Wednesday, March 23, 2016

Phorbol Synthesis

Today, our paper entitled “Nineteen-Step Total Synthesis of (+)-Phorbol” was published online in Nature. The chemistry is thoroughly described in the paper so here I will just briefly highlight a key reaction which led us to success. This concise synthesis was achieved based on our two-phase terpene synthesis strategy. We hypothesized that an ingenol synthesis intermediate shown below would serve as an ideal starting point if we could invent a simple solution to the challenge of incorporating C-12/13 hydroxy groups.  

Thanks to LEO Pharma for providing unlimited quantities of the key intermediate!

After successfully oxidizing the C-12 position (easily predictable based on 100 years of C–H oxidation literature), attention turned to the C-13 position and re-closure of the cyclopropane. This synthetic strategy became reality by the invention of the cascade reaction shown below. The cyclopropane ring was opened to install the C-12/13 oxygen atoms, but reclosure of it was not successful because of the subsequent 1,2-shift. This unwanted 1,2-shift was avoided by forming an hemiorthoester so that C-13 hydroxy group is protected with an acetyl group along with the following retro-aldol reaction. This electron withdrawing group completely prevented the 1,2-shift after cyclopropanation to give the desired cyclopropane compound with C-12/13 oxygen atoms. This cascade reaction (from the corresponding tertiary alcohol without the TFA group) was all done in a single reaction flask, on a gram-scale, without any aqueous workup, filtration or purification.

13 transforms - one reaction flask...

Lastly, I would like to show you one of the unexpected problems we faced in this synthesis, which is not described in the paper. As you can see below (this is just part of my notes when I was working on the screening, so sorry for the mess), oxidation of the alkene (or diol) to the corresponding diketone was a real challenge.

A typical summary of reaction optimization. Every step of the synthesis was a methodology project...
If you are interested in this synthesis, please take a look at the paper. I hope you can find something interesting there. Also, if you have any questions, please feel free to contact us.

-Shuhei Kawamura


  1. Really nice piece of work.
    I always enjoy reading your blog posts almost as much as reading your papers, keep it up!

  2. Feed Burner doesn't work any more..
    "Back to Heterocycles!" is the latest article.
    Have some ideas?

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  6. Sorry for double-posting.

    One thing I wanted to ask you is how you came up with the oxidizer for RuCl3.

    Typically, one would use periodate as the terminal oxidant in RuCl3 catalyzed oxidations, which leads to RuO4, and this is a pretty nonselective vigorous oxidant (that can take methoxyphyphenyl group down to a carboxyl).

    NaBrO3 is presumably a milder reagent, I liked it for oxidation of thiols to disulphides and benzylic alcohols to acetophenones. Please do you have an isight, or was it a lit precedent/a stroke of luck? Does it produce a different oxidation state of Ru - i.e. Ru(VII)?

    1. I started with conditions for ketohydroxylation of olefins (Plietker, B. Eur. J. Org. Chem. 2005, 1919-1929.). Then, conditions were optimized as you can see above. It's only showing part of it but various oxidants were screened to find a suitable oxidation state of the ruthenium for this reaction. NaBrO3 is used for preparing TPAP from RuCl3 so I was assuming that the active species would be Ru (Vll) but we didn't do any mechanistic studies. Also, it's really important to have homogeneous reaction mixture. Once the water layer is separated from the organic layer, you will see different products. This might be because of the C-C bond cleavage though I didn't analyze these byproducts very closely (at least they were not simple aldehydes or carboxylic acids). In some conditions, I also detected C-C bond cleavage on the side chain (forming methyl ketone). Anyway, this reaction was really clean as long as the optimized conditions were used, which didn't even require column purification.


  7. Congratulations! I think it’s a great work.

    I have one thing I’d like to ask you.
    Going from compound 15 to 16, how do you rationalize the stereoselectivity at C10?