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15 October 2007 16,565 views 36 Comments


Fukuyama, Miyazaki, Yokoshima, Simizu, Osada and Tokuyama. Org. Lett., 2007, ASAP. DOI: 10.1021/ol702040y. Article PDF Supporting Information Group Website

Phew! That was quite a read. I hope you’re all impressed with the target of this total synthesis already – that’s one complex beastie! And it’s not all looks – there’s some potent microtuble inhibition going on too. This isn’t the first synthesis – there’s been a few of the natural product and of analogues, notably that of Phil Magnus back in ’92. In this paper they document the synthesis of the top indole-containing fragment and the coupling with Vindoline, allowing completion of the synthesis. However, they state that they were supplied with Vindoline, so there’s no synthesis of that here. However, those of you with good memories will remember we covered Boger’s synthesis of that nugget last year.

The synthetic action here laudibly kicks-off right at the start, and I was quite taken by the oxidative lactonization to produce the 5,5-fused gamma-lactone in great yield. I realise this isn’t news – but it is nice :)

InChI=1/C7H10O2/c8-7(9)5-6-3-1-2-4-6/h1,3,6H,2,4-5H2,(H,8,9)/t6-/m1/s1, InChI=1/C8H12O3/c1-8-5(2-3-6(8)9)4-7(10)11-8/h5-6,9H,2-4H2,1H3/t5-,6+,8+/m1/s1

Elaboration of this system (including a rather nice ring-expansion sequence) eventually led to a precursor to the indole. This was built in an interesting way – deprotonation of the lactone and addition into the isothiocyanate gave a thioanilide. They then did a radical-mediated cyclisation onto the styrene to complete the indole. A nice method, which reminds me much of Barton’s work in this area of heterocycle synthesis.

InChI=1/C31H62O4Si3/c1-13-36(14-2,15-3)34-25-31(35-37(16-4,17-5)18-6,23-29-19-20-30(32)33-24-29)21-22-38(26(7)8,27(9)10)28(11)12/h26-29H,13-20,23-25H2,1-12H3/t29-,31+/m1/s1 InChI=1/C17H15NO2S/c1-19-15-8-10-16(11-9-15)20-12-4-6-14-5-2-3-7-17(14)18-13-21/h2-11H,12H2,1H3/b6-4- InChI=1/C48H77NO6SSi3/c1-14-57(15-2,16-3)54-36-48(55-58(17-4,18-5)19-6,30-32-59(37(7)8,38(9)10)39(11)12)34-40-33-44(47(50)53-35-40)46(56)49-45-25-21-20-23-41(45)24-22-31-52-43-28-26-42(51-13)27-29-43/h20-29,37-40,44H,14-19,31,33-36H2,1-13H3,(H,49,56)/b24-22-/t40-,44?,48+/m1/s1 InChI=1/C48H77NO6Si3/c1-14-56(15-2,16-3)54-35-48(55-57(17-4,18-5)19-6,29-31-58(36(7)8,37(9)10)38(11)12)33-39-32-44(47(50)53-34-39)46-43(42-22-20-21-23-45(42)49-46)28-30-52-41-26-24-40(51-13)25-27-41/h20-27,36-39,44,49H,14-19,28,30,32-35H2,1-13H3/t39-,44?,48+/m1/s1

Opening of the lactone neatly gave them the ester and pendant alchol required, but the macrocycle formation gave them a real headache. Protection group manipulations and trouble with function group interconversions meant that it took eighteen steps to get to the next intermediate shown! Very little of the trouble they had could have been forseen – a planned amine opening of a terminal epoxide to give the desired macrocycle failed to work reliably or in good yield – a real mid-synthesis nightmare. However, they persevered with admirable tenacity, and managed to get that top fragment complete. They chlorinated the indole with t-BuOCl to give a very reactive intermediate which coupled with Vindoline in a reaction thought to go through an iminium ion.

InChI=1/C25H32N2O6/c1-6-23-10-7-12-27-13-11-24(19(23)27)17-9-8-16(31-4)14-18(17)26(3)20(24)25(30,22(29)32-5)21(23)33-15(2)28/h7-10,14,19-21,30H,6,11-13H2,1-5H3/t19-,20+,21+,23+,24+,25-/m0/s1 InChI=1/C63H76N4O14S2Si/c1-13-59(81-84(10,11)12)36-43(38-79-83(74,75)45-26-22-41(4)23-27-45)37-62(57(69)77-8,53-47(46-18-15-16-19-50(46)64-53)28-32-67(39-59)82(72,73)44-24-20-40(3)21-25-44)49-34-48-51(35-52(49)76-7)65(6)55-61(48)30-33-66-31-17-29-60(14-2,54(61)66)56(80-42(5)68)63(55,71)58(70)78-9/h1,15-27,29,34-35,43,54-56,64,71H,14,28,30-33,36-39H2,2-12H3/t43-,54-,55+,56+,59-,60+,61+,62-,63-/m0/s1

Perhaps the disconnection is a natural one, but that’s not the chemistry I would have planned – nice strategy! Completion of the natural product required only cyclisation of the tosylate onto a free amine to complete the skeleton of the top fragment, and deprotections, which all went smoothly.

This is an amazing accomplishment, especially given the trouble they evidently had – I take my virtual hat (I don’t wear hats) to the workers on this paper!


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  • AS says:

    Elegant synthesis!
    The structure of oxidation product is not correct (proton is missing!)…

  • HB says:

    This essentially the same synthesis as was published in 2002.

    i.e. 10.1021/ja0177049

  • PotStirrer says:

    So, how do you guys think that radical cyclization is working? If you look at Fukuyama’s original methodology paper, he draws a few potential intermediates, but doesn’t really speculate on a mechanism in the text. Initially, you should generate a sulfur-tin bond and create a tertiary radical next to the nitrogen atom. It would make sense for this to then undergo cyclization with the alkene. The resulting secondary radical could then propagate the chain, but you are left with that sulfur still attached to the molecule. Somehow you then have to eliminate HSSnBu3. In the original paper he also shows the possibility of losing HSSnBu3 across the C-N bond before radical cyclization, giving what you might call an imine radical that can then undergo cyclization. In either case, what promotes the elimination of HSSnBu3?

  • Spiro says:

    35 steps to make tryptamine derivative 30. I say MADNESS!!!!!!!

    To #3 : the elimination of HSSnBu3 is promoted by a thermodynamic pit : the formation of an indole ring.

  • PotStirrer says:


    I agree that the reaction is thermodynamically favorable, but that doesn’t explain why it occurs under these conditions. Perhaps instead of asking what “promotes” the elimination, I should have asked “what is making the elimination kinetically feasible?” Or more concisely, what do you think the mechanism is?

  • PotStirrer says:

    OK, how about after indoline formation, the nitrogen lone pair kicks out SSnBu3 anion, making an imminium. The sulfur anion then plucks off the appropriate hydrogen generating the indole product.

  • Niko says:

    Vinblastine is more than a potent target with potent biological activities. It’s actually used for years in chemotherapy, usually in a cocktail of anti-cancerous drugs. Quite interesting molecules then.

  • willyoubemine says:

    with regards to the coupling of vindoline to the top half…that is the way that virtually every previous synthesis of vinblastine dating back to the 1980′s used to complete the molecule…Below is a link to a “perspective” on the Fukuyama work:

    It points out, with refs, that many groups have worked on the coupling of Vindoline to the top half (Catharanthine-type) and established good methods to do that with good stereocontrol, long ago.

    Still, a ton of work and a kudos to those performing it, well done.

  • Elwoodcity says:

    I don’t have access to the paper. Does the final step happen with acid? I’m picturing an isomerization to an enone, followed by attack of the nucleophile to do an SN2′ displacing the chloride.

  • GB says:

    In response to HB, while this is clearly quite similar to the previous work I don’t think it should viewed in the same vein as traditional total synthesis. Instead this work’s goal is to generate the C4′ alkyne and use that as a handle to access novel analogues. Unfortnately it seems that modifcation at this site is not well tolerated, as shown by the quite significant loss of activity that the aryl analogues show. As was pointed out, this in a important chemotheraputic agent and medicinal chemistry efforts towards this challegening target is pretty interesting science.

  • pi* says:

    I’m pretty good with radical mechanism’s, and although I don’t have a pen and paper in front of me, I would say that I dont have a clue and this mech isn’t so obvious

  • radical mech star says:

    A possible mechanism for the radical cyclization to produce the indole can be found in Classics in Total Synthesis II on page 512. In fact, this chapter provides a nice background to more fully appreciate the Fukuyama work in context, as well as some of the numerous studies that preceded it.

  • PotStirrer says:

    Actually, page 512 of Classics II goes into no further detail than the original Fukuyama paper. In fact, it is just a simple redrawing of Fukuyama’s scheme. Again, my original consideration was how does HSSnBu3 get eliminated and neither Fukuyama or Nicolaou care to comment on that. I think what I came up with in Comment 6 is pretty reasonable though. :)

  • ZZZZZ says:


    Snyder’s book is amazing. He reinvented the way books are written, etc.


  • rosko says:

    A synthesis of such a complex molecule is very impressive. However, I wonder how much of an impact such syntheses will have on the manufacture of the compound for clinical use. It seems unlikely that even a top-notch, concise (relative to the target complexity) synthesis will be able to out-compete the current source (which I assume is a semi-synthesis from a Vinca alkaloid biosynthetic precursor, or maybe even direct extraction). Maybe I’m wrong.

  • arnold says:

    Yep ZZZZZ. He even reinvented the way ChemDraw must be used…(among other hundreds of accomplishments…)

  • willyoubemine says:


    I believe the current source is taking the naturally available vindoline and catharanthine portions and coupling them via the ways in the literature since the 80′s. Has anyone compared Fukuyama’s synthesis of Vindoline and/or the top half, to those of Boger, Magnus, Potier, etc? Doesnt seem, if memory serves that this is as concise or direct.

  • chemaxtry says:

    I appologize; I have a question completely off of the subject:

    Can someone help me find a procedure for making reverse phase silica so i can run flash columns with it. I’m trying to mimic a particular analytical column i’ve had luck with, found here:


    Although a procedure for making any other form of reverse phase columns would also be very useful.

    Thanks, sorry for interupting the conversaation.

  • This is also off subject but a plea to synthetic chemists for assistance to synthesize a molecule to help end a 10 year study:


  • TWYI says:

    tert-butyl hypochlorite has saved me many times when reluctant p-aminophenol—->quinone imine type 2 electron oxidations wouldn’t work, no matter what oxidant I used.

    One of my favourite reagents.

  • rb says:

    I have to disagree with the previous posters. Sorensen is the one that set the bar in writing about total synthesis, not snyder. classics I is much better than classics II. The writing style is cumbersome in II and most of the syntheses are by the KCN group. talk about mental masturbation. Sorensen is a much better writer and the scope/breadth of classics I is incredible. I took a synthesis class from Sorensen/KCN using that book which was the best class I have ever taken.

  • jimbo says:

    I have to disagree w/ rb. Classics II is better by far, and many of the KCN syntheses (and really, who is better equipped to discuss them?) are compared directly to routes by other groups.

    Both Snyder and Sorensen (and KC, and many other academic faculty) use overly flowery language… I can’t read any papers by the above mentioned groups without getting a pre-vomit flavoring in my mouth. That said, the content is usually stellar.

  • GYA says:

    clearly jimbo you have issues. i’m with rb, as i’m sure are most others. not sure why you’re delusional.

  • TWYI says:

    Authors of textbook in bigging up their own work shocker.

    What did you expect? If you don’t like it, don’t buy or read it. Simple. :roll:

  • ZZZZZ says:


    Once again not everyone picked up on my sarcasm…OK, back to sleep…


  • jimbo says:

    GYA: clearly. I disagree with you so I must be delusional.

  • Stella Kro says:

    No applying interest for this natural product. Vinka alkaloïds, Vinblastin, are used for many years in anticancer therapy. It is extracted from Madagascar flowers and an hemisynthesis of the drug is prapared cheaply from this material. Total synthesis of this molecule has no interest for the science today. More potent fluorous analogues are already in developpment. It’s the same thing with Taxotere prepared from advance natural product, by hemisynthesis.

  • oxone says:

    The reaction shown here (right after the smily) is incorrect.
    Instead of H, You attached methyl on the center bottom. Check it.

  • [...] on ChemSpider and that’s nice to see but we started there so that’s irrelevant really. I also see a link to a TotallySynthetic.com blog posting. Excellent. Clicking on the link I open the page and there it is. Vinblastine. Nice. Oh, and a list [...]

  • nassima says:

    can you send to me the specter RMN of alkaloids minovine and vincadifformine with here etalements
    if you want because i need him in near time

    Please help me in this research

    Thank you

  • Tot. Syn. says:

    Why would I have it?!! Why don’t you look in the supporting information for a synthesis of Minovine… like here:

  • Dude says:

    Nassima – you are a fricking twit.

  • kookimebux says:

    Hello. And Bye. :)

  • [...] back-to-back from one group!  This target has clearly developed from their work in vindoline and vinblastine, using similar synthetic techniques.  Their interest in this target in particular was to assign [...]

  • [...] back-to-back from one group!  This target has clearly developed from their work in vindoline and vinblastine, using similar synthetic techniques.  Their interest in this target in particular was to assign [...]

  • [...] TotallySynthetic.com » Blog Archive » VinblastineI’m pretty good with radical mechanism’s, and although I don’t have a pen and paper in front of me, I would say that I dont have a clue and this mech isn’t so obvious… [...]