Wednesday, August 27, 2014

Diterpenoid-Alkaloids are so...Fancy (You Already Know)

The second paper on our efforts toward diterpenes and related diterpenoid-alkaloids is out in JACS now.  This is building off of work previously published in Angewante last year.  The story of this project goes back more than 5 years.  I’ll try to spare most of the painful details.

Summer 2009: My initial project was to make ent-kauranes and ent-atisanes and oxidize them with what people used to call C­–H activation and now seem to call C­–H functionalization.  (Does that make me sound old?)

Several months later (Spring, 2010), I came across David Gin’s synthesis of nominine.  Like so many others, I was awestruck. Being relatively new to complex-molecule-synthesis, it took me a few months to realize that nominine (and other hetisines) were structurally related to ent-atisines.  I didn’t notice this right away because people draw these diterpenoid-alkaloids in strange ways (see below).

I realized that I could target these more complex alkaloids from ent-atisanes with C–H functionalization and as they say, the rest is history.  I drew up a ridiculously ambitious and naïve plan for Phil in May 2010.  The plan was impossible, so of course Phil gave me his blessing to work on it.  It was going to be as easy as 1, 2, 3…whatever that means…

Step 1: Nothing ever goes as planned.  Three long years passed before we finished steviol (step 1 of 3).  Meanwhile, behind the scenes we worked on what was arguably the more interesting part of the project: making steviol into a bunch of complex molecules with complex reactions.  How did we start on steps 2 and 3 when we hadn’t made steviol?  Well, we bought it…sort of.  We bought stevioside—5 kilos of it to be exact.

Now, at this point you are probably wondering, “Why would Emily go through the trouble of making steviol if she already had access to decagrams of it?”  That’s a great question, but one that I don’t have time to answer right now.  Remember, I’m giving you the super short version of this story.

Step 2: Making isosteviol from steviol is known and boring, so I’ll go ahead to the synthesis of methyl atisenoate.  This chemistry is pretty straightforward.  The cute maneuver in here is the Mukaiyama peroxygenation/fragmentation sequence (proposed mechanism shown below.)

Step 3:
Part a: For the atisines, the major challenge was the selective C20 C–H activation.  I had to experiment with many different directing groups, light sources, solvents, reagents, and temperatures to optimize this one.  It took about 5 months to identify the best directing group and get the reaction working well.  Depending on the conditions, we can either get over-oxidation to give the imine or not.  In the case of isoatisine, we wanted that oxidation so we ran with it.  In 9 easy steps, we can get to a substrate containing an aza-ent-atisane skeleton and oxidize it.  In the same pot we hydrolyze the imine to an aldehyde.  Why? because it’s labile and it was easier to just take it off for characterization purposes.  After elimination (Martin’s sulfurane was key for exo-selectivity) and diastereoselective allylic oxidation (a la Gin’s nominine synthesis), the synthesis could be completed by simply adding ethanolamine into the iodo-aldehyde.

Part b: “It would be challenging to exaggerate the difficulty experienced while attempting to forge the C20-C14 bond present in the hexacyclic hetidine skeleton.” (I wanted to put that line in the paper, but some people felt it was too sensational.)  No joke folks, it took me YEARS to find a good way around this problem.  Years.  I tried obvious ideas, not-so-obvious ideas, good ideas, plenty of bad ideas, simple ideas, complicated ideas, and every idea in between.  I talked to Phil about this over and over again.  I talked to my poor lab-mates about this over and over again.   I even spoke to random professors visiting Scripps if I had a chance to meet with them and discuss my chemistry.  The final idea is very simple, but please don’t equate simple with easy:   

Yup, all I did was take a very similar iodo imine to the one I had made previously and heat it up with some allyl amine in methanol.  To all the haters out there who look at this and say “well, duh,” I say, “Where were you for the past two years when I needed a good idea!?” 

Part c: When the literature let’s you down:  After deprotecting the hetidine core, we were ready to go after the hetisine skeleton.  I really thought I would just take some old lit procedures performed on pretty much identical compounds and that would be that.  There are only so many ways to magically net-dehydrogenate something with a secondary amine as your functional group handle.  

After trying those lit procedures and having them fail for us over and over again, we did what we always do: we tried to come up with something so crazy it just might work.  We thought of nitrenes, nitreniums, trans-annular hydride shifts, every variation of an HLF reaction we could fathom.  Maybe if I had more time, something would have panned out, but nothing we tried worked before it was time for me to move on to greener pastures.  So yeah, my last step failed and I didn’t make the hetisine skeleton.  Bummer.  This will probably haunt my dreams for the rest of my existence.  (Actually, I graduated about a month ago and I’m over it.)

To end on a positive note: I did a lot of cool C–H activation chemistry.

And I grew this awesome crystal! Check out that sweet N-Cl bond!
Like so many students working on complex natural product total synthesis, I worked many years to try a final, supremely amazing, and well-precedented key step only to have it fail.  Luckily, when your failures are good enough, you get to publish those too. 

At my thesis defense, a first year student asked me if I had any advice to give to the younger students just starting out.  I said something totally expected like, “Don’t give up.”  Now that I have actually had a chance to think about that, I’d like to change my answer.  I would say that when you are going through difficult points in your chemistry during your graduate school, and (if you’re doing it right) you inevitably will, remember that this is SCHOOL.  You are here to LEARN.  Failing at your chemistry is not the same as failing at graduate school, as long as you learn something and become a better chemist as a result.  I really believe that.


  1. To address the existential question in step 1:
    Q: "Why make molecules?"
    A: "For total synthesis"

    Q: "Why do total synthesis?"
    A: "To make molecules"

  2. hej, nice post and here are some questions: You're using a "90W lamp" and i was wondering what kind of lamp that is. Do you have any idea which wavelength you need for the N-I bond dissociation? Since you activate primary and secondary postions, have you made any experience with tertiary CH functionalisations using light and directing groups? <jo

    1. Hi Jo! We use a 90 W flood lamp. I picked mine up at Home Depot. It’s exactly the same or almost exactly the same as this one: The spectrum for the lamp goes from near ultraviolet (around 400 nm) well into the IR region. For the N-I bond cleavage, the specific wavelength required can vary depending on the nitrogen substitution, but visible light was sufficient for us. A UV lamp was unnecessary (and led to inferior results). Tertiary positions work; I have not personally done this, but Suárez has.