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19 February 2011 49,476 views 53 Comments

Vanderwal, Martin. Chem. Sci., 2011, Advance Article.DOI: 10.1039/C1SC00009H Article PDF Supporting Information Group Website

Yep, it’s back.  However, no promises as to when I write my next total synthesis article!  The next blog post will in-fact be an egotistical diatribe – explaining what I’m doing now, and why my life has got a bit busier.  But if anything was going to haul my arse back on-line, it’s sweet little syntheses like this one!  As I’ve written about before, Strychnine has a bit of history to it, bound inextricably with the career of one Robert Burns Woodward.  Fully characterised by Sir Robert Robinson, he described it thusly: “..for its molecular size it is the most complex substance known..”.  Times may well have moved on, but this beast is still a challenge, and one that the Vanderwal group have cracked in only six steps!

The synthetic action kicks-off with a nice cycloaddition, using a class of diene that I never knew was named.  It turns out these amino alpha-beta gamma-delta unsaturated aldehydes are known as Zincke aldehydes – and effectively derived from pyridine.  A little base and a tickling with the bunsen (not that anyone actually uses one these days…) was enough to complete the intramolecular reaction and build two carbon-carbon bonds, setting three stereocentres (in a relative sense).

A little palladium removed the allyl protecting group from the amine (yeah, I kinda missed that too…), allowing addition of a  more complex organosilane-based moiety.  This group itself was made in only two step from a simple acetylene, using hydrosilylation to append the TMS group.  Why all that effort?  Well, with one neat little Brooke rearrangement, the group make two more rings, almost completing the natural product!  If only they could improve the yield of this reaction.  Vanderwal postulates that the problem is protodesilylation, resulting from rather acidic protons in the substrate.  Any ideas in the field?

As I said, the group were almost there – in fact, the product of this reaction is the Wieland-Gumlich aldehyde (masquerading as a hemi-acetal).  This intermediate is a common feature in Strychnine syntheses, and the transformation is applied like so:

That’s it – all done in six steps (longest linear).  Nice paper to return to!

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  • See Arr Oh says:

    FINALLY! Been waiting so long, had to get me a new job in the meantime!

    Next up: psychotetramine? Flustramine? Quinocarcin?

  • KC says:

    Good to have you back! That´s a really sweet synthesis.

  • QQ says:

    Vanderwal using his methodology “ALKALOIDS FROM PYRIDINES” as key step synthesis the Strychnine, the strategic was well-known.

  • milkshake says:

    the obvious approach to fix the low yield in the Brook rearrangement/conjugate addition step is to mask the aldehyde into something that is non-enolizable while still acting as electrophile for a cuprate-catalyzed reaction. Reducing the aldehyde to alcohol and making pivaloyl ester of the OH there selectively would be the way to do it (allylic pivalate esters are good electrophiles for cuprates) but one would need quite a lot of protecting group manipulations before and after (to turn the exomethylene product back to aldehyde).

    I wonder if one could turn the aldehyde to some acetal and use vinyl aluminum species with copper for the cyclization. (Brook rearrangement is nifty but one can make analogous vinyl aluminum species by DIBAL addition to propargylic alcohols)

  • Bif says:

    Amazing step!

    It could be renamed in a Brooke rearrangement-induced Vanderwal cyclization. With this six-step synthesis, it is gonna be pretty hard to do shorter for such a beast. Really, what a nice job!
    I didn’t know this interdisciplinary RSC journal. Impact factor should be pretty good in a couple of years.

  • asian chemist says:

    Great synthesis. Great post.

    I was thinking of Overman’s type prins cyclization as an alternative approach to try to improve the yield?…but may need to protect the alcohol first and then cleavage-induced cyclization?

  • G-M says:

    Retraction of the infamous NaH Oxidation.


  • ChemLiion says:

    Great Synthesis but how many can access the articles, at least the first one by Prof. Woodward. If a patent can expire in ten years, why not copyright of the publications?
    Countless amount of wealth of all forms is associated with research, from common people (read tax payers) to professionals all around the world in their own capacity. Researchers prepare and scrutinize (editors and referees) the articles, even type set them (templating) for free to publishers. Handful of these control the knowledge generated over decades of effort for their petty income.
    Is scientific community being exploited by these business houses? The effort of a researcher will be recognized worldwide any way and a unified open access platform would exponentially increase the research output around the globe.

  • suecita says:

    If you want the article order it for the nominal fee from the relevant authority, in this case the publisher. same as for any other publically avaliable information.

  • andy says:

    Hey guys check ACIEE webpage on the article of the day column:


    noticing something stinking there?

    • ChemCowboy says:

      The Bionic Brothers live on!

      I can’t believe this is still floating around, hiding among all the real science and credible authors. I mean I would take it back if JJ could prove to me that he (and his humble co-workers who aren’t even co-authors!!!) actually made that eyesore of a molecule, and that two compounds really can have the same NMR, but I’m inclined to believe Rychnovsky and Porco on this one…

  • HPCC says:

    ALl my thoughts are with Japanese scientists, most preferably organic chemists, reading this blog right now. Wishing you all the best in this adversity, and hoping that you can advert any nuclear disaster. Sincerely.

  • R. B. Woodward says:

    Sorry to hijack this thread, just wanted to let you guys know that David Gin passed away on March 22, 2011 at the age of 43.

    • hdhao says:

      Really? Any details. He is a creative chemist i’m admired.

    • Tot. Syn. says:

      Damn… Such a talented and decent guy. I’ve covered a few of his papers in the past, and loved the work. Even applied for a post-doc with him, but took a job instead. Total synthesis and science in general will miss Professor Gin considerably. Condolences to all who know/work with him.

      • Yuan says:

        Tot. Syn. , thanks. Dave is a fantastic advisor. I can’t ask for a better one. He is warm, creative, helpful. His door is always open for us. Whatever career path you choose after graduate school, he’ll always be 100% behind you. Even now it’s still hard to accept.

  • Chymist says:

    What a sad news is that!:(
    The world has lost two brightest rising-stars of organic chemistry in about a year…

  • yonyodonio says:

    His synthesis of hetisine is probably one of the more elegant and impressive synthesis have seen during last decade. Terrible news…

  • THAI Chemist says:

    I would like to further my studies in a PhD program in Organic Chemistry. What are the top Organic chemistry Programs at Universities in UK? Which university would you recommend?
    Cambridge, Oxford, Bristol, Manchester, York, Edinburgh,Leed,Notthingham, Bath, Warwick….etc.?

    • ChemCowboy says:

      Ignore F-C. There is lots of nice chemistry going on in the UK. I can’t vouch for the quality of the individual programs, but some of my favourite chemists are in the UK right now – Darren Dixon, Matthew Gaunt, Tim Donahoe. I would narrow it down to a sub-discipline (synthesis, organometallics, methods) and start looking at professors from there.

    • Gilgerto says:

      To this you can probably add Jonathan Clayden, Varinder Aggarwal and Guy Lloyd–Jones… I do quite like Dixon, he does nice stuff!

    • R. B. Woodward says:

      If I were you, I would not waste my time with European universities and focus on finding a position in the US. Being from Europe myself, I am ashamed for how negatively our universities are percieved in the US.
      That goes even for places like Oxford or Cambridge. Europe lost its edge in science a long time ago and it does not look like it is going to regain it in the foreseeable future.

      • Gilgerto says:

        If you don’t plan to work or post-doc in the US, I guess you shouldn’t give a **** about what people in the US think. It is well known anyway that for Americans, anything outside of the US is crap…

    • Friedel-Crafts says:

      If US is too far for you, try Germany or Switzerland. The current situation on the job market in the UK pretty much reflects the level of science in the organic chemistry division in the Empire.



      • Safety conscious says:

        So the current UK job market in chemistry is a reflection of the standard of science? In which case, please comment on similar site closures, dwindling career opportunities and dire chemistry job market in the US relative to the quality of science in US academia.

        It’s got flap all to do with science, and everything to do with economics.

        • Matts Chair says:

          Top 10 aside (and that includes Oxford, Cambridge, Imperial and ETH) there is little difference in quality of chemistry departments in the US and UK. The main difference is the work ethic with US labs pushing 12 or more hours a day, 6 days a week and the money available to form larger groups. Simple maths, more hours from more people = more science.

          European chemistry can’t be that bad if the likes of Dirk Trauner, Andrew Hamilton and P Andrew Evans have all returned in the last 2 years!

  • Friedel-Crafts says:

    Don’t bother. Go to the US.

  • THAI Chemist says:

    Thank you very much for your comments and suggestions.
    I can’t work abroad because I have been granted a full scholarship by the Royal Thai Government and have to return to Thailand after completion of my study.
    Many universities in Germany and Switzerland, such as Max Plank and ETH, are very good but I may have some problems with English…
    At the moment,I’ve applied only U. of Edinburgh and I’ve just got an offer letter. In my view, the group I will join is the best…

    • PotStirrer says:

      The top programs in Germany and Switzerland conduct most of their work in English…that won’t be much of a problem for you.

  • suecita says:

    At the max planck university you may be able to get away with german, but english is probably a bit of a requirement at least at some level.

    hope this helps.

  • Ian says:

    Go to the US

    Top unis like Columbia have Dalibor Sames and Scripps has tons of contacts with La Clair

  • lovesorganometallics says:

    Off topic here, but I need comments!!

    So, I am planning to run a synthesis of a topologically complex molecule. And since I wish to primarily work on transition metal catalysis, I was hoping to apply mostly C-H activation reactions, & Palladium cascades.

    Would the scientific community look ill of it saying ‘oh sad, the dude doesn’t know any other chemistry’?? And am I at an added disadvantage that my synthesis couldn’t be the BEST one, because it has a lot of T-Goal disconnections??

    And FINALLY, what is it that gets a paper in a journal like nature for a molecule that is not so complex – 5 rings, 5 contiguous stereocenters, and a benzylic quartinary carbon (if you know natural products from the tip of your head, you already know what I’m talking about). Also this molecule has around 18 syntheses covering its head. *gulp*, although I personally don’t feel anyone is so great and concise

    • Starvinmarvin says:

      Instead of worrying ‘what people say’ or ‘would I get my paper into Nature?’ try first making the molecule. And don’t get discouraged if and when things don’t go according to plan. Remember, even the best plan rarely survives contact with the enemy. Don’t be surprised when once your molecule is done, the route is not even close to what you planned.

      Have fun and good luck :)

      • lovesorganometallics says:

        Oh thanks. That did bring me closer to reality. :) :) I’ll try my best to make it perfect, but yeah, I have no idea what could happen.

        Thanks again – for the advice and for the wishes. :D

  • lovesorganometallics says:

    Oh, and does anyone know what it is like to work in Trost’s lab (as an informal Visiting researcher) There is good chance I’d be going there… and I wanted to know – does he impose schemes and tells people to work on them?

    Where does he give freedom?

    • Martyn says:

      You should have a look at Dylan’s Tenderblog archive in the links section up there^, he was a PhD student with Trost. Login ‘tender’, password ‘button’.

    • SpeedyGonzales says:

      @lovesorganometallics I would also add, it would be unlikley that you could work on your topologically complex molecule of choice in the Trost lab, as the one you have mentioned already has a history in that group. http://pubs.acs.org/doi/abs/10.1021/ja0283394 (I hope I guessed it correctly). With a few honourable exceptions, PIs generally don’t revisit syntheses. The Hudlicky and Rice syntheses are reasonably concise though, and anything that could not compete in terms of step count or yield would have no chance of being published in a higher tier journal without some other remarkable advance in methodolgy. And by higher tier, I mean ACIE, JACS or even Org. Lett. The chances of a total synthesis for the sake of synthesis of a molecule like morphine getting into a journal like Nature or Science are approximately 0%. You really need to push the frontiers for that, like for example answering how opioids are endogenously formed in vertebrates. Don’t let this discourage you though, total synthesis provides a fantastic training, and I think the Trost group is one of the best environments. You do not need to work on a “famous” molecule to get a great training in total synthesis. What I would look for in a target is something that can both have a reasonable expectation of providing results (not necessary to complete the synthesis) and something that has a high likelihood of expanding your repertoire of reactions. The primary point afterall is to get an education, not to make some specific molecule. As for the Trost group itself, I have briefly met people who work there, and I get the feeling that while Trost is very engaged, the group is large enough that students get breathing room to make their own decisions, and make their own mistakes, and try to fix them on their own, which is a vital part of any education. Good luck!

  • lovesorganometallics says:

    I am so glad that there is help out here. @Martyn – THANKUU. :D I’m checking the page out.

    @SpeedyGonzales – well, you know your natural products well. haha. but thanks for the advice. I have read it closely and I’ll stick to it. Thank you SOOOOOO MUCH!!!!! You’re right. I’ll work on something interesting, hope it works, add a pinch of novelty as well – and even if it doesn’t work, its my education process. And ofcourse, that something can no more be morphine – I wasn’t aware he had a publication on it – although it seems likely it would come in his to-do list.

    And as you’re helping me, and since there are people out here to help
    I have to know – well, I don’t have the most formal education in the subject, I just kept reading.. (too complicated to explain). And I’ve carefully studied like 8 monographs on Organometallic chemistry -where I want to specialize – (compared to March’s advanced org chem and the strategic app of named reactions, and joule and mills on heterocyclic chemistry and a few books for the other minor stuff like 6 membered transition states, stereochem, classics in total synthesis, reactive intermediate chem and what not)

    And I’ve started to keep myself in touch with literature as well.

    What else am I EXPECTED TO read and do?? I have ABSOLUTELY no good source of useful guidance around here and I really need the help. CLEARLY organotransition metallic chemistry is what I wanna specialize in, and I think I have a well equipped background in the fundamental organic chemistry as well. so, what else is expected out of me?! HELP – SERIOUS

    • SpeedyGonzales says:

      Your reading list sounds impressive in terms of organic chemistry. A book that I have found very helpful is “Transition Metals in the Synthesis of Complex Organic Molecules” by Hegedus. I have an earlier version, which is out of date, but it is still an excellent survey of what is out there. I will add I do organic synthesis where I heavily use organometallic reactions, but I am not inventing new catalysts or transformations, rather adapting known transformations to my specific substrates. I make a lot of the catalysts I use, but actually designing/ developing them is a whole different story, involving quite different skill sets. There is an updated version of the Hegedus book that was published in 2009 that I have not seen, but I imagine if it still contains and expands on the material in the earlier books that it would be well worth reading. The Organometallic Chemistry of the Transition metals by Crabtree and the new Hartwig book Organotransition Metal Chemistry, from Bonding to Catalysis are also great books, with Crabtree being more on the fundamental side and Hartwig having more modern examples of applications. However, there is only so much that reading about the field can do for you. I don’t know what your research background is like, but actually becoming a good researcher in a new field is something you learn by doing, not by reading about. Obviously you also have to have a good foundation of knowledge (such as your reading lists are giving you) to give you the toolbox to interpret your results in the wider context of the field. When I started graduate school, I knew probablly most of what I know now about mechanisms, named reactions, and other such background things. What I have learned and continue to learn is how to do research itself, how to ask the right questions, the best use of my time, the most powerful experiments to run. Even if you have only a mediocre background in a field, it has been my experience that anyone with a passion to learn can do well in a lab as long as they do not mind a steep learning curve. Actually doing the experiments and being around people doing likewise has a remarkable effect at sharpening your focus for what to read. Don’t be afraid of a steep learning curve. A favourite quote of my advisor (who will remain nameless) is that “Success is paid for in advance”.
      Good luck.

      • lovesorganometallics says:

        @Speedy Gonzales – you have NO idea how much I owe you! I get the point I guess. Experience comes first, then comes the reading, and btw, the first book that I read on transition metal catalysis was by Hartwig. :) The rest are monographs for specific elements, on which I want to focus on.

        It was absolutely lovely reading your reply, so thanks A LOT again for the help.

  • hexanes says:

    I wanted to solicit some advice from the chemical community. I am a 5th year grad student in the US looking for a postdoc. After my postdoc I want to work at a large pharmaceutical company, such as Merck, BMS, Amgen, etc. I know jobs are scarce in this time of economic hardship, so I would like to ask whoever has experience in this area, what you think are the best postdocs that have the most connections with these large pharmaceutical companies? From what research groups do these companies like to hire from? In other words, of the people that ARE getting hired at these companies, where did they do their postdocs? Any help is appreciated!

    • mannose says:

      unfortunately there are no guarantees with ANY advisor right now. Additionally, I am unaware of ANY of the big pharma companies (Merck, Pfizer, Bristol-Myers, etc.) that are hiring “entry-level” chemists. That said, I realize that certain of the larger, more well-known groups have inside contacts that certainly couldn’t hurt your cause. Currently there seems to be a major change in the focus of the big pharma companies with much less attention being paid to small-molecule targets, due to the time and $$$$ necessary to produce a drug. If I was you, I would look into a different “specialization” — i.e. bioconjugation, organometallics, parallel synthesis, etc. than the traditional natural product synthesis route. Hopefully this can compliment your graduate studies and payoff in the long-run. Just another quick note, there are a TON of unemployed organic/medicinal chemists that have industry experience that will (usually) give them priority when competing for the same job. BOTTOM LINE: look for an industrial postdoc (even with a mid-sized, or smaller company), which will give you the industrial experience that you need to land that job with big pharma.

    • R. B. Woodward says:

      I have to agree with mannose. Even the biggest chemists like Nicolaou, Roush, etc. have huge difficulties getting decent, let alone big pharma, jobs to their favorite students. If you come from an average or below-average group, you would have to really impress one of these big guys to even have a shot at a decent job in pharma.
      Realistically, be prepared to take whatever you can get and consider yourself lucky if you get any job at all. Many grad students and postdocs from big groups are fighting for jobs that would have been considered demeaning before 2008.

    • industry chemist says:

      Danishefsky, Trost, Smith, MacMillan, Boger, Crimmins and Jacobsen have excellent conections with big pharma. Baran consults for BMS and sends students there. Overman lab is another feeder into big pharma.

      Of course, connections alone won’t get you a job. Kicking ass during your post doc and having strong interpersonal skills is what will impress your prospective employers the most.

  • Friedel-Crafts says:

    Try to look for an opportunity to work on a highly-impressive project, ideally total synthesis. It seems that the only people who landed jobs in the big pharma in the last year or two are both: from the biggest groups and have been lucky enough to complete a world-class piece of work.

  • hexanes says:

    hey guys,

    Thanks for the great advice. I always planned on kicking ass in my post doc, I was just curious to see if any groups still had connections into big pharma, and I think Industry chemist gave some good insight.

    Thanks for the help!

  • xyz says:

    Is this Blog Dead?

  • ch3mical says:

    Aspidophylline A?