“What’s cooking?” was the question that Phil had asked me
whenever he wanted to start a conversation back when I was a second-year
student. Apparently, at that time, he was into “what’s cooking in chemistry.” In this post, I would like to talk about how
did we come up with the idea of using quinone diazides in "our recipe" (a recent ACIE publication,) but
firstly…what is a quinone diazide? it is a "handsome" diazo compound! We classify
it as an acceptor/acceptor diazo compound. It was discovered in the 19th
century, so it’s a really old species. Diazonaphthoquinone (DNQ), an o-quinone diazide, is commonly used in a
positive photoresist called DNQ-Novolac photoresist.
When I first
joined the lab, I was given a retrosynthetic analysis of prednisone, a
precursor of cortistatin A. In Baran lab
terminology, my research topic is described as “ a cyclase phase of steroids.” Breaking the B ring of a steroid probably
results in the most convergent synthesis, and according to Corey’s retrosynthesis
logic book, it is a topologically strategic disconnection. Interestingly,
Denmark has proposed an identical retrosynthesis for the cortisone skeleton, and
has successfully made the right side, but has never accomplished the molecule
(TL, 1984, 1231). Personally, at first I wasn’t
really into this project because originally I wanted to deal with reactions
that are “weird,” reactions that you don't really get what is going on without deeper
thought. However, since I didn’t have anything else in mind or other options, I
told Phil “yes” after a week of consideration.
The key step of our
retrosynthetic analysis is an enol-phenol oxidative coupling that can go wrong for
a hundred reasons: thermodynamically unfavorable (dearomatization), kinetically
unfavorable (para is more sterically hindered), and stereoselectivity issues...
After trying this key step for 9 months without achieving any C-C bond
coupling, one afternoon, Phil called me to a white board and started discussing
about other retrosynthetic possibilities.
At one point during the discussion, Phil accidently (!) connected the
C9-C19 bond to make a cyclopropane and asked me if we can make it from…the
corresponding diazo compound. Looking at the weird diazo compound for a few
seconds, Phil shook his head, and asked me to come back for another
discussion.
When I went back to
my office, thinking about the strange species, Will (a senior student at the
time) yelled to me “it exists!!!” …Apparently Will had also witnessed our
discussion and immediately ran a Scifinder search. I conducted more detailed searches and
brought it to Phil’s attention. He
replied, “this is it, Hai!” and this was how we “re-discovered” quinone diazide
chemistry.
I quickly prepared
a simple substrate to test the key reaction.
Luckily, it worked perfectly after several trials. I went to discuss with Phil after confirmation
of the desired product, and in less than 5 minutes, he gave me a “recipe” (this
was around July 2012). If you have read
our paper (accepted in Aug 2014), you could easily recognize that the only
thing different was that it’s in ACIE instead of JACS, or the lack of some
“flavor” that I couldn’t achieve.
I continued working
on this recipe for the next two years.
It took me less than two weeks (14 days) to make the model substrate
(without the D ring), however, it eventually took me more than 14 months to
make the desired cyclopropane. The rate-determining steps were: making the
right side, conditions for the conjugate 1,4-additions (Turbo
Grignard was superior), and finding the magic effect of sub-stoichiometric Li2CO3 as an
additive for Eschenmoser’s methylenation, and of course the scale-up. However, I was lucky with the double deprotection to release the quinone diazide and the key
cyclopropanation, which worked at the first try.
The cleavage of the
other two C-C bonds of the cyclopropane intermediate was achieved easily, but the
C9-C19 bond (that Phil accidentally connected) was unbreakable, even after half a
year of hard work. This is kind of
unfortunate because the product of that C-C bond is a natural product, a really
important “flavor” of the recipe. Another 4 months of optimization in the reaction
of quinone diazides with olefins (Table 1 in “recipe tables” or 1 and 2 in the
paper), and Phil let me submit, and luckily the recipe was accepted to Angew. Chem.