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18 July 2007 12,097 views 36 Comments


Coldham, Burrell, White, Adams and Oram. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200701943.

Now this looks a little different from the past two syntheses: a nice pentacyclic alkaloid! Another difference is the brevity of the synthetic route: nine steps! When I saw the title, I was sure I’d seen a classic synthesis of the target, and this was confirmed with a reference to the Stork synthesis from 1963. In this paper a key tricyclic ketone was perpared in thirteen steps; in this work, Iain Coldham’s group manage this in six!

The key to this brevity is their formation of an azomethine ylide from an aldehyde and a primary amine, following an in situ N alkylation! The ylide then performs a 1,3-dipolar cyclisation onto the olefin, forming a five-member ring. This type of process was previously developed by Pearson, but Coldham has taken this forward considerably. The substrate for the cyclisation was made very quickly and easily (I like the mono-elimination in the first step), basically doing two alkylations.

The ylide formation / cyclisation went really well forming four new bonds,
three new rings, and three new stereocenters as a single diastereoisomer! Good stuff! I’ve not drawn the reaction transition state, which is “S shaped”, but there is an interesting discussion of this in the paper. To complete the synthesis of the Stork intermediate, all that was required was a deprotection of the ketal, and concomitant epimerisation of the adjacent stereocenter. Three further steps from the literature then completed the target. Nice read.

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  • ZZZZZ says:

    Stork’s synthesis was awesome, and it was a hundred years ago. Stork’s the man.

  • Spiro says:

    This Aspidospermidine synthesis is a great one.

    But Stork’s has seriously disconcerted me. I feel really sorry for those chemists before us who had no NMR and no minute X-ray. They conclude that they made the correct product, based on IR, mass spec and TLC. I wonder how many docs and postdocs it took to get the matching TLC!!!!!!!!!!!

  • hetchem says:

    No doubt, synthesis of pyrrolidine by a azomethine ylide cyclization is Coldham’s touch, [3+2] cycloadditions using aldehydes and glycine are quite common, but the intramolecular generation of ylide and subsequent cycloaddtion is a great job.
    I think the precursor of cyclization could be realized by bi-directionnal synthesis and a subsequent desymmetrization, what do you think about it???

  • WillisWill says:

    How does the decarboxylation take place in?

  • Tex says:

    It’s thought to occur via the cyclization of the carboxylate onto the iminium ion, forming an oxazolidinone, which then expels CO2 via a retro [3+2] and forms the ylide. It really is a neat reaction. There is quite a lot of work in this area by the Grigg and the Tsuji (sp?) groups.

  • The Canadian Chromatographer says:

    Bottom line, I really loved that key step when I read the paper.

  • Jose says:

    Alkaloids are perty…. macrolides are boring.

  • bibi-p says:

    i agree with u..

  • ArrowPushingMonster says:

    In order of interesting structures Steroids/terpenes > Alkaloids > CO2 > Macrolides

  • GYA says:

    No sir! Alkaloids top the charts–followed by terpenes then a distant third are steroids maybe!

  • milkshake says:

    I too will take alkaloid or terpene over macrolide every day. Just try to smoke a macrolide.

  • willyoubemine says:

    hahaha, milkshake game, set, matched that debate.

    I agree though, at least alkaloids still have new ground to be broken. Terpenes and steroids and macrolide syntheses, while impressive, all seem to be old hat type chemistry.

  • The Canadian Chromatographer says:

    There is one terpenoid spectacular coming up in Angewandte (see VIPs), though. Ley’s group has accomplished the tour de force of finishing azadirachtin. One hell of a beast. After 20-something years of work… Looking forward to those back-to-back papers. Any bets on the number of steps? I’ll say 48, longest linear sequence. Maybe I’ll soon bite my words…

    Except for that, I will take an alkaloid over any macrocycle, unless it may present novel disconnections. That is, no Grubbs, no Yamaguchi…

  • willyoubemine says:

    exactly, the methods of terpene, steroid and macrolide synthesis are so well established, you almost have to invent a problem, solve it with a “novel” methodology, then force that methodology into a synthesis for it to be different.

    I mean even this alkaloid work, while nice and impressive, is virtually Stork’s disconnection and approach.

    Favorite alkaloid syntheses??? Anyone?

  • GYA says:


  • GYA says:

    Willy, I think you’re severely confused. The disconnection here is completely different and very creative. Stork’s is a very classical and methodical approach. Coldham’s is a homerun by comparison. And as far as azadirachtin, the problem is pretty much a mountain some feel needs to be climbed and although its completion will no doubt be impressive. It will probably lack creativity and any important lessons for the community. There will always be exceptions to the rule as far as strutural novelty, such as peptides like vancomycin and thiostrepton. But, as a whole, alkaloids stand to teach us more interesting lessons than most natural product classes.

  • Giagan says:

    #12: “Terpenes and steroids and macrolide syntheses, while impressive, all seem to be old hat type chemistry…”
    #14: “…the methods of terpene, steroid and macrolide synthesis are so well established…”

    Well, if people do continue to pursue syntheses of these targets only with existing methods, then you’re right. But the diversity of structures found within these classes will continue to inspire many. I feel that the real excitement with these natural products is that there is room for improvement, both incremental and mind-blowing. Some of my favorite examples of the latter include:

    Paquette’s hypnophilin synthesis

    Pirrung’s isocomene synthesis

    MacMillan’s organo-cascade catalysis
    I don’t think any syntheses have been published yet, but if you have a chance to see Dave talk, don’t miss it!

  • willyoubemine says:

    both involve a very similar ketone to be formed into the indole ring. the synth of said ketone varies, but does that make it a drastically different strategy? I dont think so.

    Corey’s, Magnus’, Fukuyama’s are different strategies. This is a better way to approach Stork’s strategy.

  • willyoubemine says:

    btw, i know i included aspidophytine syntheses too, so similar.

  • ddd says:

    question: can I use selenium oxide for oxidation in the presence of iodine group?

  • Spiro says:

    What kind of iodine? alkyl iodide, aryl iodide, vinyl iodide, iodoso, …?

    Be more precise.

  • kiwi says:

    what do these guys smoke when they plan their retrosyntheses? and where can i get it?

  • ddd says:

    more precise: If i have 2-methyl-3-iodo-pyridine can I use SeO2 to oxidize methyl group into aldehyde? I know you can do it with 3bromo or 3chloro pyridine, but I wonder with iodine will tolerate SeO2

  • ZZZZZ says:


    just try the SeO2 reaction on 50 mg and see if it works by crude nmr


  • spottospot says:

    number 9, your funny because you are right.

  • typical organic chemist says:

    In CO2’s defense, it makes plants, er, live. Let’s see your precious rapamycin do that shit.

  • ArrowPushingMonster says:

    Hahahaha… No ones saying CO2 isn’t important, however lets have a show of hands who would rather spend two years making a structurally interesting nat prod over 2mins work synthesising CO2 (hmmmm bicarb + Acid?) :)

  • Liquidcarbon says:

    Hey guys! I developed a biosynthetic route to CO2!

  • willyoubemine says:

    really? i have long had a self-sustainable route to CH4. Been working on it for years, much to my wife’s chagrin.

  • willyoubemine says:

    Hey 26. If you use that route, you will be infringing on my Patent #3422472-A, How to make a Volcano from Vinegar and Baking Soda.

  • ArrowPushingMonster says:

    Hahahaha… Personally my Hydrogen sulphide biosynthesis after a curry is my best ;) Willy: Vinegar and baking soda volcanos are boring show the kids something interesting…like a volcano inside an old microwave, complete with lightning storm affect (best to do in the garden though unless you have a good fire extinguisher or a friendly fire service….)

  • willyoubemine says:

    anyone do the lightbulb in a microwave? it goes all these crazy colors then burns out. best 30sec of my life.

  • Liquidcarbon says:

    30: I know one. There is a nice route to prepare nanoparticles of metal oxides – to fry a solution of metal nitrate and big excess of sodium chloride in microwave – wash away NaCl matrix et voila. BUT! A guy sort of ran out of sodium chloride, and sodium IODIDE came handy. I was like “uhm… iodide + nitrate?..” This didn’t stop him. So, microwave in a cloud of iodine, then a cloud of nitric oxides… That was spectacular! :)

  • kiwi says:

    Baking soda volcanoes? nothing says volcano like a pile of ammonium dichromate, with a stick of Mg ribbon poking out the top. Light the ribbon, stand back: NH4 -> N2; Cr2O7 -> Cr2O3. Neato

  • Liquidcarbon says:

    More home chemistry: heat this Cr2O3 from volcano in a spoon over a candle or smth and throw it in a bottle filled with ammonia vapors from household ammonia. NH3 burns in air, on the hot Cr2O3 particles. Sparks! Caution: may explode. It actually did exploded once in my experience.

  • TWYI says:

    Iain Coldham is one of the nicest guys I have ever met in acadaemia. He also did Carruthers proud with the new book.

    Nice work!