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.
