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 sp3 carbons), 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!

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 2007, 63, 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 1987, 235, 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

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

Radicals can DELiver for DEL

You may have noticed that our work on sp³-sp³C-C coupling for DNA encoded library (DEL) synthesis was deposited on Chemrxiv about two months ago. Recently, we found a nice home for this DEL-related work. I am not talking about the keyboard.

It’s out in PNAS today. While the paper offered a detailed account of mechanistic work by the Blackmond lab alongside an assortment of working substrates, I would like to share with you some behind-the-scene stories of this “non-traditional” project. 

In a nutshell, this project can be likened to our effort to “radicalize” DEL synthesis. It all started in 2017 when our long-time industrial collaborator, Pfizer, approached us for ideas on new reaction manifolds for DEL synthesis. We learned about the stringent requirements for DEL prior to putting together a substantive proposal: 

First, a "DEL-able" reaction requires, inter alia, reagents and conditions which are compatible with DNA. We had our in-house biology expert do a group meeting on DNA chemistry – a universal verdict from his presentation appears to be that, despite thousands of years of revolution, our DNA is chemically fragile – a vast majority of reagents under the sun (or even the sun itself) can cause troubles. Second, a DEL reaction requires a solvent system comprising >20% water. While life subsists on water, to most organic reactions, irrigation breeds irreversible damages: 

 Third, the reaction temperature must not exceed 90 ^oC and the reaction pH must stay within the comfort zone of 4-14. Most dauntingly, the reaction concentration must be below 1mM. 

After some deliberations, we decided that perhaps radical reactions are well suited for DEL – after all, radicals are generally moisture insensitive and chemoselective (over the years we have run such reactions in many unconventional solvents). Toward this end, our lab has a long-standing interest in the radical decarboxylative cross-coupling reactions of carboxylic acids using nickel catalysis. Methods have been developed to forge carbon-carbon and carbon-heteroatom bonds. More promisingly, these reactions were compatible with solid-phase peptide synthesis. To a chemist like me, all biomolecules are perhaps equal (thus, there is a likelihood our technology will translate from peptide to DNA). (I soon learned that some biomolecules were more equal than others…). Pfizer showed strong interest in this project as it could offer access to the much desired sp³-rich space, a promised-land in the realm of DEL chemistry. Thus, the project was initiated…   

Since I have given a group meeting on “Reactions in the Presence of Water” in June of 2016, I was perhaps considered a more “hydrophilic” individual than any other lab members. Thus, I was charged with this project. Maybe destiny brought me here.

It didn’t take me too long to settle on the decarboxylative Giese reaction as the focus of the study. We started to evaluate the feasibility on small molecules at first. I was soon baffled by a seemingly trivial problem: how do I determine product yields when my reaction is 1 mM in water? NMR analysis regularly gave >100% yields (who needs conservation of mass/energy, right?). In a desperate move, I even tried to isolate the products, once obtaining 11 mg of products out of hundreds of milliliters of solvents! 

Jason came to the rescue here -- he built up the ‘Automated Synthesis Facility’ here at Scripps in 2017 and brought the analysis up to speed. I can easily get 20 reactions analyzed within an hour. More importantly, no workup was needed at all. To cheer my spirit even further, I was joined by Helena Lundberg, a really talented postdoc from the Blackmond lab. She provided extensive mechanistic insights through her kinetic studies that also provide a general protocol for converting organic reactions into DEL-compatible counterparts. With her help, we were able to get >70% yield which set the stage for evaluating functional group tolerance as well as translating to on-DNA synthesis. 

Then I was joined by another two talented chemists, Shota and Pedro, both of whom hail from a “hydrophilic” locale (Japan and La Laguna, Spain). With their help, we were able to evaluate all sorts of functional groups (thanks to Pfizer team providing suggestions and carboxylic acids) – gratifyingly, most of them were tolerated under the reaction conditions.  

However, our happiness was “ephemeral”. Our mock-DEL conditions were found to be incompatible with DNA molecules. For 8 months, we begrudgingly awaited the advent of another superhero. This time round, it was Dr. Stephen Brown, a brilliant Pfizer scientist, who discovered that by diluting the reaction by yet another order of magnitude and using DMSO as a co-solvent, the reaction worked nicely on DNA, providing the product in 40% yield. Starting from this, I was able to optimize further and demonstrate this transformation with 22 on-DNA examples.

As a historically organic synthesis-based lab, we are not equipped with any instrumentation for DNA synthesis. Thus, we are indebted to the generosity of other TSRI labs (e.g., the Romesberg lab) and Pfizer (both La Jolla and Groton) for helping us with much of the analysis.  We are also grateful to LGC for a great deal on the DNA headpiece starting materials. Our creativity also evolved during the study. For reactions that require inert atmosphere, we put the Eppendorf into a test tube and exchanged with argon. Since a stir bar is usually not an option in DEL synthesis, we bound the Eppendorf to a rotavapor and let them rotate together (inspired by Lara). For reactions that require heating, we wrap the Eppendorf with parafilm and aluminum foil, bind with a sinker and put them together into an oil bath (mimic the role of thermocycler). Fortunately, Phil didn’t ask me to demonstrate a gram-scale synthesis this time.

Doing DNA chemistry in a synthetic lab can be rather painful, especially at the very beginning. We constantly change our substrate in order to better mimic DNA functionalities as well as obtain good LC separation [LC traces could be unbelievably messy when we were using super stoichiometric reagents (>100 eq is very common in DEL)]. Setup, analysis, purification… each step seems to pose problems. Moreover, on such small scales, it is challenging to diagnose problems, let alone solve them. During the dark times, I was jealous of my colleagues – as they are able to “concentrate” on their hydrophobic transformations while I constantly battled the consequences of “low concentration” and water. Nevertheless, ultimately, I find this experience greatly fulfilling and the final protocol was reproducible and reliable. It is always a satisfying learning experience when working with a team of dedicated and talented scientists. In this case, I particularly relished collaborating with a number of brilliant people withvarying areas of expertise. The science shown in this recent publication is the result of a collaboration among Baran lab, Blackmond lab, Scripps Automated Synthesis Facility, Pfizer La Jolla and Pfizer Groton. I would like to express my heart-felt gratitude to all of them!

Lastly, I hope our DNA chemistry would one day translate into an NDA of your research program… (Special thanks to Dr. Ming Yan for linguistic suggestions and contributing to the jokes here.)

Feel free to let us know if there are any questions you may have! Thanks for reading.

Jie

Pyrone Diterpenoids: A Not-So-Boring Journey 4 Years in the Making

Today, our work on the synthesis of natural products from alpha-pyrone diterpene family is out in JACS. While the paper details our final approach to these compounds, I would like to share the behind the scenes journey towards these molecules. Some of you may recognize that this topic was presented by Phil during his DOC lecture last month.

In the summer of 2014, our long time industrial collaborators  at LEO Pharma asked our lab to synthesize subglutinols A and B due to their reported immunosuppressive properties and potential as therapeutics. At that time, Kevin (postdoc in the lab and now a medicinal chemist at Eli Lilly) and I were charged with accessing these natural products in a concise and divergent manner. Assuming that Suzuki cross-couplings are always supposed to work (perhaps naively), we wanted to append the pyrone to the terpene skeleton via a cross-coupling strategy. To cut a long story short, after 8 months of starting the project (see SI for failures to this intermediate), we prepared the substrate to try our key step. However, it won’t be a good story (only in hindsight) without a catastrophe. Although “borono-subglutinol” could be cross-coupled with simple coupling partners like bromobenzene, the coupling never worked with the required bromo-pyrone, and we spent another 9 months trying to install the pyrone. However, all our efforts with met with spectacular failure. 

With the project in shambles, we decided to come up with a boring route (as Phil calls it) to prepare the natural product so that LEO could do the biological studies. We could in fact synthesize subglutinol A in 25 steps (detailed in the SI), and the natural product was delivered to LEO. Based on our “boring” route, we identified the following key limitations; (1) It took 5 steps to install 5 out of the 6 stereocenters on the molecule (including the core and subglutinol A THF ring) but 16 steps to install 1 stereocenter (C4 stereochemistry) as well as the pyrone; (2) While we had a way to access both subglutinol A and B THF rings selectively, the divergence occurred fairly early on in the sequence, and we wanted to delay this as much as possible; (3) We had a material throughput problem – the polyene cyclization required 3 grams of Mn(OAc)₃and 1 gram of Cu(OAc)₂for every gram of SM which resulted in purification nightmares!!

I won’t go into detail about how we ended up solving each of these problems ,but the key highlights are:

(1)For the polyene cyclization, electrochemistry allowed us to reoxidize Mn(II) to Mn(III) during the course of the reaction, making the reaction catalytic in Mn salts and resulting in a much simpler workup procedure.

(2)To fix the other problems, we came up with a “revised retrosynthesis”. So far, the sterically hindered C18 methyl group and diortho substituted pyrone had been the bane of my existence. We decided to kill two birds with one stone via a more radical disconnection. Disconnecting C4–C20 bond would allow us to use the sterics of C18 methyl group to our advantage (blocking the top face of the molecule). With regards to the late divergence to access both subglutinols A and B, we believed that under radical cross-coupling conditions, the C12 stereochemistry could be inverted through a stereoablative radical intermediate from a more sterically hindered cis THF ring of subglutinol A to a more stable trans THF ring of subglutinol B. However, the core of the molecule that we could easily access had an extra carbon at both the C12 and C4 position. One way to burn off a carbon to generate an alkyl radical was to perform a decarboxylation transform! This was helped by the fact that our lab was working decarboxylation cross-couplings at the same time and therefore, we thought this would be a good opportunity to develop decarboxylative Giese and alkenylation transformations.

To cut a long story short, we went on to develop a general decarboxylative Giese and alkenylation transformations of redox-active esters, and they could be implemented to the synthesis of subglutinols A and B. Eventually, we could also demonstrate our “revised retrosynthesis template” to prepare sesquicillin A and finish the first total synthesis of higginsianin A. We considered this a less-boring route, but not as exciting as this kind of boring. 

I have been on this project for the past 4 years, and while there have been a lot of ups and downs (definitely more downs), we did eventually reach our desitination! I just want to give a shout out to two extremely talented visiting students, Alex Novak and Yutong Lin, as well as thank our collaborators at LEO for their patience. If you have any questions about the chemistry or natural products themselves, please let us know! Thanks for reading!!

Rohan