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15 February 2010 14,100 views 18 Comments

Boger, Campbell, Zuhl, Liu. JACS, 2010, ASAP. DOI: 10.1021/ja908819q. Article PDF Supporting Information Group Website

A busy week in the Boger group; it’s been a while since I blogged papers 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 the absolute stereochemistry; only one synthesis has been completed so far, and they didn’t check all the boxes in the submission form…

Synthetically, the first thing of note (for me at least!) is their synthesis of a 1,3,4-oxadiazole – not a hetrocycle I’m planning to crow-bar into my syntheses.  Their method was surprisingly neat, using exactly the same type of substrate for the more common furan and pyrrole analogues – a 1,4 dicarbonyl.  The difference here is that the spacer groups between the carbonyls aren’t the usual methylenes but a hydrazine group.  This doesn’t seem to affect the reactivity – dehydration with tosyl chloride and base does the job nicely.

So why were they making such an exotic beast?  Well, if you’ve read the earlier posts (don’t tell me you haven’t?!!), it’s all about this [4+2] / [3+2] business Boger’s got going on.  Y’see, heating the 1,3,4-oxadiazole up causes a [4+2] onto the alkene. At this stage, the fragile looking dinitrogen bridge decides to exit stage left, leaving a 1,3-dipole, neatly stabilised by the surrounding functionality.  This then reacts with the proximal indole, completing three rings and setting five stereocenters.  Not bad, then.

However, this technology actually overshoots the goal.  To get to the target, we need to swap out a ring, and completely remove a stereocenter.  A few steps after the cascade, the group have successfully traded the methyl ester for a nitrile.  Treating this with hydrofluoric acid strips of the TBS group, and provides a sufficiently acidic environment to close onto the N,O-acetal and generate the THF necessary.  They still had to bin that cyanohydrin, though, which took a bit more work.

First to go was the nitrile, removed using selectride.  The hydroxyl took a bit more effort, with the group going old-school and forming a xanthate ester.  This seemed to be pretty convenient, as it gave then a lovely crystal structure.  Good times, as they were able to separate the enantiomers with a bit of chiral preparative HPLC, and use the resulting X-ray structures to assign the absolute configuration of the natural product.  Not quite as elegant as an asymmetric synthesis, but still nice.

All that remained as this point were a pair of reductions to do a Barton-McCombie deoxygenation and cleave the benzyl group.  Unfortunately these had to be done sequentially, but it did give them the target – so all’s well!

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  • metallabenzene says:

    Should one really be allowed to put (+) in the title if it takes an HPLC resolution to get to an enantioenriched product?

  • HK says:

    Would it make a difference if they used a classical resolution instead?

  • krest17 says:

    Efficient! TS – Missing nitrogen in Scheme 2.

  • krest17 says:

    Could it be possible to find right chiral cat. for 4+2?

    • milkshake says:

      I would try Evan’s chiral Lewis-acidic copper(II)-Box complexes because they work for glyoxylate-ene reactions and hetero-Diels-Alder reactions as well. The oxadiazole reasonably close so maybe it can do chelate to Cu(II).

      by the way oxadiazole are lovely, if you need one with free NH2 the fastest way to get it is to take a methylester, make hydrazide from it, then treat it with 1 eqiv of BrCN and KHCO3 solid in MeOH at OC – high yields, the unprotected phenol does not interfere.

    • NoName says:

      considering this cascade is three-stage transformations, chiral induction in the first [4+2] would suffice the enantioselectivity of the product.

      I would imagine the lack of the commonality in the reaction conditions between first [4+2] and second retro-[4+2] (aka. nitrogen expulsion) stage bother them to try such endeavor. That probably would make them stop the first stage and execute the next stages.

      some might say that is less elegant.
      I would say “really?” and scratched my head.

  • UBChem says:

    How did Padwa miss this? Oh maybe, he didn’t see the obvious “entropically favored loss of nitrogen to envoke a [3+2] dipolar cycloaddition on indole.” sarcasm.

    • krest17 says:

      When I ride my bicycle I oftentimes ask myself: “How everybody did miss it for so many years, it is so obvious???” :-)

  • Tot. Syn. says:

    Folks, I’m currently at a Med Chem conference; all LLEs and diversity quotients. Normal service will resume shortly!

  • jq says:

    Excellent synthetic effort. The efficiency is eaqual to the synthesis of Aspidophytine by Corey (JACS 1999,6771. Oh,Altom!).

  • optional says:

    Canada busted Russia’s buttocks today! Go Canada

  • ChemistryGuru says:

    This is another nice showing of Boger’s ability to transpose his pericyclic creativity into beautiful chemistry. An initial discussion of the versatility of this synthetic approach can be found here: Boger et al. J. Am. Chem. Soc. 2002, 124, 11292. Boger updated this initial paper in another JACS publication in 2006 (there were many inbetween). On a related tangent, Scott Denmark also put together a fantastic review which includes tandem [4+2]/[3+2] cycloadditions of nitroalkenes (Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137) which is a good read if you enjoy heterocyclic chemistry.

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  • H. Balzack says:

    Can someone explain why this work is in JACS when Patwa’s work is only in Org. Lett. 2006, 8, 3275? They both have similar disconnections and are both racemic.

  • chaitanya says:

    Why always the attack of indole 3rd position on carbonyl centre is from upper side? Even in aspidophytin by Corey also the same thing.Is it something that can be understood by model studies?