Taxol

Taxol! The fearsome jungle-gym-like structure of this molecule has attracted worldwide attention since the late 20th century. Our group was of course one of them, and has been working on this molecule for >10 years, which has culminated in this recent JACS article. PLEASE READ the SI because it describes what actually happened and rationalizes why/how we arrived at the final route; looking only at scheme 1 could give a false impression that everything worked as designed from the outset. It was the longest project run in the lab and I happened to be the last person. Here I shall share some personal stories I  experienced through this arduous oxidation-state-pyramid climbing.

My first TOC draft. Phil said no.

In Dec 2015, a super postdoc Shige (currently an assistant professor at Tohoku University) took over the Taxol project. (Phil said) there are "only" two more oxidations to complete the synthesis.  However, these are very specialized and each are one of the most challenging sp3 C–H bonds to be oxidized. Shige recruited me for the project in Jan 2016. For the record, back in June 2015, when I joined the lab, Phil offered three projects that I could work on and one of them was Taxol. I consulted with senior students in the lab and EVERYONE said "DON'T DO Taxol". In spite of this advice, I was naive enough to commit to the Taxol project. It must have sucked for Shige to work with "1st year me," who barely knew how to stain a TLC place. But he patiently taught me a lot of chemistry, experimental techniques and how to strategically carry out a total synthesis. We went through a lot of failures (see the 1st generation route in SI) but finally, it was found that C–2 β-OH was critical for C–1 oxidation, which led us to the 2nd generation route and established access to a handful of C–1 oxidation product.

Around this rough time, we got a letter from another, more junior, "Baran", which made daddy smile and me pale.

We were happy to "complete" one of the two most difficult oxidations. However, the happiness in total synthesis always has a short half-life and we immediately hit a wall called C–2 reduction. The challenge was two-fold: First, this ketone was a brick. The most difficult ketone reduction ever, it sometimes even survived super harsh conditions such as Birch and LiDBB. Second, it always gave us undesired C–2 β-OH in diastereomerically pure form. These were the worst sorts of optimizations because the results did not tell any directions to pursue, we were basically shooting in the dark. It was particularly painful since most substrates took about 20 steps to prepare, which all ended up failing. 

Never saw the physical state of compounds until we started collecting SI, since we never had enough material to see it.

This deceptively benign-looking reaction took us 2 years (the 2nd and 3rd generation routes) to figure out. Long story short, things finally got better when we found the C–4 α-OH β-Me motif, which gave us α-OH upon C–2 reduction on a model substrate. We integrated this moiety and carried out a new oxidase phase. Fortunately, both C–1 oxidation and C–2 reduction worked smoothly. 

For the C–7 oxidation, with the C–5/6 epoxide installed, the oxidation relay idea immediately emerged. C–6 iodoso elimination was more or less the first examined idea and worked beautifully well. The final key C–6/7 epoxide opening also went smoothly with Nugent-RajanBabu reagent in the presence of so many sensitive functional groups (carbonate, tert-OH, OTMS). This completed the two major objectives to achieve the total synthesis of Taxol. And indeed, this is actually our final route. The 5th generation route was already laid out 2 years ago from now.

C–7 oxidation relay.

The day I was confirming the stereo- and regioselectivity of this reaction, Phil was obviously excited. He came to my office asking how the 2D NMR looked every 40 min, even after I told him my NMR wouldn't even start in 4 h. In sum, with all key structures installed, it took only <100 experiments (including scale up) to pave the route to this key intermediate. 

The photo evidence Phil chasing me around.

After the completion of two key oxidations, our substrate and Holton's intermediate looked so similar that we stopped pursuing this route, assuming the downstream reactions should work without problems. Phil Baran is never satisfied when it comes to a synthesis and we started looking into more ambitious strategies (both the 4th generation route and also attempts that were so random that they are not even included in the SI or my thesis). They ended up not being incorporated into the final route but provided some fascinating insights (see SI).

We never really talked about the cyclase-phase in this blog post but we needed to go through the sequence so many times to provide a sufficient quantity of material to do any oxidase-phase chemistry. The cyclase-phase works amazingly well, but our lab is not designed for kg scale reactions and it was just physically tough. I had to run through the entire building and collect all the 5 L flasks from other labs.

#scaleupsucks

It was around this time that Chemveda offered us a collaboration opportunity, and prepared >100 g of the cyclase-phase end product. I have to say the cyclase-phase is not the most straightforward sequence, especially on scale. But they bravely undertook it, overcame issues associated with the scale up, and significantly improved the overall sequence. If there's anyone in Pharma looking for a great company to collaborate with, Chemveda is amazing.

The cyclase-phase end product prepared by Chemveda.

In the following year, we were joined by a talented postdoc Hugh, to finally complete the synthesis. As previously mentioned, our intermediate was almost identical to one of Holton's intermediates, so we optimistically assumed the only thing left was to make more material and push it to the finish line. Starting from the substrate shown below, we could indeed intercept Holton's intermediate (see the dirty NMR).

(top) Holton's and our substrates. (left) Following the tradition, I celebrated the formal synthesis by drawing the structure, which turned out to be too soon. (right) What small-scale life looks like.

However, that was the time we recalled a lesson "There's no such thing in total synthesis as 'almost done,' nor 'the last scale up.' "  The deceptively simple-looking C–4 acetylation (again, challenging steps always look easy on paper) worked in 3% yield. We spent as long as 3 months trying to install this small piece, but could not fix the step. We decided to take a detour which fortunately worked out alright. Although Holton's procedures worked on some of our substrates, their reactivities were often different, which required some modifications to reaction conditions. Overall, the end game ended eventually which completed the two-phase synthesis of Taxol. 

Vanilla with banana cream cake. Yes, I put anchovies on pizza. 

As a reward of 5 years of journey, we got to have a cake thanks to Sol publically shaming Phil. In the end, we submitted from home because of the current situation. This also made me defend from home via Zoom (>100 people came!) but it went remarkably smooth! Maybe I am the only Baran alum who got Ph.D. from home?

Post-defense Zoo party. Thanks everyone for coming!

I should note that this synthesis was achieved by standing on the shoulder(s) of previous practitioners, of course, including those who worked on the two-phase taxane project before me: Yoshi (the first graduate student worked on taxane project), Abraham (a brilliant postdoc now PI at Stockholm University), Nathan, Mine, Changxia and Yehua. I just joined the lab at the end and happened to be the one to finish this. I would like to thank again all those who dedicated their time to this project.

– Yuzuru

(–)-Maximiscin

Greetings fellow social isolationists. If you’re here, it may be because you spotted our recent synthesis of (–)-maximiscin in JACS, thanks for stopping by! If you’re looking for a harrowing tale of anguish, suffering and overcoming insurmountable odds, don’t worry the taxol blog post is coming soon. All jokes aside, this molecule was no pushover and it took some creative solutions to bring it across the finish line. Hopefully I can convince you of this, while providing a brief distraction from whatever you might be bingeing on Netflix.

Are you not entertained?

Before getting into how we made maximiscin, it’s worth considering a little about why we targeted it in the first place. In addition to having a cool name, it has a relatively unique structure, originating from the union of three separate biosynthetic pathways. The molecule actually exists as a mixture of interconverting atropisomers, resulting from the hindered sp²-sp³ bond connecting the pyridone and cyclohexyl fragments (C3–7). Back in 2017, when this project began, the lab was very into decarboxylative cross-coupling. As a result, we wondered if (surprise, surprise) a decarboxylative cross coupling could be applied to construct the hindered C3–7 bond of maximiscin. Not only would this enable a simplifying disconnection, but it would also allow us to push the limits of sp²-sp³ cross coupling, which remains challenging for hindered systems. Additionally, an alkyl carboxylic acid coupling partner would be more stable than its halide counterpart, and would be “spring loaded” to undergo radical oxidative addition, via extrusion of CO₂. 

After devising a route to our carboxylic acid coupling partner, we tried a lot of different conditions to effect the cross-coupling. Nothing worked, until we used a set of ligand-free Ni conditions initially reported by the Molander group. With Ni(dpm)₂, our heteroaryl zinc reagent and Zn powder (organozinc too hindered to homocouple and access Ni⁰) we were miraculously able to form the cross-coupled product in 9% yield. We tried many different things to optimize this reaction, (see SI) but could never dig ourselves out of that 9% hole, and eventually abandoned the cross-coupling approach. Despite this disappointment, I still think it’s remarkable that we were able to form the bond at all. The product is doubly alpha-substituted, doubly ortho-substituted and exists as a mixture of atropisomers. It represents, to my knowledge one of the most hindered sp²-sp³ bonds built using cross coupling. Huge shout-out to Amin Minakar, an amazing visiting student who slogged through the better part of this cross coupling saga with me.

Realizing that our previous disconnection wasn’t going to work out, we re-tooled our retrosynthetic strategy. What we came up with was a rather non-intuitive disconnection, opting to cut the central pyridone right down the middle. Perhaps naively, we envisaged that the ring could be forged at a late stage from an activated diacid, by “clicking in” an appropriately designed nucleophile. In addition to making the synthesis completely convergent, we anticipated this might ease construction of that constrained atropisomeric ring system by pre-establishing the hindered C3-C7 bond. We also liked that this would allow us to avoid a late stage pyridone N-oxidation, which I can tell you from experience is a terrible reaction. For the sake of brevity, I’ll touch on a few interesting steps we developed along the way.

Revised retrosynthesis

One of the key steps of this synthesis is a nifty desymmetrizing C-H activation, which defines 4 stereocenters in a single step from a meso-carboxylic acid precursor.  It took us a while to find the right directing group/set of conditions, but we were eventually able to form product in 58% yield with outstanding selectivity. I’d like to thank Feng-yuan Wang, an incredibly talented vising undergrad for all his help preparing the various functionalized directing groups we screened for this reaction. Unfortunately, it wasn’t all smooth sailing, and I learned an important lesson during this process: never trust an old sealed tube, especially on scale. The consequences of such a decision can be seen here… extracting that oil bath was not fun. An important feature of this chemistry was that we could actually remove the directing group after the reaction (a frequent limitation of C-H activation methods), and could even recycle it to make more C-H activation substrate!

Desymmetrizing C-H activation

Sad day in the lab

With desymmetrized material in hand, we turned to a (wait for it…) decarboxylative homologation to build out the diacid fragment. Our initial tactic used conditions previously developed by the lab. The reaction worked beautifully, but our pesky substrate was perfectly setup to do a 1,5-HAT, generating a more stable alpha-oxy radical. This led to a competing double addition pathway via trapping of a second equivalent of phenyl vinyl sulfone. We realized that if we could oxidize that intermediate alpha-oxy radical, it would provide access to a later aldehyde intermediate directly; what we needed was a reductant and oxidant in the same pot. We initially had success with photoredox (PET) chemistry. Blue LEDs aren’t a common sight in the Baran lab, but the reaction worked so we ran with it. A set of conditions were identified which were reasonably efficient, but had issues with scalability and purification (reactions were messy and aldehyde product silica unstable). Nonetheless, this was an important proof of concept and we continued searching for a more tractable solution. Specifically, we wanted to get away from the activated ester and use the carboxylic acid directly. Oxidative decarboxylation seemed like the obvious solution, and we began investigating the Kolbe electrochemical decarboxylation, motivated by its robust 100+ year history. Unfortunately for us, we could never get much more than 5% yield. 

Other motivating factors were also at play

What ended up saving my (Canadian) bacon were the humble Minisci conditions: Ag⁺ and persulfate. Although the initial yield was modest (6%), we discovered a pretty cool Fe co-catalyst effect, which led to a remarkable enhancement (71%). This finding was completely serendipitous, we were evaluating other more common radical oxidants (e.g. Cu), and Fe was sort of an afterthought – it almost didn’t get screened. We think it may be acting as a selective radical oxidant; it’s known from the old Fenton literature that Fe will selectively oxidize alpha oxy radicals, but leave other alkyl radicals untouched. The final conditions could be run one-pot, directly from the lactone after in situ hydrolysis, and proved highly efficient on scale (91%). As an added bonus, the crude material was remarkably clean (see crude NMR) and could be telescoped into the next step, which solved our aldehyde purification issues. I think there are two important lessons here: (1) don’t overlook the simple solution – we started out using some very trendy, very powerful methodologies, but ultimately dump and stir chemistry from the 70’s worked the best; (2) don’t talk yourself out of an experiment – it’s not as satisfying, but sometimes blind screening is what gets the job done.

Decarboxylative homologation 

Crude NMR using one-pot Minisci conditions

After a few more steps, it was finally time to roll the dice on our late stage pyridone synthesis. Our first attempts came up snake eyes – when we combined our diacid chloride electrophile with a functionalized oxime-ether nucleophile (X=H), we ended up with some pretty sad looking reaction mixtures. Our diacid electrophile pooped itself, as the reaction color suggested, and we recovered the oxime-ether nearly quantitatively. We had to tweak our initial conditions quite a bit, adding AgOTf to activate our diacid electrophile, and using a silane to spice up the nucleophilicity of our oxime-ether(X=TMS). The latter modification was an interesting development, and led to the creation of an “aza-Sakurai”-type system. An added benefit of this TMS activation effect was that it generated TMSOTf in situ (TMS derivatization observed by LCMS). This led to capping of our pyridone C-4 OH  in non-polar reaction solvents (e.g. PhMe) and prevented product from reacting with activated diacid starting material. Unfortunately, despite giving the best yield, acetonitrile proved too harsh for the TMS group to survive, leading to some derivatization of product with starting material. Fortunately, we found that a simple methanol quench could liberate derivitized product and return the diacid as a mixture of mono- and dimethyl-esters. Our final set of conditions delivered the protected natural product in 41% yield. Luckily for us, the final deprotection went smoothly, to reveal maximiscin and complete our synthetic journey. Special thanks to the isolation chemists Dr. Lin Du and Prof. Robert Cichewicz for sending us authentic material for comparison.

Initial attempts at pyridone synthesis

It’s interesting to consider how this synthesis evolved over time. We started with the goal of developing a hindered cross coupling reaction, but this morphed into a completely different strategy, and resulted in the development of some pretty cool chemistry. There were certainly ups and downs on this project, but overall I had a blast making maximiscin – I even got a cake for my efforts (don’t worry, Sol finally got his cake too).  Thanks for reading!

Let them eat... molecules?

– Kyle M.

Edit: Some people have asked about the mechanism/stereomodel for the C–H activation step. Unfortunately we were never able to isolate a palladacycle to validate our stereomodel. Based on the plastic model, there is obvious steric clash between the t-Bu of the directing group and one of the alpha-methyl substituents. We think this leads the palladium to C–H activate one methyl group selectively via CMD mechanism (J. Am. Chem. Soc. 2008, 130, 10848) to give the favored Pd(II) cycle. This is oxidized by NaIO4 to Pd(IV) which can undergo reversible X-ligand dissociation to form a cationic complex (J. Am. Chem. Soc. 2014, 136, 12771). The latter species is trapped by methanol in an SN2 fashion to give product.

Tryptorubin A

"It's just a peptide, how hard could it be?" That was Phil's remark in late 2017, when I set out to pursue the total synthesis of the alkaloid tryptorubin A.

Fast forward two years and a bit, and the lab has published the molecule's synthesis (Download paper here). That means it's my turn to write another blog post, on topics (at least vaguely) related to that paper.

A summary of the paper if you feel the manuscript is tl;dr, or you're behind a paywall:

• Tryptorubin A is a neat indole alkaloid. It's isolated from an interesting ternary symbiosis: Leaf-cutter ants pile up leaves to compost into mulch. Then, the mulch they have generated goes into little mushroom farms, where the ants grow mushrooms to eat. This is their main diet. Meanwhile, on top these farmed mushrooms live a variety of defense bacteria. One of those bacteria, a Streptomyces sp., generates tryptorubin A as a metabolite. From these bacteria Clardy et al. isolated the molecule and published its fascinating structure (link to isolation).
• Actually, none of this is in the paper but it's just cool trivia about the molecule.
• Although nothing is known about the bioactivity or biological role of tryptorubin A, we pursued its synthesis strictly for reasons of structural interest. This is a somewhat old-school, very academic way of thinking. The project was incepted as follows:
• <scrolling through JACS ASAPS>, "Hey, that's an interesting structure. I bet it would be hard to make."
• Me, to Phil: "This molecule would be hard to make."
• Phil, to me: "Great. The best projects are ones where people are slightly scared at the start. Have fun."*
• Me: "Damnit, now I have to make it."

• Off I set to make it. The chemistry is pretty self-explanatory (tons of peptide couplings, an Ulmann and a Friedel-crafts), so I won't go into much detail there. However, I will note that in the SI, we briefly highlight a dozen or so failed strategies (SI pages 8-10), if you're curious to see some early things we tried.
• The extremely short summary of chemical lessons learned is (a) don't try to close highly strained macrocycles with macrolactamizations, if possible, and (b) KISS. Fancy ring contraction or other trickery never beat out simple, straightforward old school robust chemistry.
• I made what I thought was the natural product <9 months into the project. This is where stuff got interesting. 
• None of the NMR data matched the real natural product.
• However, the 2D data unambiguously confirmed that we had the correct atomic connectivity and stereochemistry.
• What the hell was going on?
• At this point, we reached out to team Clardy and got all the original NMR data. I spent about 2 weeks simply staring at NMRs trying to understand what could possibly be the difference between what I had made and the natural product.
• This was, by far, both the most challenging and the most rewarding couple weeks in my graduate career.
• I don't have many photos relating to this project, but I have this one, which summarizes the era nicely. This was taken at about 4AM. Coffee in one hand, beer (unopened?) in the other. Cumulative sleep in the preceding 72 hours? Approximately 6 hours total. Structural assignment is great. And also terrible.

• Finally, we hit the conclusion. Both natural tryptorubin A (compound 1a in the published manuscript) and what we had made (compound 1b) had identical connectivity and point chirality, but were inside-out with respect to one another. Formally, this renders them 'non-canonical atropisomers'**
• We spent a lot of time thinking about how to communicate this isomerism most clearly, and our best efforts are represented with cartoon drawings in the paper, reproduced here:

• We of course still had to make the natural product. Luckily, a crystal structure (compound 7) in the paper gave us a big hint: The indoline's point chirality enforced a pro-atropisomeric conformation that only allowed the bicycle to close in one way. We're not the first to use point chirality to relay to atrop-control, but to our knowledge this is the first control of such a "right-side-in vs. inside-out" molecular shape in a natural product.
• We made the molecule, and everyone was happy. Well, I would be happy, except I haven't gotten my fricking molecule cake. Phil, I know you're reading this. Everyone who finishes a molecule gets a cake. Where's my cake? Cake please.
• Given the interesting structural nuances of this story, we desperately attempted to get solid-state structures of the respective isomers. I launched a collaboration with Hosea Nelson @ UCLA to try to do MicroED, and also with James Nowick @ UCI to try high-throughput crystallography screening, but unfortunately, never got any structures. So, we're still reliant on NMR for all conclusions.
• In parallel with finishing the synthesis, we were also lucky to tie in with the Clardy group who was further elucidating the biosynthesis of this molecule. That's an interesting story in itself, but not mine to tell -- the extremely short version is this molecule is a RiPP, not an NRPS as originally believed, and there is some very cool CYP machinery to close the necessary macrocycles. More to come on this side of the story, I hope.

Fundamentally, this is a synthesis paper that's not about synthesis -- it's about understanding molecular conformation and supramolecular isomerism, and about how we can control said isomerism in a flask. We hope it's an enjoyable read.

I want to close out by thanking the incredible team I was lucky to work with throughout this process, most notably Yang Gao, who is an all around killer chemist. Thanks also to Jon Clardy and his talented postdocs Allison, Eric, and Emily for being a pleasure to collaborate with. And Phil, of course, is an amazing boss to work with. Even when he forgets to buy cake.

Y. Gao (left) and S.H. Reisberg. The Baran lab student subset of the tryptorubin A team. 

                                                                            

*TANGENTIAL SIDEBAR #1: "Why the heck do we still do total synthesis in the modern era?"
I want to start this sidebar with the statement that opinions here (and throughout this blog post) are strictly my own and may not represent Phil or the lab's overall perspective. For Phil's opinion on the utility of total synthesis in a modern context, it's worth reading his recent perspective.

With that note, here is my hot take on total synthesis in the abstract. My viewpoint is that the goal of a total synthesis must be considered with intentionality, and that the total synthesis, once completed, should be scored against that intentionally-designed goal. In my view, any of the following are perfectly reasonable drivers of a synthesis:

• Scalable access to material is needed
• SAR of unnatural analogs needs to be probed
• The robustness of a method for a key step is being tested, and the synthetic target is simply an arbitrary vehicle on which to test a new methodology
• Drivers for new methods are desired, and the total synthesis is being pursued to illuminate "which bonds are difficult to make with existing methods" with the explicit plan of spinning out new methods projects
• Blind faith that with structural complexity comes chemical insight, and that some serendipitous discovery occurs
• Sheer aesthetic work (directly analogous to a concert violinist's profession; creating beauty for the sake of creating beauty)

I feel that synthesis done under any of these umbrellas is useful. The problems start to arise when the declared goal is not actually enabled in the synthesis. It drives me up a wall when people introduce synthesis as 'a tool to make scalable amounts of material' and then make <1 mg. Because, at that point, you're not actually progressing solutions to the problem you're trying to solve. Likewise, if someone has a declared goal of exploring SAR, and subsequently make a single analog, it amounts to snakeoil salesmanship.  These kinds of farces are where the field bears risk for stagnation.

So, I encourage everyone considering a synthesis to spend some deep introspection asking, "Why should I make this molecule," and subsequently throughout the project enforcing that all strategic decisions are well-aligned with the answer to that 'why.' 

                                                                            

**TANGENTIAL SIDEBAR #2: "What's in a name?"

One issue that is worth discussing is the complexity around naming the isomeric relationship between 1a and 1b. The easy layman's explanation that 'one is inside-out relative to the other' is somewhat difficult to translate into formal language. Originally (i.e., before the peer review process), we referred to these compounds as topoisomers. If you poke around for the formal definition of topoisomer, the two definitions that pop up are "two compounds with identical connectivity but non-identical molecular graphs" and "two compounds with identical connectivity and point chirality, but that can only be interconverted via scission and reformation of bonds." Now, according to the former definition, 1a and 1b are definitely not topoisomers. According to the latter definition, things begin to get a little hairy, because if one ignores the physical limitations of bond lengths, 1a and 1b can interconvert (see Figure 4), but it's a very unphysical transformation.

However, a very thoughtful reviewer (thanks!) was kind enough to point out that physicality should be ignored in the topoisomer definition, and thus we can't think of 1a and 1b as topoisomers. For this reason, they should actually be called atropisomers. This risks swinging too far in the other direction, though: 1a and 1b's isomerism ('inside out') is categorically different from a prototypical atropisomer (e.g., binaphthyl) -- tryptorubin's isomerism has way more going on than simple sigma bond torsion.

To give a sense of just how confusing all this nomenclature can be, we decided to run a small social experiment. Phil tweeted a poll about lasso peptide isomerism:

Now, before we view the results of this poll, note that lasso peptides are just like tryptorubin: They are formally topologically trivial, but have a very defined set of shape-based isomers. 

Go to twitter to read some of the fascinating commentary, but the short version is this: Even Twitter experts (people with the doctoral degree TweeHD?) have diverse and contradictory views on what this isomerism should be called. 

Combining all of this, we coined the term 'non-canonical atropisomerism' to encapsulate tryptorubin's (and, for that matter, lasso peptides') shape-based isomerism. For me, the upshot of the entire nomenclature story is a classic 'a rose by any other name would smell as sweet' -- what we call the isomerism basically doesn't matter; the important part is that it's communicated clearly, and hopefully the manuscript (and especially structural graphics) make everything comprehensible.

Decarboxylative etherification

Our most recent work in electrochemistry was published today: A method to make hindered ether compounds from abundant carboxylic acids. Given the extensive information in the >400 pages of SI, we are not going through the details of the work in this blog post, but instead decided to present some details from behind the scenes.

As a project that required massive work, you might be wondering how it got started. Actually, Phil always got the consulting question that how to construct hindered ether bonds effectively from the pharmaceutical industry because they are quite important in drug discovery. It surprised us that in the 21st century, people still rely on acid promoted hydroalkoxylation to make such bonds, which often fails in the real-world cases due to a lack of chemoselectivity and sluggish reactivity. Being aware of this, we decided to tackle this problem.

By digging into the literature, we found an interesting reaction called the Hofer-Moest reaction which has a >100-year old history. This reaction enables generation of carbocations that can be intercepted by solvent quantities of alcohol to form the ether products. Without even understanding the details in the original paper published in 1902 (written in German), we started our journey towards the hindered ether synthesis. Carefully studying the follow up literature, we found this reaction is extremely limited in terms of the scope of both carboxylic acids and alcohols. In order to develop a practical method that can be used by the industry, we thought the key was to find a suitable solvent and electrolyte that enabled us avoiding use solvent amount of alcohol. After extensive evaluation (>1000 experiments), we identified a new set of conditions for this old chemistry. To make a long story short, here is an example of just how simplifying this chemistry is, in the context of synthesis of biologically active intermediates. Using compound 1 which is an intermediate of aurora kinase modulator as an example, previously, a multi-step route was employed requiring over 6 days of reaction time (<4% overall yield), wherein the key C–O bond-forming reaction—the treatment of methylenecyclobutane with BF3•Et2O—provides the ether in only 11% yield. Now with our electrochemical method, it can be accessed in only 2 steps, 51% yield and most impressively 15h.

While we think the step-count and time savings largely speak for themselves, our colleagues who are industrial process chemists are much more rigorous about efficiency characterization.

Process chemists tend to use “PMI,” or Process Mass Intensity, as a quantitative measure of a synthetic route’s efficiency. Our friends at BMS have conveniently developed an app, the “PMI Prediction Calculator” (Click here to play with the app yourself), that enables people quickly to know the efficiency and PMI of a certain process. We used this app to calculate the PMI of the old vs. new route to 1. The result: Our route to synthesis of compound 1 has a PMI of 252, versus 1304 for the previous one. This result clearly demonstrates the high efficiency, robustness and greenness of our new method.

Ideality is another way to quantify the parameters of efficiency for a synthetic sequence. We calculated the ideality% for the 12 real-word applications based on the definition published a few years ago (this paper). Amazingly, for 9 examples, the current methods have an ideality of 100% which are much higher than the reported routes.

Lastly, it is a tradition for our lab to showcase the limitations of the methodology that we have developed, to give the readers a better understanding of the reaction. Some of the limitations for the decarboxylative etherification and hydroxylation are shown below. In general, the secondary acids without any stabilizing effect such as benzyl or hetero atom will be problematic for this etherification reaction, due to the relatively instability of the corresponding carbocations. We hope this may be helpful for those who decide to try this reaction on similar substrates.

Let us know if you have any questions or comments regarding the work! Thanks for reading!

Ming, Jinbao and the etherification team

Cyclofeign?

We came across an interesting compound in Natural Product Reports Hot off the Press today:

 This rather precarious-looking [3.2.2] bicyclic compound was originally isolated from Bacillus sp., in a 2015 report, and the same compound was re-isolated separately from Melocanna baccifera in a new 2018 publication. Curious about this unique structure, we did what any good chemist would do, and attempted to build a model of it. After breaking some plastic we quickly realized that this compound, if it existed, would have to adopt a bent-arene conformation wherein the pi-system of the arene is bent out of conjugation (see haouamine for an example of a real cyclophane that exhibits this behavior).

 Seeming to contradict this unconjugated structure were the reported 13C NMR shifts (published earlier by Zeng et al), which were within the expected range of an unstrained para-substituted phenol. Additionally, the reported HMBC data reported by Zeng and coworkers lacked any correlations spanning across the supposed ethereal oxygen (e.g., between C-5 and H-3), which would have provided key evidence for the bicyclic structure. The reported mass [M+H] = 121.0645 is consistent with an [M+H] ion of the disclosed structure; however, it would also be consistent with an [M - H2O] ion from 4-hydroxyphenethyl alcohol…

Fortunately, we had a bottle of the latter compound hanging around the lab. A quick NMR confirmed our suspicions – the proton and carbon chemical shift data (see below) for this primary alcohol are exactly the same as those reported by the authors for the "bicyclic" compound. Furthermore, after shooting our commercial material on the LCMS we observed a major ion peak at 121.1 ([M - H2O]), with none of the 139.0754 one would expect for M+H of 4-hydroxyphenethyl alcohol. (EDIT: A kind reader pointed out to us that the much larger peak observed at 107.1 corresponds to [M - MeOH], via C-C bond homolysis to give the benzylic radical cation)

Further, a careful observer of the MS data could have known this off-the-bat: In the 2018 report, the authors ionize the compound on negative mode, and see a large peak at 137.06, corresponding to [M-H] of the (correctly assigned) compound.

Here's our data for commercial 4-hydroxyphenethyl alcohol:

We thus reassign the proposed structure to the much simpler 4-hydroxyphenethyl alcohol.

Our conclusion? If something looks really unusual, check all the reasonable hypotheses before you propose something exotic. Sometimes, things are zebras, but if you hear hoofbeats...it's probably a horse.

– Kyle M. and Sol

You heard it here first

La Jolla, California -- Sources close to Professor Phil "Strongman" Baran inform us that he his quietly announced his surprise early retirement. Says Baran, "I'm really tired of organic chemistry, and want to move forward in pursuing my passion project -- artisanal organic free-range grass-fed bodybuilding supplements. Given the immense responsibility of running an ethically-sourced supplement company, I just can't juggle being a PI any more."

Analysts at BBT (Baran Bodybuilding Technologies) announce their excitement about the newly-developed supplements: "We've developed a secret formula that maximizes development of so-called vanity muscles (pecs, biceps, and abs), while minimizing any undesired hypertrophy of annoying functional muscles (e.g., quads). Finally practitioners can achieve that 'ripped-torso, chicken-legs' look that everyone strives for."

Baran doesn't have an estimate of when his product will go to market, saying, "I've got to graduate all these pesky PhD candidates in my lab first. Then, the real work can begin."

You heard it here first, folks.

Happy April 1.

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