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Fostriecin   

17 November 2009 15,254 views 32 Comments

fostriecin

McDonald, Robles. Org. Lett., 2009, ASAP. DOI: 10.1021/ol902365n. Article PDF Supporting Information Group Website

It’s been a little while, but there’s been nothing too exciting (total synthesis-wise) in JACS or ACIEE.  However, a quick glance in Org. Lett. produced a veritable cornucopia of syntheses, with this lesson in catalysis nudging to the fore.

The target is a newbie to this website and to me too – but not to the chemical community at large.  Indeed, the list of prior syntheses is quite unnerving for the prospective student-synthesizer, including Kobayashi, Boger, Cossy, Shibasaki, Reddy…  This brings a certain amount of knowledge, perhaps about unviable intermediates or recalcitrant couplings – but also demands that something new be brought to the field.

With a triene in the target, there’s no surprise that palladium mediate couplings are the order of the day.  Rather neatly, McDonald managed two in quick succession, using a gem-dibromo olefin.  The first Negishi coupling goes for the more reactive trans- bromine, generating a good yield of the diene.  Then, a little more palladium and ligand, along with dimethyl zinc allowed methylation of the remaining bromine.

fostriecin_1

I wonder if there was any hope of doing both couplings in the same pot.  Perhaps give it a day or so with the first coupling, then dump in some dimethyl zinc… but the ligand is a bit different, so perhaps the two are incompatible.

With that done, it was time to oxidise that somewhat reactive looking diene.  As can be seen in the target, what they needed was a syn diol, so a bit of Sharpless’ tasty osmium seems to be order of the day.  However, there’s a bit of a selectivity issue here, with only a methyl group differentiating the two halves of the diene.  It appears that is enough, though, with a pretty decent yield of the desired regioisomer (13% went the wrong way)

fostriecin_2

There’s quite a bit left to do, but it was done quickly; revealing of the acetylene and formation of a vinyl iodide by iodation and diimide reduction brought them to an intermediate in Jacobsen’s synthesis.  However, rather than go to the pub, they went off-piste, and coupled the RHS using Suzuki rather than Stille conditions (citing nasty, nasty tin as the rationale).  However, to get the reaction to go at RT (the triene doesn’t like heat, unsurprisingly…), they needed to use thalium carbonate – a might nastier.  Hmm.

I’d have stuck with the smell of tin, but you can’t touch the rest of the synthesis.  Nice work.

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32 Comments

  • Tianfei Liu says:

    Tin is sweet-smelling :P

  • Molecular Bail-Out says:

    Nothing too exciting going on?! Did you miss this groundbreaking paper in Org. Lett.? It will change the way Nanoputians drive on gold surfaces forever!!

    http://pubs.acs.org/doi/abs/10.1021/ol902312m

    • Tot. Syn. says:

      A lab-mate pointed this paper out to me today.

      I know total synthesis takes a lot of flack from some scientists, who suggest that it’s a waste of money to make molecules for the syntheses sake. However, this nanoputian stuff is a lot of bollocks. Now, molecular machinary could be useful, once we get past the quantum effects. But nano-cars/men/animals/houses is sheer bollocks.

    • Will says:

      The Smalley institute for Nanoscience Technology?

      You can’t make stuff like that up

  • BY says:

    In the words of MC Hammer: U can’t touch this (doing my parachute dance)…Frank McDonald, you rock!

  • Yshi8141 says:

    heard that Phil Baran just finished palau’amine. True?

  • MetalUpYourS says:

    No, not again. Just when a Baran paper is in print, the Baran-machinery starts to wonder in the blogosphere if this or that target could be made, or who would finish it first. Deja vu?

  • ch3mical says:

    ^^Yes, I heard the same. ???

  • real-munson says:

    I have heard that another, lesser known group is wrapping up their endgame strategy, under 20 steps total.

  • questioning ethics of the blogosphere says:

    I think that posting speculations on unpublished work represents an ethical dilema. We should all exercise good judgement in this respect. Would you want someone to do it to you?

  • fake-munson says:

    It is a brazen suggestion to restrict commenting on a blog about “rumors” in the field. Unless any specific chemistry is divulged, why is it an issue? I’ve heard countless comments about people finishing hot targets–they have all been false up to this point.

  • Crickets says:

    The only difference there is that the vinigrol paper came out shortly after a very advanced “approach toward” paper…it didn’t hit us out of the blue.

  • No Way says:

    The forces of the trans-5,5 are too powerful, rendering Palau’amine invincible. I don’t even think Baran can make it, even with the labs past experience with other members of the pyrrole imidazole alkaloids.

    • Dean McToste says:

      Agreed. People will get close but not finish. Many people have been working on endgame for years now.

  • Put your hands up! says:

    Put your hands up for Palau’amine, I love that molecule!

  • Rumor Mill says:

    Its done. Expect it soon.

  • GYA says:

    of course someone will make it (or has already made it)! also, on rumors, some of them may be from public disclosures anyway such as talks at other universities or companies. what’s wrong with mentioning something like that?

  • ch3mical says:

    Any suggestions for enone reduction by hydogenation without aromatic dehalogenation? Anyone used PtO2 or sulfided palladium before?

    • ... says:

      Use diimide. Org. React. 1991, 40, 91.

      • milkshake says:

        5% Pt-C from Aldrich in EtOAc as a solvent when used under a balloon of H2 eats halogens very slowly – I like to use it for reducing nitro-chloro (bromo, fluoro) compounds into anilines without dehalogenation

  • JohnLennon says:

    Lucy in the sky with diamonds, Baran in the sky with palau’amine

  • furannoyed says:

    I’d be careful about saying that a particular molecule can’t ever be made by humans (even Palau’amine). It’s no fun to make molecules we know we could make easily anyway.