Our most recent work as part of a longstanding
industry/academia collaboration between the Baran group at TSRI and Pfizer was
published today in Science (on a Sunday!). As far as details of the publication and SI are concerned, we
will leave that to you to explore on your own, so this blog post will discuss the
origin of the project.
You could say that this project actually began back in 2014
when our lab was initially approached by Pfizer to solve the synthesis of
[1.1.1]-bicyclopentylamine on process scale.
This simple idea led to a much greater topic of what we called strain-release amination. A section of this work focused on the use of
strained sulfone reagents to access cyclobutanes, and a follow up report showed
that we can similarly access enantiopure functionalized cyclopentanes through
“housane” strain-release reagents. Although the sulfone functional group was useful
for subsequent anionic functionalizations (alkylation, fluorination, etc.), one
limitation of this work was that the sulfone had to be removed using strong
reducing conditions.
In particular, scientists at Pfizer wanted a way to conduct
a desulfonylative cross-coupling. Due to our prior experience in the
development of decarboxylative cross-coupling reactions, they approached us and
asked if we could help them development a transformation of this type. A key
precedent for our work was an elegant comprehensive study from the Denmark
Group at UIUC where it was shown that alkyl phenyl sulfones could be
desulfonylatively arylated under Fe catalysis with aryl Grignard reagents.
After discussing this potential project with Pfizer, we
realized that we could potentially solve a research problem that we were
interested in working on; namely, new ways to synthesize (fluoro)alkylated
arenes through cross-coupling chemistry. While we wanted to do this in a
decarboxylative sense from mono- or difluoro carboxylic acids, these substrates
proved recalcitrant, presumably due to the instability of the redox-active
ester intermediate. Fluorinated
sulfones, however, are well-established in the literature and have a high
degree of stability.
To make a long story short, we found that under Ni-catalysis
with arylzinc reagents, we could indeed conduct our desulfonylative arylation
reaction. A key to the success of this reaction was the incorporation of the
phenyltetrazole group onto the sulfone; in our hands under these and related
reaction conditions, this was the only group on the sulfone that permitted the
desired reactivity. With the help of two talented visiting students, Monika and
Cheng, we were able to quickly realize the scope of the reaction and applied
the developed reaction to a variety of examples we found in the patent
literature; in many cases, our desulfonylative cross-coupling simplified access
to drug-like compounds.
We think the key take away from this work is shown in the
scheme below; that is, from a single sulfone intermediate, three analogues
(alkyl, monofluoroalkyl, and difluoroalkyl) can be accessed divergently from a
common intermediate without the need for toxic and difficult-to-handle
deoxyfluorination reagents.
During the course of this work, we identified a few reagents
that we thought could be useful to medicinal chemists, shown in the scheme
below. In partnership with Asymchem, we prepared these on large scale and have
made them available via Twitter for free to chemists interested in trying out our
reactions. Let us know if you’re
interested, and we would be happy to ship some to you!
As many of you may know, ChemRXiv, a preprint server for
chemistry, was recently established, and the idea of preprints was intriguing
to us because it would allow for our work to be viewed and used even prior to
publication. We decided to take the plunge and become the Baran Group’s
experimental test case in preprints. We really enjoyed the streamlined process
by which the work shows up online; within a day, our manuscript was viewable to
anyone interested free of charge.
While the manuscript was in review, we were curious about the ranking of alkyl PT sulfones relative to other electrophiles in terms of reactivity. We were pleasantly surprised to find that under the optimized conditions for desulfonylative coupling, the primary RAEs (TCNHPI and NHPI) react preferentially whereas the PT sulfone reacts faster than the primary halides (Cl/Br). There, the qualitative trend would be:
Cl/Br<SO2PT<NHPI/TCNHPI.
Rohan, Jacob, and
Tian
