The Disconnection Approach - Automated!

In my time as a synthetic organic chemist the most important advance in the field was definitely the introduction of searchable databases such as SciFinder and Reaxys. Life before these involved spending days on end in the library flipping though dusty tomes of chemical abstracts and Beilstein. And at the end you weren't even sure if you missed something of critical importance. The introduction of open access LC-MS and high field NMR has also had a big impact for me by speeding things up considerably. However, besides these milestones I think that I have pretty much been doing chemistry the same way >25 years. Anyway, what I am getting at is "what will the next BIG thing be?" It's been a considerable time since we had a major technical breakthrough for the synthetic organic chemist. My colleagues and I have been discussing this for more than a decade and now I think I am spotting the next big thing - Chematica! Chematica was developed by Polish scientist Grzybowski and has been around for quite a while. Basically it is a computer programme that disconnects your molecule and suggests ways for you to synthesise it. What's changed since I first heard mention of Chematica ~5 years ago is that apparently now it works the way you would like it to. Recently Grzybowski and co-workers published an impressive paper where they synthesise 8 very different and rather challenging molecules. The abstract from the paper nicely summarises the achievement:

"Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificial intelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design."

You really should read this paper. These are not simple syntheses and would have taken quite some time to come up with if at all. Now it is still early days and Chematica is only for those with deep pockets. I am personally waiting for a quote right now and am very curious to see exactly how deep my pockets need to be. BUT it has started and I believe that now it's just a question of time (I'm guessing  less than 10 years) before you simply hit the disconnect button in ChemDraw, look through the suggestions that appear on your screen and pick the one that you like best.

And there is more. Another game changer is already here and everyone with a PC can do this: Machine Learning. My next post will be on this topic that we are already using to great effect at my work place. D!

Transfer of nasty stuff with a syringe and needle

Synthetic organic chemists often have to transfer something pyrophoric, toxic, volatile, smelly etc. from a commercially acquired sealed bottle such as a Sigma-Aldrich Sure/Seal bottle using a needle and syringe. Even with great care it has a tendency to drip from the needle tip, which is the last thing you are interested in. Now a Danish team has published a simple DIY solution that should be adapted broadly since it solves the problem and increases lab safety.

Basically they have developed a 3D printed mount for the sealed bottle that makes is easy and safe to remove what you need (using both hands) and the needle tip is contained inside a small airlock during transport to the reaction vessel. I have taken the liberty of inserting a figure from the paper above that describes the set-up nicely. If you use this set-up and remember to always employ Luer locked syringes I believe that most accidents can be eliminated and that we can avoid another Sheri Sangji incident in the future. D! 

Faking it - Elemental Analysis!

Earlier this year I was refereeing a rather good paper and had I not taken the time to inspect the experimental section I would have accepted it with minor corrections. However, whoever wrote the experimental had clearly never run an elemental analysis before and was hopeless at making them up. The numbers were simply to good and although everything else looked great I had to reject the paper due to serious misconduct/fraud. This made me think that there must be thousands of papers out there with made up elemental and HRMS analyses  as these are really simple to make up. Have a look at this web page for inspiration for realistic elemental data: http://internal.eps.hw.ac.uk/services/analytical/chn-league.htm

After this incident I always read the experimental section first and check the spectra and I really wish that my refereeing colleagues would do the same. The crap you find in the experimental section of all journals including the most prestigious ones is simply unbelievable. Even when the experimental stuff looks great it is remarkable how many procedures we are completely unable to reproduce in our lab.

Anyway, not all hustlers are equally talented as a good friend of mine pointed out yesterday when he sent me this interesting paper by Reto Dorta and co-workers: http://pubs.acs.org/doi/abs/10.1021/om4000067

My friend simply wrote check out supplementary information page 12. And so I did and this is what I found (click on image to enlarge):

Many thanks to Reto Dorta and co-workers for this excellent example of what I guess must be classified as attempted fraud since the fake elemental analysis was never added. D!  

Total Synthsis?

We had our weekly journal club this morning. Interesting paper from a Korean group but maybe the ACS editorial office should wake up. D!

Triazoles in Peptidomimetic Chemistry

Self Promotion time! Our review on 1,2,3-Triazoles in Peptidomimetic Chemistry was just published in EuroJOC.

Useful stuff if you are working in the peptidomimetic area. You can get it here or by emailing curlyarrow@gmail.com. D!

NMR Impurities Tabulated

If you didn't already spot this useful paper on NMR impurities you should go get it now. An excellent addition to the classic paper by Gottlieb et al. that you can access here. D!

Hard Science

There's some seriously hard science in the latest issue of ChemComm. D!

Evil Molecules Part 1 - Explosive Azides, Diazidomethane

Say hello to diazidomethane. Is it time for a change of underwear yet? I work with azides on a daily basis and I even determine the melting point of my azides. My azides are nice a stable because they all adhere to the 6 heavy atoms (carbon or heavier) per azido-group rule of thumb. However, if you stray from the 6 heavy atom path you are looking for trouble and if you decide to do 1/2 a carbon per azide as we have in this case you will be looking for a new chemistry department.

In this really interesting paper from Alcon Research Ltd. they unintentionally made a fair bit of diazidomethane when performing the synthetic sequence shown in the scheme below. To remove residual dichloromethan after the first step the chemists at Alcon redissolved the crude product in DMF and concentrated it to dryness. To my (and theirs I'm sure) surprise this doesn't remove all dichloromethane despite a huge difference in boiling point. After performing the second step, they worked the reaction up and concentrated it on a rotary evaporator.

 This is what they observed when they came back the next morning:

“... it was noted that about 30 mL of a twophase liquid had collected in the glass crosspiece at the bottom of the condenser assembly.”

When they attempted draining the stuff it decided to go nuts. All I’ll say is that nobody died but you’ll have to dig the paper out yourself if you want the full story.

Remember, halogenated solvents (dichoromethan, chloroform, 1,2-dichloroethane...) and azide ions are bad news. Don’t do it!

Diazidomethane explosion, R. E. Conrow and W. D. Dean, Org. Proc. Res. Dev., 2008, 12 (6), pp. 1285-1286. D!

The Skraup Reaction - How to Make a Quinoline

Recently, Derek Lowe was discussing reactions he hadn't done at his blog In the Pipeline. Among these were, in his own words "the widely disliked Skraup cyclization for quinolines". This was somewhat surprising to me. I have very limited experience with the Skraup reaction but it has worked for me and one of my former colleagues said it had always been a great reaction in his hands. Personally I was surprised how well it worked considering the reaction conditions. This is what I did: 

Easily the most extreme reaction conditions I have employed. Hardly surprising this is a lively reaction. Adding acrolein (boiling point of 53 oC) to a 70% sulfuric acid cocktail at 110 oC is rather exciting. Things are vaporising, spraying, hissing and instantly turns into jet black tarry goo. After 45 minutes the reaction is allowed to cool and then you attempt to work the black polymeric goo up with 25% aq. NaOH, brine and ethyl acetate. I suspect that the modest yield is due to loss of material during this annoying work-up. Scaling the reaction up is likely to improve the yield. The Skarup reaction is indeed performed on ridiculous industrial scale so it can't be all that bad. My system was rather elaborate containing two phenolic ethers and still I managed to pull out 47% and it was reproducible. Unfortunately, I cannot give full structural details as this was done in industry and I seem to recall some papers I signed explaining my life would end if I ever mentioned any of that stuff.

I should mention that it is rather important that you don't use too much acrolein as this will turn the whole thing into a rubbery solid (as I discovered) that is impossible to work with.

Anyway, the conditions I employed here a slightly different from the standard method so it may be worth giving a go if you are into quinolines. The full experimental details can be found here: C. O'Murcho, Synthesis, 1989, 880-882. By the way that's Zdenko Hans Skraup himself on the photo above. D!

What is Click Chemistry?

2001 was a big year for K.B. Sharpless. He received the coveted Nobel Prize in Chemistry and introduced the concept Click Chemistry. I had the great pleasure of meeting him in 2001 and his lecture on Click Chemistry completely changed the way I think about chemistry.
I do not do Click Chemistry or even Click Reactions but I like the overall concept and I fulfil about half of the Click Chemistry commandments in my daily research.
Most chemists have no idea what Click Chemistry really is and think making a triazole makes you a Click Chemist. This is incorrect and many papers are published with Click Chemistry in the title even though it isn't Click Chemistry! Click Chemistry is not a specific reaction it is a concept. Here's a condensed version of rules you have to fulfil to become a Click Chemist.:

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The reaction must be:
(1) modular
(2) wide in scope
(3) give very high yields
(4) generate only inoffensive byproducts
(5) stereopecific
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The process must be:
(6) simple reaction conditions
(7) readily available starting materials and reagents
(8) use no solvent or a solvent that is benign or easily removed
(9) simple product isolation by non-chromatographic methods
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Sharpless published an excellent paper introducing the concept
Click Chemistry: Diverse Chemical Function from a Few Good Reactions, H.C. Kolb, M.G. Finn and K.B. Sharpless, Angew. Chem. Int. Ed., 2001, 40, pp. 2004-2021.
D!

How to make a primary amide - The Ley Way

Steven Ley's Group really produces some cracking results. This time they have developed a really simple method for preparing primary amides from carboxylic esters. This is very good news because this seemingly simple transformation is in fact not as simpel as one could have hoped for. In the past I have used ammonia in methanol to achieve this. The commercially available NH3 in MeOH is rather variable in quality so making it fresh by saturating methanol with ammonia using a gas cylinder is preferable. It's an annoying exercise making the solution and the actual reaction CO2R to CONH2 doesn't really work that well.So when Steven Ley comes up with a method that involves scooping solid magnesium nitride into a flask with your ester and some methanol, heating it to 80 oC for 24 hr, work up, filter, done! then that is really exciting good news to the synthetic organic chemist.

Magnesium nitride is reasonably priced, e.g. Aldrich (#415111) 10 g for less than 40 Euros. D!

Japan vs. Germany: 1-0

Just a minute ago I was looking through the early view papers for Angewandte Chemie and I spotted these two papers virtually back to back. Japan wins by three days. Can you spot the difference? D!

Open Access Journals - Beilstein Journal of Organic Chemistry

It's amazing how unpredictable life is. Only four months after I started my job in biotech I'm heading back to academia. Not that there was anything wrong with the job but I've been given an opportunity to return to Denmark (which always has been the long term plan) so I'm going with the flow. I recently had a post on open access journals and was moaning a fair bit about how we don't have any decent chemistry open access journals yet. Well I was wrong. A colleague alerted my attention to Beilstein Journal of Organic Chemistry (BJOC). This is the best attempt I've seen yet. They are publishing a reasonable number of papers, the quality of the material is good, the journal gets indexed by all the important organisations and it is absolutely free. The impact factor is still low (ISI WoK: 0.35) but this should improve with time. So check it out.

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The past year I've been involved in setting two labs up and whilst searching for information on equipment etc. I've been quite pleased with the Google adds people have on their web sites. I found a fair bit of the stuff I needed this way so I've decided to give it a go here at Curly Arrow. So sometime in the very near future adds will start appearing on Curly Arrow that should be useful to people interested in purchasing lab equipment. 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!

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!

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!

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
or
(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!

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!