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25 July 2006 12,517 views 17 Comments

Boger, Ishikawa, Elliott, Velcicky and Choi. JACS, 2006,
ASAP. DOI: 10.1021/ja061256t.
More outstanding cyclisation action, this time from the Boger labs at Scripps. Working towards a whole class of bisindole alkaloid structures, including Vinblastine and vincristine (known for their potent anti-tumour action), they have completed
the total synthesis of vindoline (not a window cleaner). This structure, also found in nature, is a synthetic and biosynthetic precursor to the former targets. Along with an accompanying methodology paper, this work describes their forays into the synthesis of this interesting motif.


The work hinges upon an immense [4+2] / N2 elimination / [3+2] sequence that creates three rings and sets six stereocentres in one pot. In the first case, they completed the synthesis of the related structure, minovine. The cyclisation
sequence went particularly well (in 74%); they then had to remove an extraneous carbonyl group, which they completed using Lawesson’s reagent to convert to the thiolactam, and then reduction with Raney nickel. For those who can’t remember (or can’t be bother looking), here’s that reagent:
They then opened the ether bridge and used Burgess’ reagent to provide a good leaving group for the liberated alcohol, which allowed then to eliminate, but unfortunately as a mixture of natural product and the undesired alkene isomer. Again, here’s that funky named reagent.

They were then able to showcase this methodology and strategy further, with short syntheses of vindorosine, 4-desacetoxyvindorosine, N-methylaspidospermidine, and finally, vindoline, which itself was completed in a remarkable eleven steps! Using relatively familiar methodology to get to the cyclisation precursor, they produced both cis- and trans- material, and cyclised. Both gave the expected products, with the trans- cyclising faster, and the enantiomers separated
using HPLC. Then, reducing-off the carbonyl as before, along with ether-bridge opening retuned the target.

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  • tsri says:


  • Tot. Syn. says:

    Ah. Not as in sKagg…

  • ddd says:

    diels alder….gah…50 yo reaction what can I say. And oh…200C seems like very “attractive and mild/friendly conditions”

  • Tot. Syn. says:

    Yep, >50 years old, and it still impresses me! Okay, they had to do a separation of enantiomers, but that is one sweet cyclisation. And it was only 180C. Far nicer than 200C…, positively luke-warm…

  • Vince says:

    But, if I may play the devil’s advocate, Padwa has done quite a few of these alkaloids based on a similar (not exactly same, I realize) strategy. Granted, the N2 leaving group inside the furan is clever…

  • Tot. Syn. says:

    Very true; indeed, this isn’t a very fresh natural product – it’s been made a few time:
    Büchi, 1975
    Kutney, 1978
    Ban, 1978
    Danieli, 1984
    Langlois, 1985
    Rapoport, 1987
    Kuehne, 1987

    And that list is only accurate to 2000 (stolen from Nicolaou’s uber review: http://dx.doi.org/10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L )

  • Hap says:

    This seems like a neat synthesis, but hasn’t Boger made this before by a similar route?

    Padwa’s research seems similar (similar reactive intermediates), but doesn’t he like to use rhodium-mediated diazo compound decomposition to generate his? The discussion under Gin’s synthesis indicates that Padwa has used and developed other methods to make the dipolar reactive intermediates. This method (using oxadiazoles and a [4+2] to generate the dipole seems nicer in that the source of the dipolar int. is bench-stable and readily accessible; it seems even neater in that Boger can generate a whole bunch of stereochemistry from an achiral starting material, although that then forces a separation of enantiomers later on.

  • ddd says:

    yep..and rhodium is more friendly and does not require 180…Carbonyl ylides. Actually Schreiber used exact Padwa’s strategy in a recent org lett paper something like “folding strategy in combinatorial…blah blah blah alkaloids”

  • TPG says:

    I guess it depends on your perspective and the types of molecules you’re used to working with, but I would consider a reaction that calls for heat and no reagents to be milder and cleaner then one that calls for no or less heat and a reagent or catalyst. I think Boger published a JACS communication not too long ago on Vindoline. I think this is the followup full paper.

  • TPG says:

    My mistake, it was an Org Lett paper, 2005, 7, 4539.

  • ddd says:

    To TPG: do you classify 1 mol% catalyst in the reaction mix as a “reagent”????? While yor temperature goes down from 180 to ambient…

  • TPG says:

    No, that’s why I said reagent or catalyst. I was speaking more in general terms, though I’ve worked with many substrates with a variety of sensitive functionalities that would tolerate 180 for up to 48 h with little protest. If you have other functionalities present that could be affected by a certain catalyst, thermal conditions may be preferable. The lower the catalyst loading, the less chance of undesirable side reactions, I agree, however.

  • Hap says:

    The diazo compounds don’t need 180C, but even if they did they probably wouldn’t be able to stand it. The thermal conditions aren’t great, but the compound should be bench-stable (and unreactive under most conditions); it also doesn’t have a whole lot of complexity, and any complexity present can be assembled piecewise. The rhodium catalyst for diazo compound cycloaddition runs about $160/g (Aldrich, ’03 – probably about $20 for a 5 mmol-scale reaction), and the diazo compound is going to have to be generated from something else more stable. Unless the reaction is messy and has lots of byproducts, thermal (that doesn’t require FVP or any of its ilk) reaction of a stable precursor seems preferable to the generation of a diazo compound followed by RT reaction – but YMMV.

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