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Phostriecin and/or Sultriecin   

6 February 2010 12,260 views 19 Comments

Boger, Burke, Haq. JACS, 2010, ASAP. DOI: 10.1021/ja9097252. Article PDF Supporting Information Group Website

Figured it out already?  I bet it caused a few scratched-heads in Dale Boger’s group when, having made the published structure for Sultriecin, things didn’t tally-up.  We’ve discussed quite a few reassignments here over the years, but the majority are antipodal stereoclusters, or isomerisations at worst.  In this case, even the molecular formula was wrong!  The group may well have been suspicious before this point, though, as the related fostriecin, cytostatin and phospholine all contain the phosphate-mono ester that eventually replace the sulfate group initial assigned.  Their journey in reassigning this centre is best read in the pdf, but the synthesis is pretty damned good too!

First up is a fairly simple coupling of an acetylene and an acyl chloride.  Now, I would have cracked-out the BuLi in this case – but not Boger, who used a bit of palladium catalysis.  This certainly has an advantage from a ‘mildness’ point of view, but I not sure why it was necessary.  Perhaps the acetylide could have reacted with the furan?  BTW, it’ll come as no surprise to those readers who know their coupling reactions that the reference given is a Sonogashira paper.

I’m only really mentioning that coupling in passing, as the interesting reaction is one that follows after a pair of reductions.  The freshly installed hydroxy-furan was coaxed into a ring expansion using just a little base, and some NBS.  No explanations or further information here, but it is a nice method!  With the left-hand-side looking pretty much ready, it was time to tackle the other half, containing a rather precarious looking triene.  However, before you try to combine a whole load of Suzuki/Stille methods for it’s construction, have a look at Richard Taylor’s approach – opening of pyrilium tetrafluoroborate with an alkyl lithium to generate the dienal (is that a word?).  A bit of dibromoolefination using carbon tetrabromide and triphenyl phosphene completed the triene, with only a little reduction required to furnish the desired bromo-coupling partner.  What a sweet way to configure your olefins.

Then, predictably, came the coupling itself, using a rather surprising approach of lithium/halogen exchange, and then addition into the aldehyde partner.  This had the advantage of conferring a pretty decent diastereomeric ratio on the new hydroxyl group, something unachievable in the Suzuki disconnection I’d have been planning.  It’s pretty brave, though, as the lithiate looks pretty prone to rearrangement.  At least it’s not skipped-conjugation…

A really neat piece of synthesis coupled to a remarkable reassignment.  I’m amazed that this error was made by the isolation team – the fact that sulphate and phophate-mono-esters are equal in mass is well known.  A little 31P NMR would have been soooo diagnostic!

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19 Comments

  • sufuric says:

    The ring expansion/rearrangement is called the Achmatowicz Reaction. It is definitely a neat little reaction.

  • antiaromatic says:

    Overall a really nice synthesis. Also a great read.

  • excimer says:

    I’m pretty sure lithium acetylides can attack ketones. Besides, given the choice between a Sonogashira and a lithiation, I’d choose the Sonogashira every time. Sonogashiras with acyl chlorides are wonderful.

  • milkshake says:

    A strong paper methodology-wise and educational. The molecule is not mundane but it is small enough for few people to complete in a reasonable time. I think this is the right example of the value of doing total synthesis projects.

  • optional says:

    Who Dat!

  • AIK says:

    An appropriate kind of project to give to a diploma worker or two or an exchange student and give them a reasonable possibility to get their name on a decent paper.

  • Gilgerto says:

    What is new in this paper? I mean, where is the novelty…

  • Less Than Three Palau'amine says:

    Baran coulda done it better – But he’d never waste his time with such an uninteresting molecule!

    • That's Great... says:

      I know people in the Baran lab, and I am sure they are wishing your keyboard breaks so they will no longer be associated with your amazing comments.

    • Tot. Syn. says:

      Oh FFS, shut up!! If there’s one thing I know for sure he can do is write a more useful and insightful comment than you!

  • org_chemist says:

    A bit off topic, but can someone comment on Dale Boger as a PostDoc supervisor? Any idea about the working conditions? Are his students chained to the oars like in other Scripps groups? Or is Boger the more relaxed kind of supervisor? Thanx

    • LiqC says:

      He’s pretty nice. Make sure you get enough sleep before interviewing with him – he has a very soporific voice. :)

      • HPCC says:

        Boger to a grad student, saying she came in to work only on Saturday afternoon because she was doing her jogging in the morning…

        “Jogging? What’d you think, that you’re here on an athletics fellowship?”

  • PolyM says:

    I love the synthesis and mostly the discussion!

  • cfp says:

    Regarding Sonagashira, nice reaction, do you think the lithium acetylide could have reacted twice.

    The NBS step is spectacular, I remember sitting through a session at an ACS meeting where some speakers disussed this reaction in detail on the way to natural products they used mcpba following a sharpless dihydroxylation on an adjcaent olefin prior to the oxidation