In my last project, I barely made it to
the first base with the synthesis of some steroid skeletons. When I was about
to continue “the cycle” with some ideas for a further development, Phil told me
not to, and convinced me to start a seemingly non-related project, a method
for an overall addition of a methane molecule to unactivated olefins.
How did we start?
During the preparation for the manuscript of the last project, I went to
Phil to get his opinion on how to describe the figure (below) more convincingly.
Me: Since I did not make the methyl in
the C,D-ring junction, how should I describe it?
Phil: (Looks at the figure in 3
seconds)…why don’t you make it.
Me: uhh???(Thinking about his “irrelevant
suggestion”!!! Com’on Phil!I just want to PUBLISH it).
Phil: You can make an olefin in the D
ring using Hans’ method, and add a methyl group to it…maybe useing our
reductive iron coupling.
Thinking about Phil’s suggestion more
carefully, I actually liked it because it would fulfill my dream of making five
different classes of steroids from the same intermediate, thus completing the
idea of making a “steroid pyramid” using the idea of two-phase synthesis. So I
decided to give it a try. I quickly
observed some C-C bond formation with N,N-diphenylhydrazones
and O-benzyloximes while trying to
wrap up the previous project.
Quentin made the first tosyl hydrazone in
the lab based on studies reported by Kim and coworkers. However, after two
weeks of investigation, we only got some undesired rearrangements but not C-C bond forming product. Based on the previous
result with other hydrazones and oximes, I had a strong belief that the C-C bond between the olefin and tosyl
hydrazones should also work. In addition, a quick search showed the feasibility
of reductive C-N bond cleavage under basic conditions. Putting
these things together, a two-step sequence could be envisioned. It took me a
few days to prove that the C-C bond
formation with a tosyl hydrazone was indeed feasible; however it took me more
than a month to achieve the first C-C
bond adduct with formaldehyde tosyl hydrazone, The rate-determining steps in
this process were finding the conditions for in situ formation of the hydrazone and determination and suppression
of the byproducts. Importantly, the C-N
bond cleavage was also obtained just by heating the reaction mixture after C-C bond formation to 60 oC in methanol.
Chao then joined the project, and in only a week he quickly modified conditions
to a standard two-portion conditions to solve some reproducibility issues as
well as improve the yield.
During a discussion, Phil mentioned that we should call our methodology “a
molecular editing method”. So two criteria for substrate scope were to have substrates
with a “real name” and substrates with complexity. The good thing about the
formal criterion is the diversity of the repertoire of commercially available compounds,
as we basically just went through Sigma-Aldrich and TCI catalogs and ordered
substrates with olefins. Commercially available terpenes such as carvone oxide, limonene oxide, dihydrocarvone, carene,
rose oxide, dihydromyrcenol… all worked under our conditions but we could
not separate the desired hydromethylated product from the hydrogenated
byproduct; this problem is by far the biggest issue of the current work
While most of the work was completed at
TSRI, in the other side of the country, Brad Maxwell at BMS tried to apply our method in radiochemistry. I told Brad that it would be my dream if he
could make it because I don’t think I will have a future occasion to have radioactivity
data in a publication that I co-author, and he did it amazingly with a complex
terpene called rotenone using a very low concentration (ca. 1.5%) of [14C]formaldehyde.
Here is what Brad taught us about the origin of 14C:
“Typically, 14C
is not naturally in enriched form since it is not abundant enough to make the
process feasible. Instead, 14C is produced by irradiating solid
beryllium, aluminum nitride or saturated ammonium nitrate solution with
neutrons for 1–3 years in a 14N (n,p)14C reaction within
a nuclear reactor. Longer irradiation times produce higher specific activity of
14C. In the process, the 14N is converted to 14C.
After the irradiation, the material is dissolved in H2SO4
and the effluent gases are oxidized by an appropriate catalyst. The
resulting [14C]CO2(g) is then passed through NaOH(aq)
and it is eventually precipitated as Ba[14C]CO3 from
which all 14C-labeled products are prepared. The only current
producers of 14C are located in Russia.”
Looking back on what we had made in term
of (radio)labeled compounds with the current method, Phil might be right when he said: “Since there is
no other way to do this sort of methyl editing, even if it is a long reaction
time and a complex reaction system, people still have to use it.”
Like
a baseball player who undergoes the process of bating (hitting the ball/failing/trying
to hit again), running to the next base, getting tagged out by the opponent and
repeating the process again until scoring. Total synthesis requires a lot of
trial and error, with a lot of time spent in going back and changing the
strategy. In this project, the most important moment might be the lessons that we
learnt during the previous synthesis (of steroid skeletons), gave us hints to the discovery of hydromethylation of olefins. Personally, I enjoyed my experience in the lab; however,
one thing I still could not fully capture is how our “coach” makes his
decisions. Most of the time just in the blink of an eye, and sometimes it just
comes from nowhere…but it actually works (at least in my two projects).
