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Phorboxazole B   

17 December 2006 5,823 views 6 Comments


Burke, Lucas and Gopalsamuthiram. ACIEE, 2006, EarlyView. DOI: 10.1002/anie.200603656.

We covered the reasons for making Phorboxazoles fairly recently in James White’s synthesis of the Phorboxazole A last month. I also pointed out that these natural products have been fairly popular, with a further two syntheses of this beast, by Evans and Zhou. At first glance of this paper, I wasn’t particularly impressed, as much of the work has been seen in other syntheses, and seemed pretty standard chemistry. However, looking beyond the retro and into the fragment synthesis, a fine body of methodology development can be seen. Anyway, on with that relatively mundane retro:


To me, whilst those disconnections are perfectly valid, there’s not a lot to learn here. So on with the synthesis, starting with the C33–C39 lactone. The made this in a very impressive chelation-controlled hetero-Diels–Alder reaction of the mannitol-derived aldehyde with Brassard diene, using a Europium complex. This work was originally developed by Danishefsky, in this JACS paper.


The synthesis of much of the rest of the molecule is covered in a pair of Org. Lett.‘s and a JOC article:

Burke and Lucas; DOI: 10.1021/ol0354775
Burke, Lucas and Luther; DOI: 10.1021/ol0488800
Burke, Lucas and Luther; DOI: 10.1021/jo050034v

Their approach to the complex complex bis-tetrahydropyran unit was to use a two-directional synthesis followed by palladium-mediated desymmeterisation. The symmetrical tetraol substrate for this was acheived very quickly, using an ozonolysis of cyclohept-5-ene-syn-1,3-diol, and indium mediated allylation. Metathesis then bolted-on the allylic acetates, completing the cyclisation substrate.

The ground-work for this type of cyclisation was developed by palladium-daddy, Trost, along with F. Dean Toste in their seminal JACS. Their model suggests that usage of a [(R,R)-DPPBA] reagent-controlled double cyclisation would desymmeterise the substrate, producing the desired chiral product. Their paper discussed the “chiral pocket” of the catalyst as being critical in the transition state:


Optimisation of the conditions then allowed the group to deliver a 75% yield of the product in 98% e.e., along with 12% of the meso product (further rational of this step is given in the second Org. Lett.; I’m not transcribing the whole paper, but it is a must-read!).


Although the two ends of the molecule are now different, it still takes careful elaboration to functionalise one end without disturbing the other. However, the group managed this using a SAD, using the conformation of the six-member rings to control this. Only the less hindered, equatorial vinyl group reacts in their hands, stopping the incomplete reaction after three hours and recycling the unreacted SM.

So, in other words, an impressive synthesis, leaving you folks with plenty to read!

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  • provocateur says:

    the only thing i notice in this synthesis is their obsession with the use of symmetry…interesting

  • TWYI says:

    A hDA reaction without the use of any Jacobsen catalyst. Hurrah!

  • PotStirrer says:

    I love reading your blog, but was disappointed you missed Trauner’s synthesis of heptemerone B and guanacastepene E (JACS, ASAP, 12-6-2006). It came out during a flurry of total synthesis publications so I hoped you might eventually get to it, but it looks like you won’t. It presents an interesting and concise approach that compares quite favorably to both Sorensen’s and Overman’s recent guanacastepene syntheses.

  • Tot. Syn. says:

    As I’ve said in other comments, I try to get a post on as many of the interesting total syntheses as possible, but I’m incredibly busy just now. I’m actually moving labs to Oxford just now, and packing/transporting/unpacking a full laboratory including chemicals and heavy equipment takes some doing. I’ll probably re-read December’s publications when we’re settled in January, and then post some more.
    A cursory glance at the synthesis shows that it’ll be posted on this blog fairly soon :)

  • fuzi0 says:

    I’m very impressed with your marvelous blog.
    Your summaries of the articles of total syntheses are easy to understand the ideas of the articles and the key reactions.

    I’m tring to introduce articles of organic chemistry im my blog by Japanese. I would like to imitate your blog.

    May your chemistry will be very successful.

  • cjdquest says:

    Total Syn, usually you’re pretty good with the citations, but the first synthesis in this class wasn’t Evans or Zhou. It was Craig Forsyth: JACS 1998, 120, 5597. – about 9 years ago!