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