Thursday, February 21, 2019

E-Birch

Our work on electrochemical Birch reduction was published today. In case you don't want to read the manuscript, here's the Cliff notes:

  • Pfizer approached us, saying traditional Birch is bad news for med chemists (alkali metals are spooky; condensing ammonia is gross; the whole thing is a lot of effort). They asked us to make a better Birch.
  • We developed some conditions to effect the Birch transformation with electrochem. Basically, the conditions are mix substrate, LiBr, electricity, DMU, a key phosphoramide additive (TPPA), and THF. No ammonia, no alkali metals, no cryogenics.
  • Intuitively, one might naively assume that what's going on here is that the LiBr is reduced to Li(0), and from there the reaction goes through a standard chemical Birch mechanism. We assumed that, naively (at first).
  • Turns out, that mechanism is not at all the case, as demonstrated by much experimental and computational mechanistic study. Instead, the substrate is reduced directly on the electrode. Further, Li(0) is never generated at all. Safe stuff. Cool beans.
  • We went back to Pfizer with this. They seemed pretty happy.
  • Oh, also the reaction works in flow, on >100 g scale.
  • Oh, also, the key phosphoramide additive, that makes everything work, came from the Li-ion battery literature.
A huge shout-out has to go to our collaborators: Shelley Minteer and her group (led on the student side by postdoc David) for electroanalytical work, Matt Neurock and his group (led on the student side by grad student Sagar) for computational work, and our longtime buddies at Asymchem (led by Longrui) for scaleup and flow work. We should also note that this whole collaboration is driven by the CCI electrochemistry consortium, which has been a tremendous way to put people from various subfields of electrochemistry in touch with one another.

Anyway, normally, this is the part of the blog where we'd tell some funny anecdotes about the project. Unfortunately, the whole team is way too excited to get back in the hood for subsequent projects, so we didn't write anything. In lieu of anecdotes, please accept a few vaguely-electrochemical-Birch-related poems:

Limerick:

We set out to Birch some arenes;
to make a scary reaction more clean.
It turned out lack of lithium
gave us complete freedom
to safely Birch on our Electrosyeeeens

Haiku:

Birch in Winter frost
with Electrochemistry
No lithium, good.

AABBCC:

Poor Arthur Birch
did much research.
He was always sad,
for his reaction was bad.
Now we made it better
but alas, he is deader.

Oh, also we made a video, objectively comparing the time it takes to run a classical, chemical Birch, to the new electrochemical protocol. We hope you enjoy it:



- Electrochemical Birch team




Monday, January 14, 2019

Technique primer: Test tube columns

As many of you remember, a little over a year ago Phil did a AMA on reddit. On that AMA, a bunch of people requested that we do a post on how to build/run disposable test tube columns:

Well, writing up this blog post somehow slipped through the cracks for a year (Sorry!!), but without further delay, here's how we do the technique.

Step 1: Building the glassware. 

We use these columns on crude reaction mixtures from ~10 to ~500 mg scale. For smaller scale than this, we use prep TLC; larger, just a standard reusable column.

To build the column, for 10-50 mg, we just use a Pasteur pipette as the column. For 50-200 mg, we build it out of a 16 X 150mm tube. For 200-500 mg, we build it out of a 25 X 150 mm tube.

For the latter two, the first step is to pull a bottom spout from the test tube. Basically, you heat the tube with a Benzomatic torch, until you see the bottom glow orange and "wilt" slightly. At this point, you grab the glass with a pair of tweezers and steadily pull to make a long stem. It's hard to explain, but easy to demonstrate:

It's a bit tricky the first time, but gets simple with practice.

After letting the tube cool to rt, snapping off the bulk of the stem gets you a nice looking column:

(If you're using a Pasteur pipette, you get to skip to this stage)

Step 2: Building/running the column.

From here, it's just a matter of packing a small chunk of Kimwipe into the bottom, and tamping it down, followed by adding a bit of sand, and then silica gel. With modern silica gel, we have found that even <3" column height is still plenty to do reasonable separations. After equilibrating with a column volume or two of solvent, here's what it looks like, ready to load and use as usual:


One nice thing about the column sizes is that the 16mm tube (loosely) accommodates a 14/20 inlet adapter, while the 25mm tube (loosely) takes a 24/40 adapter. This way, you can run it with positive air pressure exactly as you would any other flash column. This is a 16mm tube, and as you can see, the small inlet adapter fits it nicely:


When the column is finished, here at Scripps, our EH&S allows us to dispose of the whole thing, tube and all, into our silica waste stream. Check with your EH&S for what to do at your institution.

Regardless, the best part of this technique is there are no dishes to wash!

Hope that this helps aspiring chromatographers,

Baran Lab


Sunday, January 13, 2019

11-Step Total Synthesis of Teleocidins B-1–B-4

Our paper describing the total synthesis of Teleocidins B-1–B-4 is now published in JACS! I started working on this project in November 2017 and completed the synthesis in June 2018. I then spent another 6 months optimizing the route to increase the yield and decrease the step count.


In the biosynthesis of these molecules the indolactam core is transformed into Teleocidin by a Friedel-Crafts type reaction with a terpene fragment. However, nature’s synthetic strategy provides a mixture of Teleocidins B-1-B-4 which is something we wanted to avoid. When I started to evaluate our own synthetic strategy, I immediately identified the introduction of the two quaternary carbons to the indolactam core in a stereocontrolled fashion as the major challenge (even one sterically hindered quaternary carbon can be difficult!). I knew we would have to establish the relative stereochemistry independently because the terpene fragment and amino acid moieties are quite distal. 


I also realized we needed to install a functional handle on the indole moiety in a highly regioselective fashion to facilitate coupling with the terpene fragment.With a bit of luck (and a lot of hard work) we were able to overcome these challenges and you can find the details in the paper/SI. I wanted to use this blog post to provide further insight into some of the key reactions which led us to success.

In the beginning, we had to fight against nature…


The first step in our synthesis is an electrochemical amination between our indole scaffold and valine. After optimization, I tried to scale up the reaction using some conventional large glassware which I bought from our local Japanese supermarket. However, almost no desired product was observed and even worse, I lost 6 grams of starting material along with the nickel, ligand and my time. I was so shocked that I couldn't even find my tongue! Phil suggested to try again but this time using the ElectraSyn carousel. The switch in setup facilitated reactivity and with a little optimization the desired product was formed in 51% yield.


I also want to highlight one of the unexpected problems we faced in this synthesis which is not described in the paper. While the desired indolactam is commercially available, it costs $274 per mg (Sigma) so it was a bit outside of our budget! We first tried to make the 9-membered ring by hydrolysis of the valine methyl ester followed by condensation using HATU, but the desired product was isolated in just 19% yield. However, after plenty of screening we found that the use of LDA was crucial for this reaction and we managed to obtain 2.1 grams of the protected indolactam! That was a really great day in the lab.


In April 2018 I was joined by Kosuke, a very talented visiting student from Osaka (Japan), who really helped me to optimize the route to what is now shown in the paper. Yuzuru, an amazing graduate student, also helped me by optimizing a key reaction and preparing a late-stage intermediate. I want to thank the team and especially Phil who was always ready with a lot of suggestions. I can definitely say he never compromises in the quest for an ideal total synthesis. 

Hugh and Teleocidin team

Thursday, January 3, 2019

Decarboxylative carboxylation: radiolabeling carboxylic acids the easy way

Our latest paper, which arose from a collaboration with the radiochemistry team at BMS, describes a new approach to carbon-14 radiolabeling and is now published in JACS (after previous submission to the ChemRxiv). I began working on this project as a visiting student in October 2017 and it has been an amazing learning experience with some tough challenges and valuable lessons. In this blog post I want to discuss some of the interesting problems we encountered upon diving into the field of radiochemistry.

To summarize, our synthetic approach consists of the formation of a redox-active ester followed by a chemoselective nickel-catalyzed decarboxylative carboxylation to reintroduce the (now radiolabeled) carboxylic acid. That carbon-14 label is a useful tool for radiochemists to perform the absorption, distribution, metabolism, excretion and toxicity studies required for drug development. Our method has some nice advantages including the two-step degradation-reconstruction synthetic approach (starting from the unlabeled product which is usually available in plentiful supply) and the use of [14C]-CO2, the cheapest and most common carbon-14 reagent.


During the initial reaction development, we successfully performed the desired decarboxylative carboxylation sequence using 50 psi of [13C]-CO2. Although this procedure allowed us to test the scope of the reaction (scheme 2 in the paper), our collaborators let us know the pressure and use of excess labeled reagent were big problems when it came to translating to radiolabeled [14C]-CO2.  


We first considered limiting the stoichiometry of the [14C]-CO2 to about 10 equivalents while maintaining the pressure in the system. Several options were considered included pressurizing with an inert gas (discounted due to the dependency of the concentration of CO2 on its partial pressure, rather than the overall pressure), pressurizing with unlabeled CO2 (avoided because it would dilute the radiolabel too much) or using amine additives to sequester the CO2 into solution and promote reactivity (no reaction observed presumably due to coordination to/deactivation of the catalyst). Thinking further about the factors which influence the concentration of a gas in solution we realized it may be possible to accomplish our goal by simply cooling the reaction down. Gases are more soluble at colder temperatures (when most gases dissolve in solution the process is exothermic, an increased temperature causes an increase in kinetic energy which promotes gas escape from solution). Through use of Henry’s law, the concentration of CO2 in solution under the pressurized [13C]-CO2 conditions was estimated. With this figure as a target, the temperature required to obtain a similar concentration at atmospheric pressure of CO2 was calculated to be about -25 °C. 


Running the reaction at -25 °C gave, perhaps unsurprisingly, only partial conversion of the starting material to the product. Using 10 equivalents of CO2 at atmospheric pressure and maintaining the cryogenic period for just one hour then sealing the vessel, warming to room temperature and stirring overnight gave full conversion of the sm with efficient isotopic incorporation (see the SI S12-S14 for further details)! The BMS team were now satisfied with this procedure and after making a few minor adjustments, they produced a working carbon-14 setup using standard radiochemical glassware and techniques. Upon testing the method with [14C]-CO2 we observed isotope incorporations suitable for use in all preclinical and clinical ADME studies and the project could be called a success. All in all, application of the method to the strict requirements of carbon-14 setting led us to some fun and interesting challenges and provided the answer to the age-old question…

 

Although we think Breeder Steve may have been considering one particular decarboxylation process, we can conclusively say the answer is yes #chemistrygoals! I would like to thank everyone in the lab for all their help on this project and please check out the complementary carbon isotope exchange methods just published by the Shultz group at Merck and the Audisio group at Université Paris-Saclay.

Cian Kingston
La Jolla, CA
January, 2019

Friday, December 21, 2018

Simply Strained: Total Synthesis of Herqulines

Our recent syntheses of herqulines B and C have been published today in JACS. While the paper describes the direct nature of our final approach towards these highly strained alkaloids and even hints at some of the difficulties encountered along the way, the truth is that the journey towards the herqulines was a two-year campaign plagued by failure and confusion. There were many lows along the way, but there were also some highs that made it all worth it. In the end, I learned many lessons about chemistry, but more broadly about science, problem solving, time management, and the formula for a truly winning team (huge shoutout to my partner in crime, Chi He). As I’m sure many of you know, what is reported in a synthesis paper is most likely the end result of many more lessons learned that are not visible in a short communication. Thus, I hope to convey a sense of this in the space below.

I was first introduced to the herqulines in the fall of 2016 as part of a thought experiment that we lovingly refer to in the Baran Lab as synthesis “boot camp.” In contrast to some of the other targets pursued in our lab, these tiny alkaloids don’t look like more than a simple reduced dipeptide upon initial inspection of the two-dimensional structure. It wasn’t until I built a plastic model of herquline B that I realized what a beast this thing truly is (late-stage x-ray structure pictured, gives one a decent idea what we’re dealing with). Strained is an understatement when describing the herquline core. The piperazine ring sits at the base of the macrocycle, with two six-membered rings flanking each side of the heterocycle in a
bowl shape. Throw in a pair of weird skipped enones and a 1,4-dicarbonyl at the strained ring juncture and you’ve got yourself one unhappy customer. The structural features, it turns out, were just the beginning of challenges involved when dealing with these alkaloids. As I would come to appreciate in short order, strained diamines are not only very challenging to handle from analytical and purification standpoints, but are also exquisitely unstable when the wrong transformation is applied at the wrong stage of the synthesis. In short, this was a proper adventure in total synthesis. So let’s get down to the nitty gritty. Let’s get the show on the road...

Our first approaches were predicated on the (spoiler alert: incorrect) precedent that Birch reduction of a strained biaryl was not a viable strategy towards our target. I’ll spare you from the gory details, but well over a year was spent perusing a host of strategies that ultimately led us back to the strategy in the paper, in which the macrocycle is built as a biaryl DKP.
Our task was simply to defy all precedent and reduce two aromatic rings and a DKP all within a highly strained, unstable core. Initially, I set out to reduce the DKP, while Chi fearlessly embarked on a quest to perform the first Birch reduction. For the DKP reduction, most common hydride reducing conditions resulted in either decomposition or monoreduction of the tertiary amide. One standout example, however, was Brookhart’s Ir-catalyzed amide reduction mediated by diethylsilane. However, the resulting biaryl diamine was highly unstable in our hands, and could not be isolated. It seemed that the strain was just too much and thus one of the aromatic rings needed to be reduced first.

To that end, Chi had screened a range of Birch conditions and protecting group swaps and was beginning to see some potential (see figure).

While the regioselectivity was incorrect, it nonetheless proved that this strategy could potentially be fruitful. The true complexity of the situation was soon realized when we discovered that when the DKP nitrogens are both N– H, the regioselectivity flipped and it matched our product’s requirements! This was a truly exciting day but much work still needed to be done, as the natural product of course has one methylated nitrogen.

We quickly prepared the asymmetric DKP macrocycle found in the herqulines (up until that pointN-methylation was somewhat of an afterthought) only to find that the regioselectivity was again incorrect. To complicate matters further, the resulting styrenyl position readily was reduced under most Birch conditions screened, and we even saw some elimination of methanol and additional styrene reduction.

After 
screening all known metals, solvents, temperatures, concentrations, and 
additives, we had only proton sources to screen before giving up on yet another strategy. We screened a bunch of proton sources which all gave the same negative result, with the exception of 2,2,2-trifluoroethanol, which cleanly delivered the desired regioisomer! This breakthrough was the result of empirical observation and to this day the mechanistic underpinnings of this selectivity are at best conjecture.


Recalling our above efforts to effect DKP reduction, Brookhart’s Ir-catalyzed amide reduction again reduced both amides to the corresponding piperazine. We were now one Birch reduction away from the promised land and excitement was brewing.

Of course, the synthesis gods were not ready to smile upon 
us yet, as every Birch condition screened resulted in either no reaction, or reduction of either homobenzylic position prior to any reduction of the second aromatic ring. We were back in the familiar position of despair, beginning to think that at this advanced stage we would ultimately fail once again, when it occurred to us that ketalization may be a viable workaround, given its ability to relieve strain (two more spcarbons), alter the conformation, and remove a double bond (improving selectivity).

After some screening, the ethylene glycol ketal proved a competent substrate and the second Birch proceeded cleanly, 
with the correct regioselectivity. Simple hydrolysis delivered herquline C, which, after a few days in CDCl3, equilibrated to an approximately 1:1 mixture with its more stable congener, herquline B. Treatment of herquline C (or this mixture) with DBU in toluene brought about clean conversion to pure herquline B, thus wrapping up an adventure that we will not soon forget. In the end, the simple, direct approach panned out. When I look at this route now, this pathway even seems obvious, but if you’ve read this far (sorry if I got a bit long-winded), you’ll know that this route was the result of much experimentation and intimate understanding of the reactivity and stability of every intermediate along the way. In short, this was a hell of an adventure in total synthesis. Thanks for reading!


Tom Stratton
La Jolla, CA 

December, 2018

p.s. See also the Wood group's elegant synthesis of the same molecules!

Thursday, August 2, 2018

Ψ

August marks the start of the academic year here at TSRI, and with every new semester I become a bit retrospective about my own first year of graduate school. Before I joined the Baran Lab, I was certain that I had a handle on the types of chemistry the group pursued: small-molecule secondary metabolites, usually with a twist. I arrived determined to work on a Baran standard. Instead, Phil pointed me toward a perspective written by Professor Albert Eschenmoser in which he laments the fact that, though a decidedly natural products problem, the synthesis of DNA had gone virtually ignored by natural products chemists (Tetrahedron 200763, 12821). Arguably the most important molecule in natural history and we, as a community, missed it. 

The DNA structure problem, which had been attacked and solved by non-chemists, and … revealed itself as …the major problem that nature had in store for natural product chemistry. – A. Eschenmoser (2007)

This quote became a quiet mantra of sorts, driving much of my interest in the synthesis of biomolecules (see: macrocyclization,CITU,peptide functionalization, and more musing on peptide functionalization). Then, about two years ago, a variation on the problem was presented to us by collaborators at Bristol-Myers Squibb: Can we improve the synthesis of medicinally-relevant oligonucleotides? 

Despite our collective lab ignorance around oligonucleotide synthesis, a remarkable graduate student, Kyle Knouse, was brave enough accept the challenge. It’s important to emphasize here just how courageous this choice was: The lab had no experience and no equipment with which to rewrite the rules of oligonucleotide synthesis. 

Given my stated interest, I was asked to join the project and—together with Drs. Martin Eastgate, Mike Schmidt, and the BMS team—we began to survey the existing literature.
[left](L to R): Dr. Chao Hang, Dr. Antonio Ramirez, Dr. Ye Zhu, Dr. Mike Schmidt, Dr. Bin Zheng, Dr. Jason Zhu, Dr. Matt Winston, Dr. Changxia Yuan. Not pictured: Dr. Ivar Mcdonald, Dr. Rick Olson, Dr. Stephen Mercer, Dr. Qinggang Wang, and Dr. Peter Park. [right] Dr. Martin Eastgate. 
We discovered that while the earliest reports of nucleotide synthesis relied on the natural phosphorous (V) oxidation state, the late 1970s saw the lethargic P(V) largely supplanted by P(III) in the form of phosphoramidites and H-phosphonates. Perhaps most striking was the apparent reliance on incremental modifications to advance the field; the P(III)-based phosphoramidite approach remains the standard mode of construction to this day.  
Had we any expertise, we almost certainly would have followed suit. For most, P(III) represented the most practical way to assemble oligonucleotides; to us, it was an unnecessary shackle. Liberated by our naivety, we chose instead to approach the problem as we would any other natural product: identify the most logical disconnections, limit concession steps, and aim for ideality

Adding yet another layer of complexity, both teams were specifically interested in P-chiral phosphorothioate oligonucleotides. We set forth with an ever-expanding list of requirements: the platform need be inexpensive, bench-stable, modular, and simple to purify; it must operate under complete stereocontrol, with near-equal access to both enantiomers of the chiral backbone; and, finally, it should feature a generality able to tame even the most discriminating of deoxyribonucleoside monomers. 
Building on chemistry developed in Stec’s lab, the team synthesized a P(V)-reagent in one step from limonene oxide, which served as the chiral scaffold. The original approach, while creative, fell short in several important ways; Stec himself cited the tedious reaction protocols, difficult diastereomer separations, and operational complexity as barriers to widespread use. 
The Stec Precedent
Interest from BMS continued to grow as the project progressed, and we were soon approached with the possibility of yet another application—Could the nascent BMS-Scripps reagent platform be designed with cyclic dinucleotides in mind? While there is much to be said about the medicinal potential of CDNs, I am not the person to do it; instead, I’ll direct readers to a fantastic C&EN article published earlier this year. From an academic perspective, however, we saw an opportunity: this alluring scaffold promised a challenging and underexplored class of natural products. Indeed, most CDN syntheses are buried deep within the patent literature and published without the rigor expected of a proper total synthesis campaign. As with many complex natural products, current approaches resemble a navigational land war of protecting groups and redox manipulations, not to mention the unassailable phosphorous stereocenters. Until now, synthesis of a single, pure CDN analogue took weeks. 
With another goal now in mind, both teams (the Scripps side now expanded by two spectacular post-docs, Julien and Cian) worked tirelessly and collaboratively to construct what would eventually become the phosphorous–sulfur incorporation (PSI or Ψ) reagent platform, the full details of which can be found in the accompanying manuscript. We hope you’ll agree that our mission was accomplished: PSI chemistry is practical, simple, and offers complete, predictable control over the phosphorous stereochemistry. Complex CDNs can now be synthesized in two days’ time as a single diastereomer, a point previously unimaginable. Access to diastereomerically-pure oligonucleotides has never been easier; the machine confines required of sensitive P(III) chemistry are a thing of the past.   

We leave you with a question posed by one of the giants of phosphorous chemistry, Frank Westheimer (Science 1987235, 1173): Why did Nature choose phosphates? He notes in the cited exposition that phosphates are found everywhere and can do almost everything—“genetic tape” is the colloquialism he seems partial to. By contrast, chemists have been reluctant to employ this all-important functional group with similar abandon. We respectfully suggest that the interesting question as it pertains to practicing chemists is not, “Why did Nature select phosphates?”, but rather, “Why didn’t we?” 

  Justine and Team Oligo

p.s. Ψ reagents will soon be commercially available from Sigma-Aldrich

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