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16 October 2008 13,390 views 44 Comments

Nicolaou, Dalby, and Majumder. JACS, 2008, ASAP. DOI: 10.1021/ja806176w. Article PDF Supporting Information Group Website

Not just a natural product in it’s own right, aspidophytine is a building block on the way towards haplophytine, quite a beast of a natural product.  You can read more about it in a Corey paper from two years back.  Aspidophytine is one half of the larger target, with Nicolaou’s approach towards the other half published last year, so it can’t be long until we see the finished product.  But let’s look at this fairly short paper first.

It’s basically a tale of getting the cyclisations to go in the right order, so Nicolaou separated the molecule into an indole system, and a fragment based around a piperidinone.  These two units were united by a Suzuki coupling, with asymmetry in the piperidinone generated through a distereoselective alkylation.  This very quickly took them to a precursor for the first cyclisation (nine steps), a Vilsmeier−Haack reaction (using triflic anhydride in-place of the more common POCl3).

A nice, diastereoselective reduction then gave them the desired cis ring junction.  Only a couple of steps were required to get to the next reaction, a radical cyclisation using a xanthate to control the source of radical generation.  The reaction went in a cracking yield, but gave a 3:1 mixture of allyl-radical reduction regioisomers, of which the desired was isolated in a pretty impressive 58% yield, generating two new stereocenters.  I wonder if they could convert the unwanted isomer (in which the cyclohexene olfin is in the allylic position relative to the indole N) to the desired?  Unfortunately, they had to use prep-TLC to seperate the isomers…

They only had a couple of steps left, but they mangage to do everything in one pot, in a rather tasty set of conditions.  Unbuffered TBAF removed the TMSE protecting group, leaving the carboxylate anion to do a oxidative lactonization using potassium ferricyanide.  This process isn’t dissimilar to that used by Corey in his synthesis of aspidophytine, back in ’99, where he suggests that the oxidation goes via an iminium ion, which is attacked by the carboxylate group (bear in mind that unbuffered TBAF is pretty-damned basic).  Also notable from the Corey paper is the use of a common SM in the form of the indole…

Nice work – well done Steve and co. – I look forward to the haplophytine paper!

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  • gilgerto says:

    Double bond is missing in the indole before radical cyclisation.

  • antiaromatic says:

    Overall, I would say this is my favorite Nicolaou work within recent memory. It’s got some great transformations and puts the molecule together rather expediently.

  • OZ says:

    I like the potassium ferrocyanide cyclization. Can anyone explain for me what the basicity of TBAF has to do with it?

  • tma says:

    TBAF removes the TMSE via a fragmentation reaction to generate the carboxylate-NBu4 salt, [effectively the carboxylate anion required for nucleophilic attack on the iminium ion] – the basicity is relevant as it maintains the carboxylate anion as a negative charge vs TBAF deprotections in buffered AcOH:THF mixtures which would generate carboxylic acid.

    Tot syn: NaBH2 sounds exotic !

  • TWYI says:

    I routinely buffer all my TBAF reactions, tears my compounds to pieces otherwise.

    How common/easy are Vilsmeier’s on N-Me Indole substrates?

  • gilgerto says:

    I would say it is rather easy. Tf2O activated amides are really electrophilic and the reaction occurs at the 3 position which is the more nucleophilic.

  • The Next Phil Baran says:

    just goes to show nicolaou aint smarter just richer. Two guys to do this work……sheesh.

  • aa says:

    TWYI- N-Me indoles are a little bit more reactive than N-H indoles, and they react essentially identically in Friedel-Crafts reactions in terms of rates/reactivity. Herbert Mayr @ Munchen has studied the nucleophilicity of indoles for his scales, the paper is in JOC 2006, 71, 9088

  • Cat Herder says:


    thanks for the citation! I like KCN’s approach but kind of agree with The Next Phil Baran. Did two people need to work on this? Is that the haplophytine team?

    Also, has the lactate auxiliary strategy been used before for enantioselective alkylation of beta-ketocarbonyl groups?

  • npsynthesis says:

    majumder is a really talented and intelligent chemist! Nice paper Utpal!

  • q says:

    Can you always clip primary TBS groups chemoselectively over TMSE esters?

  • Jose says:

    Whenever KCN finishes haplophytine, I sincerely hope the paper is dedicated to Jason Altom, and not EJ.

  • Bandit says:

    The next Phil Baran…so Corey aint smarter just even richer then to have 3 people do aspidophytine…. Ur alias shows how naive u obviously are.

  • TWYI says:

    I am waiting for Coreys next JOC that claims he knew all about Barton’s conformational work.

  • milkshake says:

    you all spiteful KCN/Corey/Baran/MacMillan/Amos Smith-bashing people: why don’t you try to talk down your own bosses instead? Maybe the reason for your bitter misery sits right there, in your PI’s office.

  • Cat Herder says:

    word. well said milkshake.

    Glad to see that traditional indole alkaloid synthesis is alive and well.

  • VP says:

    it’s all true, especially the lies

  • The Next Phil Baran says:

    I would never bash Phil Baran (he is my idol) and really good. Corey is light years ahead of KCN (also a poison). I only bash KCN (maybe also long drawn out 7000 steps Amos) not any of the others. These guys are good but KCN stopped being a treat to read about a decade ago. Amos is the same breed as KCN, no better. The problem here milkshake is the misplaced hero worship that is prevalent in organic chemistry. Some people deserve it, some don’t. KCN and Amos don’t. If these guys are great then a lot of other people are AWESOME! On another note: so milkshake which of the 5 you mentioned above are your supervisor/ friend of you supervisor?

  • Jame Boydell says:

    Here’s a wild idea. if you are going to criticise someone’s work, career history and character then do it under you own name, and be proud of it.

    Don’t cower behind a pseudonym like a pathetic coward.

  • HPCC says:

    Many posts turned into KCN- or big-name-bashing. This one turned into KCN-basher-bashing. LOL :D

  • The Next Phil Baran says:

    so its ok to praise someone using a pseudonym but not to bash them? Plus The Next Phil Baran is my christian name. got a problem? Doesn’t fit your stereotypes?

  • krest17 says:

    The Next Phil Baran – who the heck are you? What do you really know about Phil, KC and Amos? Finally to judge this people you should be at least their level – I seriously doubt you are. They are very different but there is logic behind their work and approaches to Chemistry and if you are not able to understand it is not the reason to bash them. All in all, I should say not only PI, but students who did the job – they are real heroes. And the students of Phil are great chemists and hard workers – I know this not just by papers but personally – that’s important key for his success. Lastly, KC and Amos are incredible persons and they got their fame not just occasionally – it was a hard work behind.
    Milkshake – respect.

  • vik says:

    The next Phil Baran : Do you know that the original Phil baran was a KCN student..i.e a product of KCN lab. Being an academic chemist is more than just making molecules its about training new chemists. I beleive that KCN has clearly shown that he is not only a good chemist but also a great mentor (…Sorensen, Baran, Chen, Snyder etc). Also, you may criticize the chemistry not the chemist. Not all syntheses can be a treat to read. Some just have to be done (largely to train students). Some can have one or more elements of novelty. As far as KCN is concerned if all his syntheses are novel then that would be a lot of new chemistry..wont it !

  • pdf says:

    There we go… KCN again. What about creating an entry entitled “Synthetic Evils” just to discuss these issues? And Corey? He said it was his idea Woodward-Hoffman rules and one of his students even committed suicide because of him, among other issues as already pointed somewhere. Even as a nobel prize winner he seems to need attention all the time.

  • Liquidcarbon says:

    Oh, whatever. Might as well talk about Joe the plumber.

  • ZZZZZ says:


    …lol, great conversation in this thread, and even better grammar…


  • Jose says:

    From newest KCN, Vannusol. DOI: 10.1002/anie.200804228

    Faced with the unpleasant stereochemical
    outcome of this reaction, which otherwise performed admirably, we decided to eradicate the two newly generated stereocenters (at C-10 and C-28) through dehydration, and reconstruct them in their proper configurations by exploiting the reactivity preferences of the resulting diene system.

    Scotch tape and whiteout! Sweet!

  • The Next Phil Baran says:

    so vik you can name four of about 500 students that came out of KCN’s lab that are ostensibly rational, logical and good. those are really good percentages! this sounds more like random good people being attracted to a big name than a good teacher. I don’t think teaching is even a concern of KCN’s. His books are more about self-gratification than teaching or giving insights. What are his insights? That a ton of money and slave driving can make a big molecule? I think everyone knows this. With as many “top” students that he has attracted you’d think there would be a new paradigm in chemistry. He is a waste of time and money and that is just the way it is. He came out of Corey’s lab with some good ideas but hasn’t regained that caliber. Phil Baran on the other hand at least put a constraint on his research: he doesn’t sacrifice time and money and the readers boredom by protecting everything then deprotecting. What change has KCN made in the last 10 years? And vik if he wanted to train students he would be better off making smaller molecules and doing methodology. I mean did he really improve on Corey’s synthesis of the same molecule, shorten the steps, use cleaner technology, propose an amazing new retrosynthesis? No.

  • The Next Phil Baran says:

    Jose, dido on your comment.

  • TWYI says:

    I count over 50 pictures of himself in ‘Molecules that changed the world’

  • Homeland security says:

    Take a look at page 165 of the book TWYI cited (amphotericin B synthesis). There is a picture of KCN when young at University of Pennsylvania. He looks like a terrorist making a chemical weapon. And there are indeed several more pictures of him.

  • oracle says:

    KCN will get a new postdoc starting in the middle of next year and his collaboration with KCN will yield KCN a noble prize !! Personally, I think, KCN has both the brain and the ability to kill any beast (read organic molecule). As far as the style is concerned he is on the mark most of the times. And as far as his photo ops are concerned..well thats his style and its not bad to bring a bit of showmanship when you are doing great work..eeh. GO KC !

  • vik says:

    After reading about Palau’ amine and massadine dont you guys think that KC must be right making the molecules sometimes by using “boredom reactions”. I wonder how many days will KCN group take to tackle Palau’ amine or massadine. I am not sure if his group/s are working on it. Next Phil Baran : I understand and appreciate your view (though I dont agree on it I beleive its healthy to have two view points on any subject). If I you were my collegue it would have been great to debate on this over a beer..!!

  • Jose says:

    “KCN will get a new postdoc starting in the middle of next year and his collaboration with KCN will yield KCN a noble (sic) prize !! ”

    And then we can build a rocketship to land monkeys Mars! Yiippeeee!!

  • haihua says:

    on Vilsmeier−Haack reaction
    I do not understand why the Tf2O/POCl3 do not attack the 3-position of the indole ring, intead activating the amide bond.
    can anybody explain?

  • HPCC says:

    Phosphorus reagents and triflating agents are both highly oxophilic, and amides have a highly nucleophilic oxygen due to N lone pair donation into the carbonyl carbon.

  • haihua says:

    I appreciate it!
    so good to be here

  • The Next Phil Baran says:

    vik our positions are diametrically opposed! you can’t own both sides of the argument. Read some Aristotle……………

  • FC Barcelona says:

    practically it’s better than Corey’s synthesis, but some of the steps are just the same as corey’s.

  • thezorro says:

    Yikes, adineken Laporta had a cousin engaged to orgchem.

  • Liquidcarbon says:

    Howdy Paul, before you’ll be blogging Haplophytine, take a look:
    http://liquidcarbon.livejournal.com/29611.html ;)

  • […] strategy was simple – split the molecule in two about the obvious single bond.  This presents aspidophytine, and another bit (that’s the technical term – honest…).  As aspidophytine has been […]