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


Projects I’m glad I didn’t work on

Obviously this style of post is borrowed from Derek Lowe's Things I Won't Work With. I'm not the most original person, and this certainly isn't the most original blog.

Hopefully many of you will have now read Baran's axinellamine paper (my take here) - it's an impressive piece of work and worth a few minutes of your time. I've noticed that I keep having the same conversation about it with different people over the last day or two:

BRSM: Have you seen Baran's new axinellamine paper? It's the shit!

Chemist: Yeah, it's pretty cool, but you couldn't pay me to work on that project. Those guys must have spent a lot of time staring off the roof of the Scripps chemistry building.

BRSM: But he's so sexy!

Chemist: I have to go now, I, uh, have a TLC running...

Or variations on that theme. Anyway, I realised that actually: 1. I'm probably inclined to agree, and 2. I find myself thinking this quite a lot. As I told commenter gippgig yesterday, I saw Baran give a talk about this work back in 2009. I remember him describing the silver(ii) picolinate oxidation and saying they had to screen a massive number of oxidants to find this successful reagent. I think he described one of his students as having a 'black tar phase' of 6 months or so, where everything presumably kept degrading when they attempted to install that troublesome hydroxyl. Silver(ii) picolinate obviously wasn't high on the list  of things to try as they had to make it specially, and none of the references they give for its use are later than the early 1970s. Periods of faliure come to everyone who practises chemistry long enough, but when you're pushing the boundaries of what's known, as Baran was here, you can spend months in the lab going nowhere at all.

A couple of other syntheses from this year with similar heroic efforts at optimisation come to mind. I should say now that I think they're both fantastic, but I'm not sure I would have had the dedication and mental fortitude to see them through.

1. Vanderwal's Synthesis of Strychnine By A Longest Linear Sequence Of Six Steps

I'm sure many of you will have read the Tot. Syn. coverage from when the paper came out. I'm only going to talk about the last step here - the amazing Brook rearrangement followed by conjugate addition to the enal. This is a very cool simultaneous disconnection for the strychnine D and F rings, but, perhaps unsurprisingly, required a lot of experimentation to realise. Saying nothing of how long it took find conditions that actually gave any product at all, Vanderwal says that over 100 experiments were tried to attempt to improve the yield, and yet 5-10% was the best they ever got. I bet that was a depressing couple of months for the one student on the paper, although I suppose having their name on the world's shortest route to the racemic natural product offered some small comfort afterwards.

However, this task seems positively straightforward compared to the sisyphean effort of...

2. Herzon's 11-Step Enantioselective Synthesis of (-)-Lomaiviticin Aglycon

Obviously, when targeting dimeric compounds, a late stage dimerisation is the way to go, and this is exactly the retrosynthesis that Herzon and coworkers applied to the lomaiviticins:

The carbon-carbon bond forming reaction they decided to use was the oxidative dimerisation of enolates, which is pretty well known. The problem was the instability of the system that they chose to apply it to - enolising a ketone with a b-leaving group, for example, is rarely a recipe for happiness, especially when you start adding potentially Lewis acidic metal oxidants to the mix, as elimination, tautomerisation and irreversible aromatisation are all waiting to happen, given half the chance. And as if that's not hard enough, why not include a diazo group in the monomer for an extra challenge?


During extensive investigation of the dimerisation reaction the group found that the use of a cyclic protecting group for the vicinal diol was essential as the silyl enol ethers of compounds bearing acyclic protecting groups were unstable above 0 ºC.  Attempts to perform the oxidative coupling at lower temperatures using conventional oxidants such as CAN or copper chloride returned only aromatised material with all substrates tried. Eventually, the Manganese catalyst shown was found to be uniquely effective for this transformation. Herzon attributes its singular success to its solubility and stability in benzene, and its low Lewis acidity, factors which minimise the competing b-elimination-aromatisation. Anyway, after just 1500 experiments the group found that the dimerisation could be performed in 26% yield. To put that in perspective for non-bench chemists, that's how many reactions I did in the first two and half years of my PhD.[1] This is a truly incredible feat of endurance for the authors. Mightn't you have been tempted to stop after the first 100, 500, or 1000 failed reactions? I would have. In the words of Samuel Goldwyn's famous malapropism, 'gentlemen, include me out'.

Has anyone else seen a recent synthesis that makes them feel the same way?


1. However, I imagine the work ethic at Yale is a bit different to where I'm studying in the UK.


Comments (19) Trackbacks (0)
  1. Long answer: Yes. In fact, I happen to work on a natural product synthesis right now, but in the industry. When our patent application becomes public in six moths, check it out and say out loud: “I am thrilled I never had to do THAT”.

  2. Wow. Impressive. Unbelievable.
    I’ll still the last scheme if you don’t mind.

    • Steal? Of course, as I said on my about page, anything I post here is free to whoever wants it!

      • Great, thanks!
        The post can be found here: http://sash-2003.livejournal.com/50266.html You might need some skills in Russian 🙂

        • Well, I actually can read Cyrillic thanks to some unusual choices of holiday destinations over the last couple of years (Belarus, Uzbekistan, Kazakhstan, Kyrgyzstan and Tajikistan), but I’d be lying if I said I understood a word of that after your name. Thanks for linking me, though – I’d seen that site cropping up in my list of referrers before (I think for my TNT post), so that makes a bit more sense now!

          • wow!, so u have been in Kyrgyzstan as well? I come from there 🙂

          • Yes, but only for two weeks! In fact, I would say that of the 4 ‘stans I’ve been to so far, Kyrgyzstan was my favourite. I’ll have to get back there some day – the mountains are amazing and people are so friendly, but unfortunately I’m a bit busy at the moment. And there are still 3 ‘stans I haven’t tried yet. Never actually met anyone from Kyrgyzstan outside of the country itself…

          • It´s great to see chemist in a transition state (AKA Tynchtyk) also visits this site. He introduced me to chemistry blogs and this one is quickly becoming one of my favorites.

  3. 1500 reactions For one step of a synthesis of a relatively useless compound seems to me like a collosall waste of money and time. Think of how much else could have been done with money and effort.

      • I’m not sure I need to spend a lot of time providing examples to back up my statement since it is so clearly right. But I would say almost any other 2-3 year scientific endeavour would be preferable. As above, 1500 reactions is a lot – a substantial portion if not all of a PhD (I did 400 ish in mine – in 3 years). To gain a PhD you need to contribute substantial new knowledge. Is finding the best conditions for one reaction in a multi step process really ‘substantial’?

        This kind of grind-it-out chemistry isn’t useful and doesn’t represent a good use of limited resources. Does it establish any new principles can be applied widely? No. Does it provide broad and useful training for students? No. Would 3 years be better spent on a more wide ranging, pioneering, proof-of-principle project? yes.

        Incidentally, it could be interesting to see a survey of the reactions that don’t work, I wonder if that will ever get published. It would provide at least a small benefit from all that time and effort and money.

  4. I wish one day i will have an opportunity to work on such impressive projects.
    I will never run even 1000 reaction during my PhD,here in Russia (of course I could, but our material supply is very bad)
    also one more example of Baran’s group work on screening reaction conditions:
    The team tested scores of reagents in more than 500 reaction systems for the trifluoromethylation of a test compound, 4-t-butylpyridine

    • Ah, that’s another good example! I skimmed that PNAS paper on Friday but didn’t notice they did so much optimisation! Regarding ‘impressive’ projects, just worry about making it through your phd and getting a few papers so you can postdoc somewhere nice! I’m sure most people know that number of reactions isn’t a very useful metric for the quality of a phd anyway; a friend of mine got 5 papers and a postdoc with Matt Gaunt out of no more than 700 reactions, conversely I was on well over 1000 before my first paper (and no, it wasn’t even a total synthesis). I’d love to trade places with her!

      • When you say 1000 reactions, how many of those go through workup, chromatography and NMR analysis? I’m starting to feel rather unproductive…

  5. I think both of these projects were extremely worthwhile, regardless of the time and effort required. At the end of the day people *cared* when these molecules were made.
    When I think of projects I’m glad I never worked on, I would dread something like optimizing the protecting group scheme for a macrolide that’s already been made 3 or 4 times. To give your blood sweat and time for a project which ultimately nobody cares about – that’s hell.

    • That’s true; especially for the strychnine synthesis. I remember everyone talking about this for a couple of weeks, and it got plenty of attention online as well. Hell, we even had it as part of a group problem session. I could probably have worked on that. I was actually very excited when the Herzon paper came out at the start of this year as I was at the time writing a review on naturally occuring diazo compounds for Nat. Prod. Rep. I was supposed to have finished by Christmas, but had to delay submitting a few months for various reasons. Then this came out, and I suddenly had to rewrite a large part of the kinamycin/lomaiviticin section. I don’t think anyone would dispute there are far more banal projects to work on – at least these two are cutting edge, and as you say, people cared.

      However, I still maintain that I wouldn’t have wanted to, or been able to spend a year or more of my life on optimising that dimerisation, cool though it is. When I think about what that would have involved day-to-day, I know I couldn’t do it, but there are plenty of people who can. Which is why you have a Science paper and I’m not even going to try and do a postdoc.

  6. Let me wipe the dust from this post.
    To let you know: I’ve just found a fairy recent reference to silver (ii) picolinate in Shair’s (-)-longithorone A synthesis (doi 10.1073/pnas.0401952101). So, it’s not that old and forgotten as we thought.

    • Ha! That is interesting. I actually covered this synthesis in the introduction to my thesis (written after this post), but I had forgotten about the silver(ii) conditions. I think I only wrote about the much higher yielding conditions with iodosylbenzene (which might be the only ones given in the follow-up JACS paper). I even bought some silver(ii) picolinate myself a few months to screen for a biomimetic oxidation. Didn’t work, though!

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