to see the chemistry I have been teaching undergraduates is useful and actually works in the lab. D!

Compound Characterisation in Industry

As I have mentioned previously I'm back working in industry/biotech. One of my colleagues asked me an interesting question today:

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What is the golden standard for compound characterisation in industry?

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Where we work now we only do 1H NMR and LCMS. However, in my previous industry job we also did 13C NMR, full on 2D NMR and elemental analysis. What are you industry people out there doing and what are your views on this issue? D!

Low Vacuum Manifold

I couldn't believe my eyes when I saw this. The glass blower who made the manifold has missed the point. Five excellent high vacuum taps combined with a rubbish Teflon tap to produce a nice a shiny low vacuum manifold. Speaking of missing the point check this set up out using the same manifold. Spot 5 mistakes. D!

Sleeping with the stirring bars

Speaking of grease it appears that the spider mob has been busy again and sent one of their own to a greasy death. I'm sure that I'll have nightmares about falling into the massive silicon oil bath from hell for a while. D!

Grease

Some time ago I received an email from a reader regarding some problems keeping a constant vacuum during a distillation:

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"...What type of grease (if any) do you use for the ground glass joints during high (oil pump) vacuum distillation? I use the 'regular' Dow Corning High Vacuum Grease that comes in a funky aqua colored tube. Sometimes when I am carrying this out, all of the sudden partway through the distillation, the pressure will suddenly go from about 0.06-0.1 Torr (where it normally is) to maybe 0.6-1.0 Torr. It doesn't always happen but the effect on keeping track of the boiling point is irritating with the pressure all over the place..."

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This is a common problem and it's not necessarily a problem associated with the grease. Let's talk grease first. I have never used the grease mentioned above but I'm sure that there are many excellent greases available and this particular grease may also be good. However, I do know that if you stick to the correct Apiezon grease for your application you won't have any grease related problems. There is a whole range of Apiezon grease and for a high vacuum distillation I would recommend either Apiezon T or H. All the information you need to select the correct Apiezon grease is available here. Don't overdo it when you apply your grease otherwise you'll contaminate your material during distillation.

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Interestingly, I recently had a similar problem to that described above when setting up a high vacuum manifold. However, in this case the problem was not the grease but the use of inappropriate vacuum tubing. The vacuum I was operating at was much lower than that described above but the same vacuum surge phenomenon was observed. The solution to this problem is to buy Tygon tubing. It's expensive but it's worth all the money and you usually don't need more than a few meters anyway. Aldrich sell 10 foot pieces of Tygon. It's transparent, nonreactive, flexible, not brittle and doesn't leak. It's simply the best. There's a good post at Wikipedia on grease. Notice the smart way of applying grease using a syringe. Also if you are setting up a high vacuum manifold you should consider reading this post at Org Prep Daily. D!

Curly Arrow update

Apologies for the infrequent posting. I'm very happy to see that people keep coming to the blog despite this. So what's my excuse this time? Well I just started a new job. I have left academia (for now) and I'm working in a medium size biotech company doing some traditional medicinal chemistry to cure the world etc. However, I have been made an adjunct research fellow at the university and continue to supervise some students so I still have a foot inside the academia door. Also I have become a regular writer for the chemistry magazine published by the Danish Chemical Society which is quite exiting. Unfortunately this only gets published in danish so it won't be of interest to most of you guys. What's even more cool is that they have agreed to set up a blog on the magazines web page where the articles will also be published.
I'd like to thank people for the many emails I get with interesting questions and requests for paper reprints. Thanks for taking an interest. Curly Arrow has now been running for 1 year and seems to be a fairly popular blog (see some stats below). I've even reached the point where people are offering me money to place adds on the blog (You have to pay a lot more guys if you even want me to reply to those emails) and I have been blessed with lots of spam comments linking to porn sites (the pinnacle of my career). I almost clicked on cucumber sex to see what cucumber variety would be employed. D!

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From 18th October 2006 to 9th November 2007

Absolute unique visitors: 13,369

Total visits: 34,820 (89.47 Visits/Day)

Average time on site: 1:06 minute

The 10 most frequent visitors identifiable:

(1) Scripps Research Institute

(2) University of Cambridge

(3) Oxford University

(4) University of California

(5) Princeton University

(6) Columbia University

(7) University of Rochester

(8) Harvard University

(9) The Pennsylvania State University

(10) North Dakota State University

Authors - alphabetical vs. by contribution

After my first post on Authors and who goes on papers I have received quite a few emails from people and had some interesting discussions with some of my colleagues. It seems that everyone has a good story on this topic. Something that I've noticed can give rise to some heated discussions is whether authors should be listed alphabetically or according to how much they have contributed, i.e. the first author did most. From what I've gathered so far the alphabetical system seems to be a chemistry thing. When I mention this concept to people in biology/biochemistry they are outraged. In their area you really need to be the first or second author for the paper to carry any serious weight on your publication list. After thinking a bit about all this I have reached two conclusions that may or may not be right:

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(1) The alphabetical system only benefits the supervisor. The supervisor no longer has to have any troublesome discussions about who did what.

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(2) The contribution system also benefits the people that actually did the work. In many academic institutions and companies they look for first authorship's on papers. This is the only way they can determine if people did any meaningful science. From third author and down they could have ended up on the paper for close to nothing.

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And then there are the supervisors that mix things up:

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(1) Many supervisors will always put themselves last and everyone else by alphabet?

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(2) Others will always put themselves first and everyone else alphabetical (or by contribution). I suspect they do this so that the paper will be referred to as "supervisors name" et al. rather than "students name" et al.

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I have been through two alphabetical places and four by contribution places and I have reached the conclusion that if you want your name at pole position (at the alphabetical places) you just have to do all the work yourself. And finally just in case anyone thinks that I'm moaning and I'm unhappy about how things have panned out for me - I'm not - I just thought the topic was interesting. D!

NMR tube cleaner

I have a lot of NMR tubes and as a result I don't clean them very often and when I eventually decide to do something about it I'm faced with something like 30 dirty tubes. Now firstly if you work this way you have to soak the NMR tubes as soon as you are done with them. If you just let them evaporate to dryness you are in trouble. I normally just empty the tube and fill it to the lip with acetone and cap it. This way it wont dry out for months.

When I was cleaning my tubes the other day I had three synthetic organic chemists from three different countries walk up to me and ask what I was doing. This was somewhat surprising so I've decided to share with you what I thought was common knowledge: The NMR Tube Cleaner. These things are commercially available (expensive) or you can have your glass blower make one at a reasonable price. You can see my set up on the picture above. This is how it works:

(1) take the cap of your NMR tube and attach it to its base

(2) stick the tube in the cleaner (see picture) so that the cap seals the opening at the top

(3) squirt solvent(s) into the solvent opening (see picture).

The system is under vacuum and the solvent gets sucked through a thin tube that goes to the bottom of the NMR tube. It is very effective and I usually do a combination of solvents to get rid of everything. Its smart to have a three way tap between the cleaner and the pump so that you can let air into the cleaner without having to turn the vacuum off all the time. There's an NMR tube entry at Wikipedia that also describes the NMR tube cleaner. D!

Authors - who goes on the paper and why?

Yes I know! It's pretty quiet around here. My Internet connection at home is dead. I'm on the phone with my Internet provider every day to resolve this issue but it is a slow process.....So I guess a bit of blogging from work is required (Sorry boss. I'll run that column in 15 minutes). I'm writing papers at the moment and this always brings up the issue of authors. Who's on and who's off? Over the years I've experienced some pretty disturbing things in this category:

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(1) You send the paper off to your boss for proof reading etc. and it comes back with another name on the paper! Why? The boss feels bad about not giving that person credit for something completely unrelated and is trying to make up for it.

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(2) People doing routine analysis go on all papers. This category is a bit of a grey area as some techniques may be routine to the person doing it but does require years and years of experience. An interesting issue in this category is X-ray crystallography. Many older scientists (50+ years) don't realise that this has become a routine operation and religiously put the x-ray dude on all papers. Granted in the world of small molecule X-rays the crystallographer should go on sometimes when things aren't trivial. However, 90% of the time this is definitely not the case.

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(3) Everyone in the lab goes on all papers! This is really far out but nevertheless the policy in some labs. By everyone I also mean the technician making up the solutions.

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(4) And then there are the totally reasonable, serious scientist that will actually ask to have their name removed from the paper as they don't think they have contributed enough. I like this person much more than the evil pseudo-scientist snake that will do anything to sneak their name on a paper.

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There's much more where this is coming from. Another post on the topic coming up shortly. D!

Pay Rise Cake

Regardless of whether you are working in industry or academia there will be occasions where you will have to supply cake (If this isn't the case you've got it all wrong and should bring some cake to work tomorrow). Now I will concede that there are decent commercially available cakes that I will eat with great pleasure. However, if you consider yourself a synthetic chemist, be it organic or inorganic you MUST make the cake yourself. It's way easier than synthetic work and the final product doesn't require chromatography, tastes great, won't kill you and will make people happy. So here's a recipe to help you guys out if you have no idea what to bake. It's the cake that a friend of mine has named the pay rise cake as you are guaranteed to impress your boss with it. It's a fairly expensive cake to produce but believe me its worth it.

Banana and Chocolate Cake aka Pay Rise Cake [Serves many, 20+]
Ingredients
Flour (500 g)
Sugar (500 g)
Quick oats (50 g)
Butter (300 g)
5 x 50 g eggs
8 ripe bananas (ca 700-800 g when peeled)
Skim milk (150 ml)
Vanilla sugar (5 tsp)
Baking powder (5 tsp)
Salt (3 tsp)
Dark chocolate (300 g, Don't be a cheap skate and use good stuff. For example Lindt 70%)

Procedure
(1) Melt the butter - do not reflux
(2) Beat the sugar with the melted butter
(3) Add the eggs (not the shells) and beat
(4) Add milk and bananas (mash the bananas first) and beat
(5) Add flour, quick oats, vanilla sugar, baking powder and salt and beat
(6) Chop some of the chocolate (200 g) and mix it with the dough (don't beat it at this stage)
(7) Transfer the dough to a large baking tray (eg. 30 x 30 x 5 cm) and bake in the centre of the oven at 180 oC for 40-45 minutes. When the dough doesn't stick to a metal object it is finished (you basically insert a metal object such as a knife into the cake and check if anything is sticking to the knife). It is a good idea to check on the cake after 30 minutes as ovens vary greatly in performance. The cake approximately doubles in size depending on the baking powder used.
(8) When the cake has cooled to room temperature cover it with a thin layer of melted chocolate. You have to be careful when melting the chocolate. First chop it up (100 g) then put it in a suitable container (eg beaker) and melt it using a hot water bath whilst stirring. Do NOT add water, milk or anything else. Simply use good quality dark chocolate with a high cocoa content and you are in business.

Enjoy the cake - it is really nice. The cake is excellent for freezing and I generally have some tucked away at -20 oC for "emergencies". If a pay rise isn't enough and you are going for a promotion then you may consider serving it with some fresh strawberries. D!

Retraction - Azepinoazepine or Viologen?

I believe a new post is way overdue. Since my last post I almost ended up becoming a regular writer for a chemistry magazine and I have been reading an excellent book: Organic Synthesis - Strategy and Control. In due course I'll post a review of this most excellent book. Anyway, let's get to the point. Additions and corrections to papers are quite common in organic chemistry but you don't see retractions very often. Well it appears that Yamaguchi, Tsutsui and Sato where getting a little bit too excited about their synthesis of azepinoazepines (1). However, after the paper was accepted in Angewandte Chemie someone (probably Thomas Vaid, Washington University, US) was kind enough to point out that they had in fact made some viologens (2) (See Vaid's paper on viologens here). I guess that paper didn't last long on the CV. In Yamaguchi's defence I will say that it isn't entirely trivial to sort out the 13C NMR spectra of these compounds and when you are actually trying to make something specific you have a tendency to get carried away at times. I just hope this sort of thing never happens to me. On a similar note someone I know recently had a rather controversial opinion paper accepted in a high impact journal. However, whilst making changes suggested by the referees she came to the realisation that they couldn't actually draw the conclusions they had been making in the first place......I guess that's better than having to retract it later on but it's gotta hurt. D!

Behold cyclohexane!

Recently I was flipping through a magazine published by a learned society and my eyes were caught by this rather interesting picture. The aim of this photo is to encourage scientist to publish in certain society journals. Firstly, it seems rather lame that the teachers is pointing at cyclohexane that appears to be in its perfectly flat conformation? Is that the most acidic proton he's pointing at? Secondly, what is going on with the students. I have a feeling the guy to the left is a werewolf. Or maybe he's just split up with the girl to the far right which would explain why she looks like she's about to commit murder. And what's going on with the woman in the background? It's cyclohexane people and not Brevetoxin so stop looking at it like that. D!

Septanosides

We hardly finished talking about oxepans and Ferrier rearrangements when I spotted a paper on the synthesis of septanosides by a very similar route. This time the nucleophile is sodium methoxide and the rearrangement proceeds in an impressive yield to give a single anomer!

Interesting work by Ganesh and Jayaraman at the Indian Institute of Science in Bangalore. D!

Oxepane Nucleic Acids - Part II

Before I get started let me say that I think this is a good paper by Damha and that the compounds are genuinly interesting. However, I did find a number of things I believe could be improved.
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In the preivious post I gave the Tm data for homo-adenine and homo-thymine Oxepane Nucelic Acids (ONA) and it was quite clear that the low melting temperatures renders ONA useless from a pharmaceutical point of view. However, as I said it has a high stability in serum and activates RNase H. To date only very few oligonucleotide analogues have activated RNase H. The authors seem to be of the opinion that only four RNase H activating oligonucleotide (ON) analogues have been reported to date. However, they seem to forget the very first and most famous analogue - Phosphorus monothioates (PS). PS have been well known since the early 80s and ISIS Pharmaceuticals tried deveoloping drugs based on this class of analogues for a loooong time (they may still be doing so for all that I know). Anyway, let's have a look at the chemistry. They choose a somewhat surprising starting material and do a very funky Vorbrüggen coupling. I've never seen anything quite like it (notice the counterintuitive stereochemical outcome). Very impressive although the yields are poor. They get a fair bit of the diene oxepan product and some of the alfa-anomer too. Nevertheless a nice piece of work. Apparently an adaption of some work by Hoberg (JOC, 1997, 62, p. 6615) that I haven't checked out. People who haven't worked with nucleosides probably don't realise how difficult even the simplest transformations can be a times. Thymine and Adenine are by far the two "easiest" nucleobases to deal with. Cytosin is bad news and Guanine can be an outright nightmare. This is probably the main reason why everyone tests T and A first. Anyway, after taking the protection group off they proceed to hydrogenate the olefin which goes well. However, from here on it's a bit nasty. Firstly, they decide to use monomethoxy trityl (MMT) rather than dimethoxy trityl (DMT) because they get better yields this way. Now different molecules behave differently but I have a hard time accepting that you can't get DMT on in a higher yield than they report for MMT protection. Very odd! I wish they informed what happens instead. Maybe di-protection is a problem for some reason? Furthermore, they proceed to synthesise the phosphoramidite using the classic phosphoramidochlorodite (PCl) reagent. I see this all the time. Virtually, everyone in the area is using this phosphitylation reagent instead of the superior phosphordiamidite (PN2) reagent (See below). Back in the Jurassic when I used to make phosphoramidites I always used PN2. As a consequence no chromatography was necessary and I got >95% yield. We published a paper on how to make LNA (pioneered by Wengel) phosphoramidites using this reagent some years ago (Synthesis, 2002, 6, p. 802). Anyone interested in improving their phosphoramidite synthesis can request a copy (curlyarrow@gmail.com). So later on they proceed to synthesise their oligonucleotides and only achieve coupling efficiencies of 98-99%. As always it is hard to know why the yield is reduced. I wonder if the use of MMT protection has anything to do with it. One final comment regarding their conclusion. They seem to spot a connection between RNase H activity of ON analogues and sugar conformer flexibility along the ON strand. However, they have just mentioned that alpha-L-LNA is a known ON analogue that activates RNase H. This analogue contains a highly constrained bicyclic sugar (See Figure) and hence doesn't support their conclusion. They could conceivably be right. Maybe some other mechanisms are at work with alpha-L-LNA but I think they should at least have mentioned this. Anyway, overall a good paper from this Canadian research group. Keep them coming. D!

Oxepane Nucleic Acids - Part I

The chemistry you start your career working with tends to stick to you. Stuff you work on later seems much easier to shake off. Anyway, I started as a nucleoside/oligonucleotide chemists and although what I do now is miles away from this area every time my eyes wander over a graphical abstract with a nucleoside I stop. I just can't help it. It happened again the other day. Oxepan Nucleic Acids (ONA). Can you believe that it hasn't been made before. Apparently, no one has gone beyond the six membered ring until now. Now ONA is not a great nucleoside analogue. The T15 and A15 ONA oligonucleotides (ON) have affinities less than 5 oC towards DNA, a very low affinity towards itself (ONA T15 + ONA A15 = 12 oC) and a similar Tm towards RNA. In other words ONA is not suitable for antisense purposes due to the very low Tm. However, ONA is very stable towards nucleases and importantly activates RNase H. Now before I continue I should explain what Tm, antisense and RNase H is to the uninitiated. Firstly, Tm is the temperature at which 50 % of a duplex has denatured, ie. high Tm = stable duplex. Secondly, antisense is a different approach to drug development targeting RNA rather than proteins. The idea is to knock the RNA out before it gets translated into protein (See figure). This is achieved by synthesising an antisense ON that is complementary to your RNA target. The mechanism of action for antisense is either:
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(a) Inhibit the translation to protein by physically blocking the RNA strand making it impossible for ribosomes to translate it
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(b) Activate the enzyme RNase H that specifically targets DNA-RNA duplexes and only degrades the RNA strand.
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A lot of people in the field believe that antisense can only work effectively with RNase H activation and I tend to agree. The cell is amazingly efficient at making RNA and translating it to protein so if you have to get stoichiometric amounts of antisense ON to RNA into the cell you are likely to have a problem. The beauty with RNase H activation is that the system is catalytic. In other words the antisense ON gets released after RNA degradation and moves on to the next victim. The problem is that you cannot use regular DNA for antisense purposes as it has a very short half life in serum (~15 minutes). So you have to devise an analogue that is stable in serum, has high affinity towards RNA and activates RNase H. Now obviously this is no easy feat so why bother? The (theoretical) advantages when compared to traditional protein targeting drugs are:
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(a) Complete selectivity only for the intended target
(b) You can target anything involving RNA
(c) The chemistry is the same every time. You just have to figure out what the sequence of your target is and synthesise the required ON
(d) Getting drugs to market is rapid because drug development is significantly faster
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Obviously, things are much more complicated than this. Antisense was the big thing in the 80s. It was going to cure everything within the next decade but the reality is that only one product has made it to market. It's an ON called Vitravene (ISIS Pharmaceuticals) that prevents AIDS patients from going blind by targeting cytomegalovirus retinitis. That said a lot of advances have been made and there are numerous antisense ON in late stage clinical trials. Anyway, after this super condensed course in antisense ON I think we are ready for the actual paper. I'll let you off the hook for now. The next post should be up in a couple of days. D!

Still breathing

I happened to look at Curly Arrow the other day...it's now been over a month since my last post! Not good, not good at all. Taitauwai even enquired about my well being. Well I'm still alive (sort of). My brain is slightly fried. I'm trying very hard to get some papers written whilst also attempting to set a new lab up, get my new projects going and phase new group members in and make their projects take off....yes I'm fairly busy. All my blogging time has effectively become paper writing time. Anyway, I have lots of things I would like to share at Curly Arrow and I'll try real hard to get some stuff posted. Whilst getting new gear for the lab I stumbled over an old box containing a virtually unused Vibro-Mischer - Das ideale rührwerk für Labor und Betrieb. Check out this nice poster I found in the box. That is one sexy model they picked to promote their products. If you click on the image you will get an enlarged version. D!

The Return of Dylan Stiles

Just as we thought that Dylan Stiles, formerly the host of blog.tenderbuton.com, was a dead and buried blogger he returns. Check his post on how to make pure nepetalactone (aka Kitty Crack) in your kitchen out here. D!

Asymmetric synthesis of vinylcyclopropanes

Apologies for the sluggish posting. Life is more complicated than usual as I've moved from one research group to another and as many of you will know this essentially means that you are working in two groups for a while. Finalising old stuff, cleaning up and writing papers on one topic whilst trying to start new projects in another lab....somewhat stressful and time consuming. Anyway, enough moaning. As you can see from the previous post I've sacked my fellow bloggers as they weren't blogging. So now it's all down to me (which it was anyway). I've been meaning to post this stuff since I read the paper in late December 2006. I have had a long lasting affair with cyclopropanes, in particular cyclopropane amino acids so I was very pleased to see this paper by Deng et al., DOI: 10.1021/ja056751o. These guys from Shanghai are doing some real cyclopropane magic using some easily obtainable camphor-derived sulfur ylides:The work is very throrough and makes up an 11 page JACS paper (not including any experimental). Many chemists would probably have split this work up in two papers. It's really nice to see these guys decided to stick the whole story in one paper. In brief these guys discover that they can make trisubstituted vinyl-cyclopropanes in high yield, diastereoselectivity and enantioselectivity. Moreover, they can make both enantiomers of cyclopropane selectively by switching from endo- to exo-sulfur ylides. This table from the paper illustrates how sweet this stuff is:Only "problem" here is that they are using stoichiometric sulfur ylide. However, they address this by developing a catalytic ylide cyclopropanation. The yields are not as impressive and the ee's are down to 50-80%. Still pretty cool and I bet these guys are working hard to improve the catalytic system. Finally, they decide to pull off a short and high yielding formal total synthesis of a known cyclopropane amino acid.
Obviously, they are making both enantiomers as well as both enantiomers of a diastereoisomer. And here I'm messing around trying to improve my lousy dr's on the racemic synthesis of the same target. Crap! D!

You're fired

Dear Steve and Chris: You're fired, both of you. Your license is revoked. All privileges have been suspended. Pack up your stuff and leave! D!

The Mannich Reaction revisited

The Mannich Reaction (Carl Ulrich Franz Mannich, 1877-1947) is yet another one of those reactions that look brilliant on paper. However, I have on many occasions heard chemists attempting the reaction moan a fair bit to say the least. The major problem seems to be that the reaction is sluggish requiring heating/reflux to get anywhere and that the reagents (and desired product) start polymerising. You can find Mannich's original paper here: Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, p. 647. There is a detailed entry in Wikipedia on the reaction for those not familiar with it. A good alternative to the classic Mannich conditions is to use Eschenmoser's salt which I've seen used successfully in a number of total syntheses. Anyway, recently a PhD student in my lab was bitching about his Mannich Reaction. He left the lab, did some reading and came back with this nice JOC Note by A. Erkkila and P. M. Pihko, DOI: 10.1021/jo052529q. When he started using this stuff all his problems were solved. Fortunately, he sorted all this out right before I had to do my first Mannich Reaction. It also worked as a charm for me so I warmly recommend this simple, and efficient Mannich protocol.

Now Erkkila and Pihko are quite concerned about reaction times because they are thinking of industry applications. However, for the average chemist that does a lot of work overnight (whilst at home in bed) it isn't essential that it's done in 1 hour. We found that if you do these reactions overnight no heating is required and the products are of very high purity. Very clean reactions indeed. Here's four examples from the paper:

As it turns out the chemistry works really well for most systems using catalyst 1. However, some aldehydes require catalyst 2 to give a good result, eg. entries 3 and 4. The only compounds tested in this paper that failed completely were aldehydes that exist predominantly in a hemiacetal form, eg. 5-hydroxy-valeraldehyde. So there you have it. Maybe something you should consider giving a go next time it's alpha-methylenation time. D!

Chemistry Blogs

I've received some emails from people wanting me to link to their blogs and web sites and also had some people ask me why I don't provide links to certain chemistry blogs. The blogs on the lists are the ones I like and visit regularly. I have decided not to link to blogs were there is to much bitching and slander going on, in particular if the blogger is anonymous. And then there's obviously all the stuff that I still haven't had the time to check out. I've just added two new blogs this weekend that I would recommend. Organometallic Current is a great blog with detailed paper reviews and lots of mechanistic stuff. If you like your Palladium you should check it out. Also A Synthetic Environment is an excellent blog. This blog is looking at some more historic and equipment related topics which are quite entertaining. Check, check, cccheck it out man.... D!

Revenge of the NMR tube

Well I guess it had to happen to someone sooner or later. It appears that I applied slightly too much pressure when I was sticking the lid on my NMR tube the other night. As a result the tube snapped and proceeded to go straight through my glove and into my finger. Now that's obviously annoying but can be fixed with band aid. However, when the tube had finally embedded itself in my finger it decided to snap for the second time. In other words I had a piece of NMR tube thoroughly buried in my finger. This is not the sort shit you want to happen to you at 11 pm on a Monday. Trying to fish the glass out myself only resulted in pain and blood everywhere so off to the hospital. Fortunately, the hospital is only a short walk from the Chemistry Department. After waiting for an hour amongst screaming people on various drugs and/or totally shit faced with blood coming out of various openings I was attended by a very nice Doctor. She told me straight away that X-ray was no good for glass so she would have to dig around for the glass bits. At this point I would like to say thank you to whoever it was that came up with anesthetics. Anyway, after some serious digging and cutting a big chunk of NMR tube was extracted. This is what my finger looked like at 1.30 am when I was finally out of the Emergency room.
No my fingers weren't really blue. I have no idea why it keeps uploading the picture like this but it looks kind off cool and scientific. Anyway, it really wasn't particularly dramatic and if it wasn't for the glass I would never have gone to the Emergency Room. I have always heard that impaling yourself with an NMR tube is a particularly common accident amongst chemists. Nevertheless, I'm the first casualty that I know off. Does anyone else know of similar incidents? Finally, I have to say that there wasn't really anything I could have done to prevent this from happening. I used a brand new tube and applied a minimum amount of pressure when putting the lid on........just got unlucky I guess. And by the way what are people thinking off getting drunk and on drugs on a Monday. Save it for the weekend people. D!

Tethered aminohydroxylations Donohoe stylie

Back in 2002 I started on a project where we considered using the Sharpless asymmetric aminohydroxylation (AA) as a key step. However, the anticipation of major regioselectivity issues and the success we experienced using the Sharpless asymmetric dihydroxylation meant we abandoned this approach entirely. However, I clearly remember sitting at my desk drawing a tethered version of the AA reaction where the amine was attached to an allylic alcohol as a carbamate. I'm sure that hundreds of other guys where drawing similar stuff and scratching their heads, however, Timothy Donohoe, from Oxford University decided to put the pencil down and get some students to get on with it. I completely missed the first paper that came out in 2001 in Chem. Commun. (DOI: 10.1039/b107253f) and only picked up on what they were doing when they published a paper on their TA work in JACS in 2002 (DOI: 10.1021/ja0276117). Ever since I have been following the Donohoe groups progress closely. The reason that I'm posting this now is because they finally nailed the reaction down in a recent Org. Lett. paper (DOI:10.1021/ol070430v). Anyway, let's get down to business. Firstly, it's important to realise that the TA reaction isn't asymmetric. It is however, a stereospecific, stereo-, regio- and chemoselective process. In other words if you start with optically active substrates you are laughing. Here's the condensed version of the story so far:

(1) Donohoe et al., Chem Comm, 2001, pp 2078-2079 (DOI: 10.1039/b107253f)
TA of acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 41 to 61%. Here's a really nice example with a diene:

(2) Donohoe et al., JACS, 2002, pp 12934-12935 (DOI: 10.1021/ja0276117)
TA of cyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 50 to 83%. Works for 6,7 and 8-membered rings but only 5-membered rings with exocyclic double bonds undergo aminohydroxylation. Here's another nice example making a protected amino-sugar:

(3) Donohoe et al., Org. Lett., 2004, pp 2583-2585 (DOI: 10.1021/ol049136i)
TA of chiral acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 57 to 74% with excellent syn-selectivity. Some very impressive examples of TA reactions in this paper, for example:

(4) Donohoe et al., JACS, 2006, pp 2514-2515 (DOI: 10.1021/ja057389g)

Finally, they manage to get rid of hypochlorite and NaOH by attaching a mesitylsulfonyl substituent to the carbamate nitrogen. As a consequence catalyst loading can go down to 1%, yields have improved (69-83%) and homo-allylic carbamates have become viable systems. Check this homo-allylic TA out:Nice stuff innit and it gets better.

(5) Donohoe et al., Org. Lett., 2007, pp. 1725-1728 (DOI: : 10.1021/ol070430v)

And finally the climax. This is the final, and very recent paper, from the Oxford lab. Previously some of the TAs just didn't work (with the mesitylsulfonyl N-substituent) for no apparent reason. So they screen a bunch of different N-leaving groups and discover that things take off big time when pentafluorobenzoyl is attached to the carbamate. Catalyst loading is now permanently down to 1 mol%, yields are up (71-98%) also for difficult homo-allylic substrates, and it works for both cyclic and acyclic systems. Here's a nice homo-allyic example:

So it took about 6 years to develop this methodology to the point where I believe it will start finding wide spread use in synthesis. I'm itching to try one of these for myself and I'm desperately looking for an excuse. If anyone has tried running some of these Donohoe TAs I would very much like to hear any comments - is it really as good as it looks on paper? D!

Monkeys

Yes, yes, yes I know Curly Arrow hasn't exactly been a hive of activity lately. Trust me it isn't because I spend my evenings sipping red wine and watching the sun set. There's a post in the making on tethered amino-hydroxylations so come back tomorrow and check it out. Until then have a look at this most interesting Monkey Distribution Map.

You'll notice that neither Europe nor North America has any monkeys. Where I used to work we saw many similarities between PhD students and monkeys (except monkeys have better lives). However, this is clearly not reflected on this map. Anyway, serious stuff tomorrow. D!

Tempo Oxidations Part II

I've previously mentioned the TEMPO/BAIB combo for oxidising alcohols to carboxylic acid. A very smooth and mild oxidation. Back when we discussed this particular reaction we had a brief discussion about stopping this reaction at the aldehyde stage. This is indeed what this particular reaction type was developed for originally and so when I recently had to oxidise a primary alcohol to an aldehyde I thought I'd give it a go. By chance Delfourne et al. (DOI: 10.1021/jm0308702) had previously made the same compound using a TEMPO oxidation. Too easy! According to the procedure the product was obtained in quantitative yield and purification wasn't required! This particular procedure involves a crazy cocktail of reagents. This is what I did:Fortunately, all the ingredients are reasonably affordable. Mixing it all up and adding the alcohol gives a biphasic reaction mixture that looks a bit like Schweppes Orange:
However, unlike Delfourne et al. my final product wasn't clean after a simple work up. Succinimide was simply precipitating everywhere and hence some silica was required. In the end a filtration through a silica plug proved sufficient to give clean product on a reasonably large scale (18 grams) in excellent yield (97%). So despite the fact that a simple work up wasn't sufficient to clean the product up this is an easy to do reaction that I would recommend to anyone who's tired of stinky old Swern. D!

Fun with singlet oxygen

So finally I'm back fresh and invigorated after numerous bottles of awesome South Australian Wine. I'd like to recommend Primo Estate/Joseph, Kay Brothers, Pertaringa and Leconfield/Richard Hamilton in McLaren Vale and Langmeil, Rockford and Richmond Grove in Barossa Valley. Anyway, first day back at work I did a photolysis as we often do were I work. In other words a diene is irradiated in the presence of oxygen and a triplet sensitiser (in this case Rose Bengal). I love this reaction because it's absolutely beautiful. Check it out man:
Now the above reaction is obviously totally irresponsible and was only on for less than a minute so that I could take the picture. We are dealing with a fancy piece of glassware that has oxygen bubbling through it whilst two flood lamps are hammering photons away generating singlet oxygen and in the process heating the fume hood up big time. Hence, aluminium foil on the bottom of the hood is required to literally avoid a melt down and I'll be hooking a pump up that sends ice water through the cooling jacket. Moreover, I'm synthesising an endoperoxide - AAaARRRrGGGHhHh PEROXIDE - yeah I know but they are really quite stable. In fact our friends at the defence force haven't been able to blow them up so we aren't too worried. However, to avoid any nasty surprises we try not to make more than 5-10 grams of endoperoxides at any time. So as I said totally irresponsible hence I proceed to wrap this beautiful reaction up in two blasts shields covered in aluminum foil, pull the sash down and hook a cooling box/pump up to the glass ware and the final set up looks like this:
Well at least I know it's beautiful behind all that plastic and aluminium foil. This particular day I was doing the following photolysis:

Reactions of this type generally work quite well giving yields in the 40-70% range and since dienes are easily accessible using classic Wittig chemistry we consider making endoperoxides quite trivial. So why was I making this particular endoperoxide? Well if I told you I would have to kill you. There should be a paper coming out later this year featuring amongst others this particular endoperoxide turning into a supa cool cyclopropane in one (yes one) synthetic step so keep your eyes open for that paper. Some of you are probably wondering what Rose Bengal is. Behold the halogenated beast:We tend to use the bis-triethyl ammonium salt (as shown) because it is nicely soluble in organic solvents such as dichloromethane. D!