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3Jan/1312

Barium(ii) Iodide – The Shair Method

Full post on this synthesis to come when I get back from holiday at the weekend and can use ChemDraw! Sorry for the hand-drawn stuctures - I've still not found a good way to draw stuctures on my iPad, which is all I have with me.

I've never been particularly excited by phloroglucinol-derived natural products, but I really enjoyed Shair's recent synthesis of the polyprenylation acylphloroglucinol (+)-hyperforin (it's a PPAP!), which appeared in the JACS ASAPs a few days ago.

  

I'll hopefully get round to a more detailed discussion of the route in the next week, but the first step immediately caught my attention. The chemistry's simple enough - a good old-fashioned deprotonation step with t-BuLi, followed by treatment with  barium(ii) iodide and prenyl chloride. I remembered (after looking it up) that the prenylation is done via the organobarium to improve the regioselectivity of the reaction, a trick developed a couple of decades back by the Yamamoto group (J. Am. Chem. Soc., 1994, 116, 6130).

Still, I was curious about how the group carried out the reaction, and on what scale, so I delved into the SI (which, by the way, is excellent). There I found a slightly unusual tip for how to get the small barium pieces necessary to freshly prepare the BaI2:

"Using a hand drill hammer, a chisel, and a lead brick positioned on the laboratory floor, mineral oil-coated barium rod was portioned into approximately 25 mm segments... If a hand drill hammer and chisel are unavailable, a standard claw hammer and an appropriately-shaped shelving bracket may be employed in this step."

I'm not sure why, but seeing that in a JACS paper made me smile.

 

 

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  1. I worked in the lab next to a postdoc who could do finicky and user-unfriendly methodology without getting frustrated. One of the things he did all the time was allylbarium chemistry, for which he needed freshly-made Rieke Ba slurry made in situ from BaI2 and Li-biphenylide, and BaI2 is made from elements. Ba metal comes in ingots and unlike Ca or Li or Na it is actually quite hard ( about as copper) and not very easy to cut. So his method was to clean up a crusty chunk of Ba under mineral oil, then he put it on an anvil and quickly hammered it into a thin plate while it was still wet with oil and then he cut the Ba plate with scizors into chunks that would fit into a 14/20 joint flask, this all being done on the bench under argon blanket (his bench hammer and anvil setup was not exactly air-free). He had to work very quickly, especially on a humid day, because the Ba surface coats quickly with oxidized crap. So he was banging away on this thing like a mountain goblin, almost everyday

    • Sounds fiddly. There’s mention in the paper’s SI of’barium pancake’ (interestingly, a phrase that doesn’t seem to give a single Google hit).

      • Hey BRSM – thanks for the write-up on our synthesis. When we were optimizing this reaction, we were screening a variety of different sources of BaI2. Buying anhydrous BaI2 (Aldrich and Strem) didn’t seem to work that well, and what initially worked adequately was taking BaI2 dihydrate and drying it overnight under hi-vac (this is how Yamamoto prepares BaI2 in his 1998 Org Synth prep). However, on scale, this was a nightmare, giving off lots of iodine. And if you take a look in the literature, there really isn’t a prep for BaI2 out there except for a brief mention in a Corey paper (TL 1997 38 5771). So I talked to Prof. Corey, and he gave me the details on how to make BaI2 from Ba and I2 (i.e., hammer-on-anvil as milkshake can attest to). Worked wonderfully on scale.

        Please let me know if you have any other questions about the synthesis.

        • yea, the banging guy was a Corey postdoc

        • Could you answer the question for me please? That is, in the reactions involving 18 to S6 and S6 to 19, why did you use 5eq. and 3eq. LiTMP respectively? And the two a-hydrogen’s reactivity(pKa) makes me puzzled, do you have a reasonable explanation? Thank you.^_^

          • strychnine,

            After making compound 18, we needed to perform two more C–C bond-forming reactions to essentially complete the total synthesis: bridgehead acylation at C1 and prenylation at C3. Prior work towards hyperforin-like natural products have shown that both positions are similarly reactive (see the deuterium quench discussion in this Danishefsky paper: ACIE 2007 46 8840); however, these positions can be differentiated quite easily given that the C1 position is sterically more congested than the C3 position (see this Simpkins paper for some great examples: JOC 2007 72 4803). Therefore, we first exposed 18 to 5 equiv LiTMP and TMSCl to silylate the C3 position (5 equiv is a bit overkill, but the yields were consistently good at this stoichiometry).

            The subsequent bridgehead deprotonation-acylation sequence on S6 took substantially more effort to optimize. Given the steric environment at C1, you’d think that using a smaller amide base would be better for deprotonation, but smaller amide bases contain alpha-protons, and thus these bases (e.g., LiNEt2, LDA) acted as hydride-transfer reagents and reduced the C9 bridging ketone of the substrate. After screening non-amide bases to no avail, we settled on using LiTMP (which contains no alpha-hydrogens). This bulky base only deprotonates the substrate at higher temperature (≤ 0 ºC), but at these temperatures, slow decomposition would take place. And given the fact that the electrophile in this reaction–isobutyryl cyanide–contains an acidic alpha-proton, we found empirically that 3 equiv LiTMP gave the best results for this particular transformation. It was quite a delicate balancing act, but we got it to work reasonably well in the end.

            I hope this answers your question!

          • Thanks for taking the time to post such a great explanation!

        • Thank you very much!

  2. What do you do with a dead chemist?

  3. barium pancake is my new favorite band.


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