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Vigulariol   

6 December 2006 4,580 views 8 Comments

vigulariol.jpg

Clark, Hayes, Wilson, and Gobbi. ACIEE, 2006 , EarlyView. DOI: 10.1002/anie.200602780.

Another medium-ring ether synthesis, but using completely different methodology to last months excellent synthesis by Kim. But Steve Clark (now at “WestChem“, having moved from Nottingham) should know these species pretty well, having worked with Andy Holmes… Anyway, this is a great read, so on with the synthesis (no retro; you’ll see why…).

vigulariol_1.jpg

To build up some functionality for their crucial rearrangement, they used a great Sm mediated reductive cyclisation, starting with the acyclic precursor. This work was apparently developed by Nakata a few years back, and gives the resulting pyran in great yield and diastereoselectivity. However, I can’t help thinking that the enantiomerically pure SM would generate the corresponding high e.e. product… and the authors state that Williams has made that SM…
vigulariol_2.jpg

Anyway, with the product quickly transformed to the above diazo-compound in gram quantities, they were set for the exciting [2,3]-sigmatropic rearrangment; look at that yield!!! I’m yet again surprised at the trans- product, but they were able to convert the ~20% or so of that to the desired -cis material in a useful yield, completing that funky nine-member ring. With two rings in the bag, they pushed on and finished the next in only four steps:

vigulariol_3.jpg

They deprotonated the ketone in a regio-selective manner, and trapped with triflate to give them a coupling partner for a Stille coupling. This then gave them a diene to do a Diels-Alder with MVK, resulting in a 2:1 mixture of exo and endo diastereoisomers… which they epimerised with Pot-Carb to give them only the desired exo adduct. 58% over four steps – nice work!!

They then only required a few relatively simple steps to generate the precursor for the final cyclisation and step:

vigulariol_4.jpg

A deceptively simple piece of chemistry, well conceived, to generate a complex product in relative ease; my definition of elegance in total synthesis. And that sums up this concise synthesis effort and great read.

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8 Comments

  • Murmure says:

    Nice piece without supporting info.

  • yepyep says:

    Murmure: Good point. I can’t understand why they accept manuscripts without experimental data. If someone has done the synthesis, why not provide the experimentals as well? I know how annoying writing NMR data (and such) can be but that’s hardly a reason to omit the data.

  • cjdquest says:

    Nice synthesis.

    Sorry to nitpick, but you’re missing the TBS group on the SM of the key [2,3] rrgment step thought.

    Keep up the good work here at totallysynthetic

  • regularchem says:

    I think they must have provided the suppl. Information when they submitted the manuscript. However, after the manuscript is accepted, if they don’t upload the supplementary information again, it may be omitted by the piblisher.

  • Tex says:

    Just below the author information, there is a statement about SI, indicating it exists. I suspect when the paper is published (i.e., is associated with an issue), there will be a link to supporting information.

  • ddd says:

    check out JACS asap Danishefsky synthesis today

  • Tot. Syn. says:

    Umm, and the Ley and Evans papers in ACIEE… gonna be a busy weekend!!!

  • [...] (that is Tot. Syn. at least) met Vigulariol just over a year ago, with a nice racemic synthesis by Steve Clark, covered on these very pixels. However, a recent asymmetric synthesis by Dieter Hoppe was brought [...]