Sunday, January 13, 2019

11-Step Total Synthesis of Teleocidins B-1–B-4

Our paper describing the total synthesis of Teleocidins B-1–B-4 is now published in JACS! I started working on this project in November 2017 and completed the synthesis in June 2018. I then spent another 6 months optimizing the route to increase the yield and decrease the step count.

In the biosynthesis of these molecules the indolactam core is transformed into Teleocidin by a Friedel-Crafts type reaction with a terpene fragment. However, nature’s synthetic strategy provides a mixture of Teleocidins B-1-B-4 which is something we wanted to avoid. When I started to evaluate our own synthetic strategy, I immediately identified the introduction of the two quaternary carbons to the indolactam core in a stereocontrolled fashion as the major challenge (even one sterically hindered quaternary carbon can be difficult!). I knew we would have to establish the relative stereochemistry independently because the terpene fragment and amino acid moieties are quite distal. 

I also realized we needed to install a functional handle on the indole moiety in a highly regioselective fashion to facilitate coupling with the terpene fragment.With a bit of luck (and a lot of hard work) we were able to overcome these challenges and you can find the details in the paper/SI. I wanted to use this blog post to provide further insight into some of the key reactions which led us to success.

In the beginning, we had to fight against nature…

The first step in our synthesis is an electrochemical amination between our indole scaffold and valine. After optimization, I tried to scale up the reaction using some conventional large glassware which I bought from our local Japanese supermarket. However, almost no desired product was observed and even worse, I lost 6 grams of starting material along with the nickel, ligand and my time. I was so shocked that I couldn't even find my tongue! Phil suggested to try again but this time using the ElectraSyn carousel. The switch in setup facilitated reactivity and with a little optimization the desired product was formed in 51% yield.

I also want to highlight one of the unexpected problems we faced in this synthesis which is not described in the paper. While the desired indolactam is commercially available, it costs $274 per mg (Sigma) so it was a bit outside of our budget! We first tried to make the 9-membered ring by hydrolysis of the valine methyl ester followed by condensation using HATU, but the desired product was isolated in just 19% yield. However, after plenty of screening we found that the use of LDA was crucial for this reaction and we managed to obtain 2.1 grams of the protected indolactam! That was a really great day in the lab.

In April 2018 I was joined by Kosuke, a very talented visiting student from Osaka (Japan), who really helped me to optimize the route to what is now shown in the paper. Yuzuru, an amazing graduate student, also helped me by optimizing a key reaction and preparing a late-stage intermediate. I want to thank the team and especially Phil who was always ready with a lot of suggestions. I can definitely say he never compromises in the quest for an ideal total synthesis. 

Hugh and Teleocidin team


  1. Nice work! Does the amination work if you use N-Me L-Valine? Or any secondary amine?

    1. Thank you for your question!
      Basically, secondary amine can be used for this electrochemical amination. However, in this particular case, simple L-valine Me-ester gave good yield!
      Thanks for writing!

      Hugh Nakamura

  2. A really detailed and nice behind the scene look into the total synthesis. Congratulations to Teleocidin team! Supp info was excellent! loved it. Hope to see much more in near future.

  3. Thanks for your comment!

    Hugh Nakamura

  4. Very concise and elegant synthesis. Question #1: Can you use the use TIPS protecting group instead of acetate on the indole for the electrochemical transformation? Question #2: Can you make the flip the order of the steps; first make the amide bond with the aziridine and then do the macrocyclization at C3 of indole?

  5. Great question!
    Answer #1: Basically, electron deficient Ar-Br gives desired product in good yield because oxidative addition of Ni into electron deficient Ar-Br is easy. Therefore, we decided to use Ac group which is easy to remove after amination.
    Answer #2: Good question! We thought about that. However, we thought there was a issue with the construction of the 9-membered ring due to strain. Thanks!

    Hugh Nakamura

  6. curious, what's your current theory for the disastrous failure when trying scale up the e-amination in a bottle?

  7. Thanks for your question!
    In general, the surface area of the electrode in contact with the solvent is very important when setting up an electrochemical reaction. In the case of large glassware, we were not able to use the appropriate size of electrode. In addition, the efficiency of the agitation from the magnetic stir bar is also very important and we observed poor stirring in the upper part of the reaction mixture with the large glassware setup. This caused formation of Ni black on the upper side of electrode which we believe ultimately killed the reaction.

    Hugh Nakamura