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Anguinomycin C   

10 October 2007 8,042 views 21 Comments


Gademann, Bonazzi, Güttinger, Zemp and Kuta. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200703134. Article PDF Supporting Information Group Website

I’ll start by admitting that when I saw this structure in the Angewandte EarlyView list of abstracts I though “great, aldols and wittigs…” and moved on to the next article. I was partially correct, in that there are certainly aldol reactions in this paper, but there’s a whole lot more too. Gademann starts by talking about “selectivity or pRB tumor suppressor inactivated, immortalized cells”, which means little to me, so I’m glad he goes on to explain that this means “apoptosis in such tumor cell lines in picomolar concentrations, and, remarkably, induce only growth arrest in normal cells”. Now that’s a biological activity profile worth considering.

The synthesis is also rather sweet, starting with the left-hand dihydropyranone fragment. This was constructed via a DHP, developed in a Jacobsen Cr-mediated AHDA:

Nice result! But the stereochemistry wasn’t quite right – the acetal center needed inverting. Simple treatment of this with acidic IPA did the job… They then lost the TES group with a bit of TBAF, and hydrozirconated to give them the coupling partner for a little Negishi action with a vinyl dibromide. Interestingly, adding a substoichiometric amount DiBAL-H to the reaction gave the best result… A second Negishi coupling provide the required trisubstituted double bond, and also “isomerized” to the cis- configuration. This interesting result is discussed here and here by Negishi himself, but the exact mechanism at play is still unconfirmed.

InChI=1/C24H43BrO3Si/c1-17(2)27-24-12-10-11-23(28-24)14-13-22(25)15-21(9)16-26-29(18(3)4,19(5)6)20(7)8/h10,12-15,17-21,23-24H,11,16H2,1-9H3/b14-13+,22-15-/t21-,23+,24+/m0/s1 InChI=1/C25H46O3Si/c1-18(2)27-25-13-11-12-24(28-25)15-14-22(9)16-23(10)17-26-29(19(3)4,20(5)6)21(7)8/h11,13-16,18-21,23-25H,12,17H2,1-10H3/b15-14+,22-16-/t23-,24+,25+/m0/s1

Now for the other partner, a bit of Evans aldol chemistry. Rather than Evan’s own oxazolidinone, they used the Seebach DIOZ auxiliary, which they recommend due to it’s propensity for crystalline products and higher selectivities. One alkylation and two aldols later, they had their vinyl iodide and were set for the final coupling – a sweet sp2-sp3 Suzuki, completing the carbon skeleton of the natural product in great yield. A bit of deprotection, and they were there. Nice!

InChI=1/C24H45IO2Si/c1-12-17(2)15-20(5)23(27-28(10,11)24(7,8)9)21(6)22(26)19(4)16-18(3)13-14-25/h12-14,16,19-23,26H,15H2,1-11H3/b14-13+,17-12+,18-16+/t19-,20+,21-,22+,23-/m1/s1 InChI=1/C40H70O4Si/c1-16-29(4)26-34(9)39(44-45(14,15)40(11,12)13)35(10)38(41)33(8)27-31(6)20-17-19-30(5)25-32(7)23-24-36-21-18-22-37(43-36)42-28(2)3/h16-18,20,22-25,27-28,30,33-39,41H,19,21,26H2,1-15H3/b20-17+,24-23+,29-16+,31-27+,32-25-/t30-,33-,34+,35-,36-,37-,38+,39-/m1/s1

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  • psi*psi says:

    Seeing the TES ethynyl bit on there: happiness! Of course, we always just stick TES acetylene on in the last step and then leave it alone.

  • Anon says:

    Diene needs to be fixed…

  • cheyanimal says:

    i don’t think they NEED to invert that stereocenter, since they are going to oxidize it up to the lactone later. Is it to improve the dr?

  • Spiro says:

    you are right, they did not need to invert it, but they must have tried a few alcohols until they found one (isopropanol) that gave the best dr. The aim was to work with a molecule that was not a mixture of two dias for the next 20 steps.

    BTW, the concentration reported for the optical rotation is a joke ;-)

  • TWYI says:

    Just the 200 pages of supporting info then?

  • Paul says:

    @Spiro : exact, I don’t know how they can obtain a significant alpha at this concentration…

  • Tot. Syn. says:

    They tried, and that counts in my book. They only had 1 mg, so I’m sure the whole analysis process was pretty traumatic. And 200 pages of SI also counts for a lot in my book!

  • neo says:

    …and one more synthesis of Platensimycin. This time its by Dr. Corey

  • Andrei says:

    Ok, impressive supplementary, but seems a little bit paranoid for an angewandtw, ins’t it? I thought they always request hexacyclinol-style supp.infos….it seems strange to me….maybe the things change

  • Spiro says:

    To complete #4,5,6,7:

    I am very appreciative of the SI.
    But a concentration of 0.0000642 for an optical rotation, no!!! This means 0.000642 g/L i.e. 0.642 mg/L i.e. 0.000642 mg/mL. OK?

    Still not convinced? Let’s calculate the rotation they would have obtained using a one decimeter-long cell. -101.2 x 1 x 0.0000642 / 100 = -0.0000649
    How many polarimeters are there that give you such precise rotations? Not to mention of how they got the last figure : 1/10.000.000 of a degree…
    The polarimeter I use goes to 1/1000 of a degree and the precision we obtain is lower than 1/100 of a degree at best.

  • Cool Man says:

    Mans, I guess it’s just a typo…

  • Elwoodcity says:

    For the Dihydropyran, it looks like a hetero Diels-alder, but there is no diene. Is that the diene that Anon (#2) was talking about? (My institution doesn’t subscribe to anything but J.Chem.Ed. so I can’t check it myself)

  • Tot. Syn. says:

    It is, and I’ll fix it tonight! Sorry!

  • williswill says:

    @ spiro – I can’t read the paper, but if the the abs. conf. of the nat. product was unknown, then even an inaccurate alpha-D should confirm the stereochem.

  • sufuric says:

    For optical rotations it is actually g/100mL not g/L. This still doesn’t change the fact that it should still be to small of a concentration to get a good rotation value.

  • Liquidcarbon says:

    Can anyone please tell me at what temperature does DMF start to degrade with a carbonate base?

  • Taitauwai says:

    OMG!!! I haven’t drop by for a while and when I do… LOOK AT THIS! Nice layout. You had me at “hello”. Good luck in your writing up…

  • […] information. Rich Docherty over at TotallySynthetic has started tagging his posts with InChIKeys…not InChIStrings (I’ve talked about the value of this here and […]

  • bg says:

    Has anyone seen a Jacobsen HDA used at a later stage of a synthesis, and not carried out neat? Or involving an aldehyde that isn’t relatively simple? Thanks ..

  • Juan David says:

    Hi. Kool synthesis. For a good conversion in the inversion of acetalic stereocenter the difference in energies of the two compounds must be of some order to drive the reaction to the products. Why is it so great the conversion and how they detect it? How about diasteromers in the first reaction??