Greetings
and salutations ladies and gentlemen! Our total synthesis of maoecrystal V has
been published in JACS recently. It
is a fascinating molecule, in my opinion, with a beautiful array of densely
interlocked rings, myriad of quaternary carbons, and an intriguing bioactivity
profile to back it up (or not). It is no wonder, that it received so much
attention from synthetic community, especially in the first five years after
its publication in Org Lett. But
don’t be fooled by that pretty face, this molecule is a demon in disguise!
Making it in the lab is like having a crush on that popular girl in high
school: no matter what you do or how much you try, the only thing you are going
to get is a beat down by her much more handsome and stronger boyfriend. This pretty
much sums up my experience working with this molecule.
On
the very first day in the Baran Lab, I decided to go for the baddest molecule
in town, perhaps out of shear arrogance, or maybe stupidity, but most likely a
combination of both. At that time, at least in my eyes, such molecule was
maoecrystal V. This decision took me on a hell of journey, a roller-coaster
ride if you will, full of adventure and unexpected outcomes, that changed me as
person and a semi-scientist. But that is the beauty of total synthesis, in my
opinion, it pushes you to your very limits and that is when you truly realize
what you can and can’t do.
The journey began with making the
bicyclic ketone 5a or 5b, which turned out to be far from a
trivial task. I am embarrassed to admit that it took me six months to actually
make it. I have no excuse for that. The figure below summarizes some of the early
failed approaches.
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| The Journey Begins |
When
the route to 5a had finally been developed
(described in the paper), the stage was set to explore the key addition/pinacol
rearrangement sequence. At this point, Phil probably thought, “Yea... this
Cernijenko guy needs all the help in the world and then some”, so I was joined
by an awesome post-doc Rune Risgaard. We actually made a really good and
productive team because we were quite different and complemented each other
really well. United by misery and failure, fueled by unhealthy obsession (both of
us really really wanted to make this damn molecule) we became good friends and
marched on to the battlefield. We had absolutely no clue what was awaiting us.
The pinacol rearrangement and hydroxymethylation
is pretty well covered in the paper and there is additional information
regarding these steps in the Supporting Information. Unfortunately, my
therapist has forbidden me to discuss these steps to prevent further damage. Consequently,
I will skip straight to the installation of the last carbon of the molecule.
The cyanide was perfect for our purposes since it was a nucleophilic source of
carbon that had the same oxidation sate as the ester and seemed small enough to
react with a hindered C-8 ketone. The Figure below summarizes our attempts to
accomplish this task.
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| A small glimpse of the challenge |
To
sum up, the reactivity was not the problem. Most of time time the yields were
very good, stereocontrol, on the other hand, was an issue. The cyanide was
always coming from the undesired face giving us exclusively undesired
diastereoisomer. We tried different CN sources, Lewis and Bronsted acids,
solvents, and additives. The outcome was the same in almost every case.
Interesting example is the reaction mediated by I2 where CN
approached from the desired face but attacked the more hindered bis-neopentyl
ketone to give 28. I was very
surprised to see the X-ray crystal structure and to this date I still have no
clue how I2 completely switched the chemoselectivity of this
reaction. Other nucleophiles such as vinyl lithium, furanyl lithium, lithium
1,3-dithianes, corresponding Grignard and organocerium reagents did not solve
this problem. We also tried blocking the undesired face by epoxidizing the C-15/16
alkene, but CN still approached from the undesired face. However, a very
important result for us was the formation of 29 mediated by Zn(OTf)2 because it is the only example
where we achieved the desired stereo- and chemoselectivity. The compound itself was
synthetically useless but it made us realize that if we form the THF ring first, CN
might approach from desired face. Interestingly, that hypothesis lead to the
synthesis that was published today. In total synthesis things can go from
terrible to great in just one reaction.
Lastly,
I would like to discuss the very last reaction in synthesis. It is quite
strange to eliminate iodide with Oxone. Initially, we tried to engage iodo ketone 18 (formed as ~15:1 mixture of iodo
epimers 18a (major) and 18b (minor)) in classic base promoted
E2 type elimination. But not even a trace of maoecrystal V was formed despite
myriad of conditions examined. We believe that there was simply no
antiperiplanar hydrogen available for the desired elimination to take place.
While the minor 18b iodo ketone, in
principle, should have underwent E2 elimination, we think that the chair
conformation with axial iodide is highly disfavored due 1,3-diaxial strain. As
a result, 18b' is probably more accurate representation
of its conformation, where iodide is pseudoequatorial on a boat.
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| The Iodide Elimination |
This
is where we got quite lucky. After oxidation of the iodohydrin with one of the
commercial bottles of DMP, iodoketone was formed in excellent yield along with
2-4% of maoecrystal V as a by-product. The relevant portion of crude NMR is
attached below.
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| MCV hiding in the weeds |
How
did it form? Freshly made DMP or other bottles of commercial DMP did not give
any traces of maoecrystal V. It was just
that one bottle that consistently yielded small amounts of maoecrystal V. What
was in it? Long story short, we suspected that maybe it was contaminated with
Oxone (which is used to make DMP) since
oxidative elimination of iodide with m-CPBA
was known in the literature (this reaction was very messy and low yielding in
my crooked hands). Indeed, simply adding buffered aq. solution of Oxone to the reaction mixture resulted in very
clean elimination of iodide to finally give maoecrystal V. That was a very good
day in the lab.
We
were able to make decent amount of this natural product using this route, as a
result, we had the chance to explore its bioactivity profile with different
collaborators. Unexpectedly, it turned out that synthetic maoecrystal V was not
active in any of the cancer cell lines (even HeLa) tested. Our dreams of curing
cervical cancer were shattered, but we received a lot of valuable lessons from
this synthetic campaign. That was a hell of a ride! R.I.P MCV, I hope we will
never meet again.
-Art
