Monday, July 30, 2018

What if Diels, Alder, and Suzuki had a Love Child?

Today our most recent work combining decarboxylative cross–couplings with cycloadditions to generate complex C(sp3) rich compounds was published in Nature. With over 90 compounds and 1,000 pages of supporting information, this project was a massive undertaking and you might be wondering how it all started. 

Despite the extensive amount of pericyclic and radical reactions described, this work is actually of “poll”ar origin. More specifically, it was the first twitterionic species from our lab that was born out of a twitter poll.  A little over a year ago, Phil posed a question to the group during group meeting: Which reaction do you think is the most studied, yet LEAST used reaction in industry? Not satisfied with such a small sample size, Phil did what he does best (second only to chemistry), he took to Twitter. As you can see, Diels-Alder appears to be DA answer. 
Evidently, if we could find a way to repurpose the Diels-Alder reaction to make it practical for medicinal chemists, we could have a valuable new methodology on our hands. First things first though, we had to figure out why few in industry have used the Diels-Alder reaction relative to the incredible amount of time we spend in graduate school learning about all its vagaries. To do this, we thought it would be helpful to compare the Diels-Alder reaction with one of the most widely used transformations medicinal chemists use: cross-coupling reactions. To begin, the difference between the two transforms was staggering. In spite of its rich history, venerable pericyclic transformations have occupied a somewhat “peri”pheral role in industry, seeing only a handful of applications every decade. In contrast, cross–coupling reactions such as the Suzuki reaction are second only to amide bond formations in terms of popularity (see Figures taken from ACIE and J. Med. Chem.)
To us the differences between these two transforms was apparent. Not only are cross–coupling reactions some of the most reliable transformations in organic chemistry, but they are also extremely useful in terms of modularity as countless products can be made from the same starting materials. For a medicinal chemist, this is ideal as numerous analogs can rapidly be prepared from simple building blocks. However, this is not the case with the Diels-Alder reaction. Due to both steric and electronic requirements, when making even moderately complex products only specialized building blocks can be used in these reactions to ensure the reaction takes place cleanly. As is often the case, when the dienophile is prepared, the diene is already “dying” in the sun (or in the cold room). 
Coming from the Baran lab where we have a passion for natural product total synthesis, we know the value in cycloaddition reactions as they allow us to rapidly generate complexity in a single step. So, we thought wouldn’t it be great if we could just combine the two transformations? And that’s exactly what we did.

To make a long story short, we found that the best solution would be a somewhat non-obvious one. We envisioned a sequence where we first execute a facile, well known Diels-Alder reactions with maleic anhydride, a commerical building block that is cheap, bench stable and most importantly well matched to undergo many cycloadditions. Even better, by combining these cycloadditions with established desymmetrization reactions with cinchona alkaloids, in just two steps we quickly accessed numerous building blocks that were poised to undergo decarboxylative cross–coupling reactions that our lab has developed over the past few years. 
Though we thought this was a good start, we figured why simply stop with just the Diels-Alder reaction. Why not apply this same strategy to all known cycloadditions with maleic anhydride? After much work from our talented team, we found that [4+2], [3+2], [2+2], and [2+1] cycloadditions all worked remarkably well. Even better, due to the radical nature of these cross–couplings, in almost all cases we observed excellent diastereoselectivity influenced by the neighboring substituents. On top of that, after the absolute configuration is set in the initial desymmetrization, there is almost no erosion of the ee (even after two cross–couplings). This means that overall our strategy is both diastereoselective and enantioselective. In the end, we were able to use this approach to make over 80 compounds arising from simple cycloadditions as well as 6 applications in the total synthesis of natural products and drug molecules. 

Interestingly, this approach is not simply limited to radical cross-coupling disconnections. After our initial submission, we realized that when we combined our approach with a classical chemistry such as the Curtius rearrangement, we could access even more building blocks that up until this point were previously inaccessible using traditional cycloaddition chemistry. To demonstrate this, in a little under a week Tie-Gen synthesized chiral compound 118, an inhibitor of the EED protein disclosed by AbbVie that previously required chiral separation. 
Now as you might imagine, seeing as how we have over 90 final compounds in our SI -- it is a bit long. In fact, we definitely have set a lab record on this one. Some of you, including one reviewer, may question the utility of such a long SI. It is not done to evoke a feeling of "shock and awe" as the reviewer suggested (no good deed goes unpunished!). And its not because we like playing the game of CSI (see SI) throughout the manuscript. Rather, we feel that the more data we report and the more transparent we are, the easier it might be for others to reproduce our results. That is why we always try and include graphical supporting information and a Q&A section when we can. Furthermore, between all the many sections, characterization, and spectra, we were worried when we first set out to compile the SI just how to organize it. We felt the best way was to include a table of contents (and a detailed table of contents for the table of contents), descriptive overall scope for each panel in the manuscript, and individual schemes for each compound to minimize any confusion that could possibly arise surrounding the overall synthesis of any one compound.  

The great thing about a long SI for a paper is that if you couldn't care less about our lab's work (highly likely), you don't need to read it. Same goes for this Blog actually.  We actually can't come up with one good reason why an SI that includes absolutely everything you currently know about a research project (in an organized way) is a bad thing.  There is a non-zero chance, after all, that someone, somewhere  one day many decades from now might actually use this chemistry and find value in having all the details present. Please enlighten us if you can think of a reason.
Last but not least, we find ourselves in a bit of a charitable mood here in the Baran lab this summer. 
As we mention in our paper, we synthesized (±)-epibatidine•2HCl on gram scale in just 5 steps. So just let us know if you (reputable scientist with an authentic email address) are interested and we would be happy to share some to you (send email to tiegen@scripps.edu).
We want to thank our collaborators at Leo Pharma and Eisai Pharmaceuticals for the work that they put into this paper. Let us know if you have any questions or comments regarding the work! Thanks for reading!

Lisa and the Cycloaddition Team