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Guanacastepenes A and E   

15 May 2006 7,206 views 20 Comments


Sorensen and Shipe. JACS, 2006, ASAP, DOI: 10.1021/ja060847g

Furthering their interest in the synthesis of the Guanacastepenes, Sorensen et al have completed the synthesis of members A and D using an interesting fragmentation strategy. However, before this late-stage event, the A and C rings were constructed and united using a Stille cross-coupling. The required cyclobutane was then implaced via a photo-[2+2] cycloaddition:


With this in place, the cyclobutane was fragmented selectively to provide the seven-member ring, trapping with PhSeBr to facilitate elimination in the next step. A very reasonable explanation for this selectivity is explained in detail in the paper.

This left the core of the guanacastepene series, from which a few simple steps returned guanacastepene A. However, a slight flaw in the synthesis concerns the resolution of an advanced fragment, taken from a racemic model study.

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  • Klug says:

    Looking at the TLC solvent system they developed, I think it is quite clear why resolution is not tried more often. That’s a lot of leg work!

  • Jeremiah says:

    Where do you suppose the facial selectivity from the 2+2 reaction came from? Seems to me, it would be geometrically predisposed to the top face — i mean, in the end, SOMETHING is going to be bumping into that isopropyl group, right?

  • marc says:

    These [2+2] photocycloadditions are pretty interesting reactions, in that you can obtain two regioisomers depending on how the olefins line up. In this case, the [3.1.1]bicycloheptane regioisomer is not observed, presumambly because of geometric strain in the requisite transition state. The desired [3.2.0]bicycloheptane is obtained instead.

    Facial selectivity at the alpha-olefin is controlled by the allylic methyl group, which should be in a pseudoaxial position in the the transition state. This effectively blocks the bottom face of the alpha-olefin as drawn.

    Selectivity at the enone is controlled by the isopropyl group. The isopropyl group should exist in a pseudoaxial position, so as to alleviate 1,2-allylic strain in the cyclopentenone. This effectively blocks the top face of the enone as drawn.

  • Tot. Syn. says:

    Not the same system, but it’s worth checking out Marc Snapper’s paper on [2+2]’s in JACS ASAP’s this week.

  • Bill says:

    I happen to know quite a bit about this synthesis. In a model system lacking only the isopropyl group, we observed exclusive diastereofacial selectivity in the [2+2] photocycloaddition. This suggested to me that the selectivity, while perhaps reinforced by the presence of the isopropyl group, was largely dictated by the configuration at the quaternary center. If you build a molecular model of the system, you’ll clearly see that only the desired approach of the olefin to the enone is possible. The angular methyl group has a prohibitive steric interaction with the vinyl methyl group in the undesired approach.

    As for the resolution of mandelic esters…yes, it was a lot of leg work. I recall trying over 20 solvent systems before I found the toluene/DCM/ether system that finally resolved the two diastereomers. If I had had more time, there were plans to attempt to carry out an enantioselective Diels-Alder cycloaddition early in the synthesis of the C-ring fragment (2nd step of the whole synthesis). The few things I tried early on failed.

    I was quite pleased with our solution to the absolute stereochemistry of the A-ring, however. The idea to ring-contract carvone arose from a Kraus paper (Tet Lett 2000 21-24) I encountered when exploring a route unrelated to the Stille/[2+2]/fragmentation one. If I can find the time in my present position, I plan to follow up on the alpha-acyloxynitrile => 1,2-diketone transformation in a methodology paper.

  • scared_anonym says:

    we should start blogging about big moves, I was surprized to see that Hartwig moves from yale to urbana, McMillan from caltech to princeton. Any other big moves? Anyone is moving from harvard to UCLA? ;)

  • Tot. Syn. says:

    It’s UKian, but P Andrew Evans is off to Liverpool, and in Germany, Glorious is going to Dortmund (AFAIK).

  • NoName says:

    thanks for the helpful info., Bill.
    BTW, alpha-acyloxynitrile from alpha-ketoaldehyde might give 1,2,3-triketones?

  • NoName says:

    marc snapper’s paper (good read, interesting stuff) kinda reminds me of this paper from Germany.

    “Catalytic enantioselective reactions driven by photoinduced electron transfer”
    nature 436 (2005), 1139.

    Editor – the DOI is 10.1038/nature03955

  • Klug says:

    Hey, Bill: Nice paper — I’ll bet you’re very proud.

    What made you choose a mandelic ester? I’m not very familiar with resolutions, so maybe this is common?

  • secret milkshake says:

    well, we got Bill Roush to come with his group overe here to Florida but that is pretty old news. Is there any explanation about McMillan? I worked with him briefly when he was a postdoc in Evans group and I liked the guy a lot. Did they annoy him at Caltech?

  • scared_anonym says:

    everyone seems to leave caltech eventually: evans, myers, mcmillan, carreira…may be b/c it is small, inland and has no night life etc…? I do not know, never been there.

  • Bill says:

    Klug, thanks–I’m very happy that the complete story is out there.

    Mandelic esters are commonly chosen for this sort of resolution. There was good literature precedent. I can post a reference or two when I have access to that information. For now, I’m just glad it’s Friday!

  • Tot. Syn. says:

    MacMillan has personal reasons to move to the east. I spoke to him in the uk last year, and i’m not suprised he’s moved. In other news, Steve Clark has left Nottingham. Coupled with Pattenden’s retirement, they’re looking a little short.

  • Klug says:

    That’d be great!

  • sdsd says:

    what was the story in pattenden’s synthesis of phorboxazole in angewandte? he just had ONE person as a coauthor. How long did it take him? Like 5 years to make the molecule?;)

  • Joe says:

    In the move news category, Dave Gin is moving from Urbana to Sloan Kettering.

  • Bill says:


    With regard to the resolution of mandelic esters, I offer the following two references:

    Whitesell, et al. JOC 1983 v48 p3548-3551
    Breitholle, et al. JOC 1974 v39 p1311-1312

    The second actually deals with O-acetyl mandelic esters, which happened to work better for me on my system.

  • Klug says:

    Sweet. Thanks, dude.

  • […] I seemed to miss this one somewhere, probably in the move from my placement back to Cambridge. Anyway, this is a really nice synthesis of the popular guanacastapene targets (see this smart synthesis by Sorensen), using a unusual and funky Heck cyclisation. This reaction forms the main unifying transformation of the separate fragments, along with a 1,4 organocuparate addition. On with the synthesis! […]