HELLO AND WELCOME TO MARS!!: This post chronicles the path that we took to solve a 45 YEAR OLD PROBLEM and how this led to our exploration of privileged strained ring systems that look like they come from another planet.
It all started in late 2014 when we were approached by Pfizer to provide a kilo-scale synthesis of [1.1.1]Bicyclopentylamine – that’s right…..1KG!!
The need for the supply of [1.1.1]Bicyclopentylamine was URGENT as medicinal chemistry programs were HALTED due to lack of a route to provide large quantities of this material for clinical trials. Yes folks, I’m talking about a true REAL WORLD problem that required an immediate response. A problem of this ilk was a first for the Baran Lab and we were definitely blown back on our heels by this seemingly insurmountable challenge. But we
were determined to solve this in order to facilitate the delivery of potential therapeutics to patients.
After conducting an extensive literature search, it became apparent why this structure is so difficult to access in any meaningful quantity. Upon analysis of all of the previous routes, we identified an approach that we felt was the most direct route and thus, the most challenging. Due to A LOT of development in the synthesis of [1.1.1]Propellane, we figured a direct amination across the central bond would be the best approach to solve this
problem. However, we knew that this would be a daunting task as the approach was simple and surely someone has tried to develop this reaction in the past….right? In fact, several innovative attempts were made to directly aminate [1.1.1]Propellane but all of these attempts were 3 steps or more, utilized toxic/hazardous reagents, or provided non-viable intermediates that could not be converted to the desired product.
We were
inspired by a report by Ernest Della in 1990 where a halogen-metal exchange and
subsequent quench with CO2 was attempted but an unusual
reaction occurred whereby t-Buli essentially added across the central bond and
was subsequently quenched with CO2.
I then wondered if a metalated amine could do the same sort of reaction and it was around this time that Justin courageously joined my project and we sought out to test this hypothesis. During this time, I would often keep saying that "There is a light at the end of the tunnel." and Justin would respond "Umm..yeah...let's hope a train isn't on the other side though." I have to admit, he was right in saying that as this problem was anything but trivial. Anyhow, we pressed on into the dark unknown.
After countless attempts to develop a direct amination reaction, we were finally successful when we generated the lithiated amide of dibenzylamine and added it to a mixture of [1.1.1]Propellane. However, we were somewhat disappointed with this result because we obtained methylated dibenzylamine as a major product of the reaction due to the MeBr that was generated from the Wurtz reaction. Then, we thought we had an “AHA” moment when we swapped out methyllithium for phenyllitium but we just ended up getting phenyl dibenzylamine as the major product presumably from an aryne intermediate (from bromobenzene).
After countless attempts to develop a direct amination reaction, we were finally successful when we generated the lithiated amide of dibenzylamine and added it to a mixture of [1.1.1]Propellane. However, we were somewhat disappointed with this result because we obtained methylated dibenzylamine as a major product of the reaction due to the MeBr that was generated from the Wurtz reaction. Then, we thought we had an “AHA” moment when we swapped out methyllithium for phenyllitium but we just ended up getting phenyl dibenzylamine as the major product presumably from an aryne intermediate (from bromobenzene).
It was at this point where Phil asked “Can you
optimize this reaction?”….which translates as “You better fix this reaction!!”
So, we ran A LOT of reactions in an attempt to fix this reaction but we were
unsuccessful at every attempt.
It was during this time that I
remembered that Knochel’s turbo Grignard reagents have a similar reactivity
profile as non-turbo Grignard reagents but tend to display some subtle
differences in reactivity. When we generated our turbo dibenzylamine and added
it to an in-situ prepared [1.1.1]Propellane solution and stirred overnight at 50°C
in a sealed tube, we consistently obtained yields of 50-60% . WuXi was able to
successfully scale-up this reaction on 100g scale and Pfizer developed
deprotection conditions using their parallel optimization technology to give us
our desired product.
At this point, we experienced a scientific epiphany when we realized that our new method could potentially be used to "propellerize" ANY amine. I can remember the look on everyone's faces (especially the Pfizer team) when we proposed that compounds such as Paxil could be propellerized directly. The reason for this excitement is borne out of the fact that it is EXTREMELY difficult and even IMPOSSIBLE to incorporate the bicyclopentyl
moiety onto amines; especially amines within complex structures. The reason for this is that chemists are restricted to starting with the bicyclopentylamine and building up the structure of interest around it. While this may be possible for compounds such as tetrahydroisoquinoline, it is nearly impossible for compounds such as Paxil.
Next, we wondered if we could use our newly developed
reaction to directly aminate compounds that would be of interest to medicinal
chemists. To investigate this approach, we prepared a stock solution of
[1.1.1]Propellane by running the Wurtz reaction and distilling the resultant solution
via rotovap. It turns out that this methodology was very general and we were
able to “propellerize” a wide range of secondary amines including drugs such as
Paxil (Paroxetine) and Zoloft (Sertraline).
"Turbo Azetidination"
Next, we wondered if we could
extend this methodology to other strained ring systems. We became aware of a
strained precursor to azetidines [1.1.0]Azabicyclobutane or ABB. So, we
prepared ABB in-situ from the tribromide precursor and we successfully aminated
it with a range of amines and trapped the resulting amide with Boc anhydride.
Cyclobutylation with "Designer" Bicyclobutanes
Another strained ring system
that we were interested in functionalizing was [1.1.0]Bicyclobutane for the
synthesis of “cyclobutylated” amines. After attempts to functionalize
bicyclobutane failed, we realized that we would need an anchoring group that
was attached directly to bicyclobutane to make this reaction feasible. A reaxys
search revealed that substituted phenylsulfonylbicyclobutanes could be aminated
under high temperature in a neat mixture. Since we believed that a method to
directly append cyclobutanes onto amines would be of value, we sought out to
explore ways to make this reaction broadly applicable. We
started by reasoning that placement of EWG’s on the phenyl ring would increase
the reactivity of the central bond which could allow for milder conditions
which would hopefully lead to a broad substrate scope. After synthesizing a
range of substituted phenylsulfonylbicyclobutanes, we chose to move forward
with the 3,5-difluoro derivative because it offered a nice balance between
reactivity, scalability, substrate scope, and cost. We were able to develop a
room temperature cyclobutylation sequence by stirring the
phenylsulfonylbicyclobutane with an amine in the presence of LiCl using DMSO as
the solvent. The substrate scope of this reaction is VERY broad and we were
able to synthesized these cyclobutylated amines in a facile manner. It is also
noteworthy that we were able to make cyclopentylated derivatives.
With this exciting result in hand, we believe that scientists can use strained ring systems as an alternative and perhaps improved approach for bioconjugation and drug development.
* We have provided a step-by-step guide for all of our methods in the Science supporting information section. However, some of the pictures are blurry due to repeated compression. We have provided a link to a supporting information file with clearer pictures.
