Palau’amine
Baran, Seiple, Su, Young, Lewis and Yamaguchi. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200907112. 
Y’know, I was kinda hoping for a bit of break between blog-posts this winter, as the amount of online publications tends to tail-off around the year-end. However, not only have the publications been thick-’n'-fast (got quite a lot of material to get through), but up pops palau’amine. I really did think that Angewandte would hold-off until sometime in early 2010, but here it is – and it lives up to Baran’s reputation. I mean that in every sense, as in some ways there’s a slight dissapointment, as he has a way of making the synthesis look to obivious, too easy. However, it was undoubtedly a challenge; Baran states that ‘the synthesis of palau’amine has thus far eluded organic chemists despite the dozens of Ph.D. theses… Many well-founded and logical plans to secure the peculiar trans-5,5 core of [palau'amine] in our laboratory resulted in unfortunate outcomes‘. This goes some-way to explaining the brevity of this blog post, but I intend to follow-up this post with a quick review of other routes that have been attempted in other labs.
Cutting to the chase, the problem with palau’amine has always been the 5,5′-fused system. For about ten years, this was thought to be in a cisoid-configuration, but a recent publication by Baran and Kock reconfigured this as trans. This both helped and hindered synthesis, as whilst trans-5,5′-fused systems are more difficult to make, it brought the target far closer to that of it’s siblings, such as the axinellamines (more on that soon). Anyway, on with the synthesis of our favourite apostrophied natural product.
The starting point to the chemistry should be familiar to regular readers – hark back to Baran’s 2007 synthesis of the axinellamines, and a familiar intermediate crops up. Using very similar chemistry to that used in the earlier synthesis, Baran’s first move was to install the sole hydroxyl group using silver(II)-picolinate. This stereo- and chemoselective transformation targets only the secondary amine, and remains un-molested in the subsequent synthesis. From there, building a second 2-aminoimidazole was done by simply adding cyanamide in brine – rationalised by the propensity in other solvents for the secondary chloride to be displaced. Presumably have a load of chloride ions in solutions favours the desired side of that equilibrium. Bromination of the new aminoimidazole provided a functional handle for the next fragment coupling – a masked pyrrole synthesis. Estchewing more modern methods using palladium (which failed when attempted) to perform a direct coupling, Baran did an alkylation to complete the C-N linkage, followed by a series of acid-mediate methanol eliminations to give the aromatic heterocycle, conveniently with the free acid functional group.
Next up, and completing the synthesis (!!!) are the final three reactions. A bit of hydrogenation using palladium acetate – conditions new to me – in a hydrogen atmosphere reduced the azide groups to a pair of primary amines. Treatment of the amino-acid system with a bit of EDC/HOBt formed a macrolactone, presumably favouring the nine-member ring over the ten. This macrocycle, dubbed ‘macro-palau’amine‘ by Baran was the key to his synthesis, as the addition of a bit of acid promoted a transannular cyclisation between amide-nitrogen N-14 and imine C-10. Astoundingly, this reaction was selective for the trans-configured 5,5′-fused system, and thereby completed the synthesis of palau’amine.
Now that’s a damn nice piece of work. But I’m eagerly waiting for the full paper, which I’m sure will put this synthesis in context, as then we’ll have a better idea of what didn’t work. That is perhaps the legacy of palau’amine – confounded logic, and ultimately the triumph of human endeavour. So what’s next?
(34 votes, average: 4.47 out of 5)
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awe-inspiring. every single step in this paper is a jaw-dropper.
Baron continues to make total synthesis relevant as both science and art. I’m an unabashed fan of that man’s prowess.
iawtc. awesome work.
Unreal, the man takes down vinigrol and palau’amine in the same year. What a monster. Incredible, I’m sure this will be but a footnote in his Nobel Laureate speach.
So, what’s the next hot target in total synthesis?
Maeocrystal?
……. and he will ad one more milestone in Noble Laureate history “Youngest Noble Laureate”.
Relevance, maybe?
all known reactions, how much did they make for biological testing?
Which reaction is known Ian? I can’t find any of them in scifinder except cyanamide to make an aminoimidazole.
Bioactivity? Do they need to publish that in this communication?
how many Ph’Ds for half a Milligram – lets hope it goes to the right people
Read the last line of the paper. Give baran bros a year and they’ll shower you with material (eg haouamine).
and sent to the relevant biologists I hope
NIH?
yeah, just read the paper… damn nice work!
seems to be his favorite reagent …
interestingly in all but one step he uses TFA
can’t wait to see the full account
…and fluorine his favorite element.XeF2, CF3COOH,
I have a sad feeling that big and extremely powerful titans are racing through the world trying to find something or somebody they can defeat. They are very eager to find and often fighting with each other for the prey – just to prove for the rest of the world that they are the best – nobody doubted indeed for a long time already.
and then there are those heroes of total synthesis who are more like Ernest Shackleton…
impressive. as always.
I had the privilege of hearing Phil give a talk at our university when I was a grad student. At the time he had just completed Stephacidin B and was working towards the protecting group free synthesis of Sceptrin. There weren’t a ton of guys that impressed me at our seminars, but he and Jef DeBrabander I will never forget.
Download the SI. Lots of goodies in there. So well done!
RIP Eugene von Tamelen
Great achievement! He completed an impossible work which was tried by L.E.Overmann for more than a decade!
Baran is off the hook! He is so pimp!
Shocking story. Impressive that they pursued what they thought the natural product was rather than what was reported by scheur and what everyone else was working on. Also, macropalauamine is not just brilliant, it’s scary.
Agreed with the above. The macro-intermediate is just off the charts, and alone places Baran is rarified territory. It is not just non-obvious, it is totally counter intuitive on many levels, and shows that Baran is thinking about things in ways totally beyond anyone else in the field. I don’t know of any other set of interconnected syntheses where each was a piece of the overall puzzle. Staggering.
While this synthesis is stunning, the idea of using a macrocyclization to construct the phakellin-like fragment was proposed ten years ago by Al-Mourabit and Potier (TL 1999, 40, 5519 – sorry no DOI). Also, didn’t DuBois use a macrocycle in a synthesis of saxitoxin?
Sorry – hit submit before finishing. Of course proposing and executing a strategy, particularly with something as elaborate as macropalau’amine, are two different things.
Everyone interested should read that paper and all of potier/mouribit’s other papers. This team is famous for publishing countless ideas and disconnections but doing nothing actually useful or important. This is not chemistry – to write all possible disconnections of a molecule and have any claim to anything. Dubois uses a macrocycle to make saxitoxin in a completely different context. I suppose since macrocycles in general are known that nothing is new – but that is nonsense.
My guess is that Tex = someone in texas that got scooped (romo?).
The response to Jose was simply to point out that the idea had been proposed (but not executed), and so others in the field have thought about the idea. And while Dubois’ saxitoxin chemistry is different, a transannular reaction is used to form the natural product ring system.
There was no intent to criticize the chemistry – it is simply stunning, it was the notion that nobody had thought of this type of strategy previously.
As far as the Al-Mourabit/Potier group is concerned, they have published a number of proposal-type papers, but they have also published several nice papers, including some of the earliest total syntheses in this area (only oroidin monomers I believe).
Not Romo
I am just glad guys like this exist in our field
Great stuff
10 years ago the field was all over Andrew Myers
He is still awesome!!
Lets also keep Movassaghi into perspective. That guy is kick-a$$!
And don’t forget sorensen, dubois, harran, and brabander. Might as well list everyone if your gonna mention movasagi.
Sorensen publishes nothing.
10 post-docs and 1 org lett in 2 years?
I like Steven L. Castle work
Incredible piece of work. Using TFA to promote the final stereoselective cyclization, and at the same time circumvent the known instability of Palau’amine in neutral and basic media, is just brilliant.
Can anyone help explain how the Ag(II) step works? Does the water attack an imine intermediate? Can’t seem to piece together the mechanism for that oxidation step. Thanks.
For the silver oxidation, there are two reasonable mechanisms. 1) single electron transfer to oxidize to the imine, which is then intercepted by a water molecule 2) the N attacks the silver picolinate and then the imine is formed by deprotonation forming the imine and kicking off silver 0, and the imine is then hydroxylated.
Thanks TLC.
Is everyone stunned into silence? Sheesh. I assumed this would be a hive of activity this morning!
Well right about now someone asks why synthesis is important or if the paper is worthy of the journal or general hateful remarks. So we still have to go through that. Perhaps later today? Or maybe someone can focus on science and answer bokChoi’s question.
Ian already started with some sour grapes earlier, but it seems the bait wasn’t tantalizing enough for anyone.
Way to groupthink.
So just to keep the conversation going, can anyone in simple words explain why “the problem with palau’amine has always been the 5,5?-fused system”? There are many spiro compounds out there, what is so special about palau’amine?
for years it was thought the relationship of the 5,5 system was cis, but then it was reassigned to be trans. the cis system gave people fits for years. i think the trans system has its issues as well, but didn’t remain an unmet challenge for as long. the degree of substitution of the cyclopentane in either arrangement is a major challenge.
The ironic thing is that the trans system is far more strained than the cis. so the revision made things worse for synthesis people.
The structural re-assignment involved more than switching the cis to the trans [5,5] system. For example, the chloride stereochemistry was also inverted. Consequently in the original assignment, one essentially has a cyclopentane core where the alpha face is fully substituted. As Carreira and Starr would no doubt attest, this stereochemical arrangement is highly prone to epimierization. So, I wouldn’t say the revision made the problem more difficult… both targets have their unique challenges.
spiro is very different from fused
If Nicolaou ever gets around to Classics Vol. 3, it’s gonna be a Baran highlight reel.
He’s visiting our dept soon so I hope we get to hear about this.
Are you at UMN?! He’s coming here in March; I can’t wait!
no. dont know where UMN is?
It’s a google search away… fool…
Actually, the second volume of “Classics” already contains 2 Baran syntheses (CP-molecules and okaramine N). The first was done in Nicolaou’s group during Baran PhD studies, the second – in Corey’s lab as a postdoc.
Moreover, Nicolaou chose okaramine N synthesis as the central one in this volume.
Baran #1
Atep Nurdjaman #1
WTF is going on here? Check out the website hot-linked by Fungus – to quote:
“The Title of Me is: Good Job-Researcher at Harvard University-USA, United States of America,
Excellent,
Professor of Professor in Study of Fullerenes,
Professor of Professor in Study of Nanotubes, I am Foreign Prof. Professor (2 Professor of Professor, both each is Professor of Professor in Study of Fullerenes and Professor of Professor in Study of Nanotubes) that gived by do Nobel Foundation in September 25, Year 2007 and got approval on behalf of the Organic Chemistry by do Professor. Dr. Abdel-Sattar S. Hamad Elgazwy, The Professor(A) of Organic Chemistry, and also as representative of all of staff The Department of Chemistry in Faculty of Science, in Ain Shams University , in Cairo , Egypt . Beside that I am Nobel Laureate who got 6 (six) Nobel Prize in Chemistry 2007 Without Prize (Note: without prize of money, only name and proud and also dignities as the winner), unofficially announce to peoples only to researchers in around the world who the best in field of organic chemistry and related. I am Good Job-Researcher also.”
Islamic version of Borat!
Talk about well-rounded! 6 Nobel prizes in 2007? This guy is not only a master chemist and physician, but also grand king literary scholar and economist! Keep him away from my job pool, I can only handle so much competition.
awesome… his degree is DR(tm) and he works for THE RAN Institute?
too lol!
This synthesis is really an impressive piece of work! Can’t wait to see the full paper to get to understand how they ended up with what they did in the end!
But guys: there is no way anyone will ever get a nobel price for total synthetic work these days. It’s sad, but that’s the way it is…
I was thinking the same thing, but didn’t say it ‘cuz it’s not unprecedented. There’s clear dominance of methodology in terms of organic chem prizes, and with biologists now winning the chemistry prize the competition is even more stiff.
Nonetheless, the description of Woodward’s prize could also be easily applied to Baran.
one could say the same for all the x-ray crystal prizes.
woodward didn’t care about practical syntheses, just pretty ones. Give baran some time. agreed the odds are not great. But, he’s only 32.
Hyperforin has been finished too.
What compounds are now left to make? (maitotoxin aside)
Who finished hyperforin? It looks like a Porco molecule…
Shibasaki
Has Shibasaki published yet?
Also in regards to this total synthesis, it is really good, especially because some of these intermediates must have been a bitch to handle. Seriously, having to always think how the hell you are going to purify an extremely polar compound (sometimes hellishly water soluble) without having to use HPLC can be such a downer.
I look forward to see what else he does in the future. Perhaps his expertise could be offered towards work in non-total synthesis related (long standing) problems that exist. I think Baran is proving quite rapidly that no molecule will be resistant to the endeavours of total synthetic chemists if carefully planned and executed…..except for maitotoxin (I just wouldn’t bother with it).
there it is… ACIE early view
Staggering amount of work for that synthesis. If you include the synthesis of the diene portion, a whopping 49 steps!
Has Shibasaki published yet?
Also in regards to this total synthesis, it is really good, especially because some of these intermediates must have been a bitch to handle. Seriously, having to always think how the hell you are going to purify an extremely polar compound (sometimes hellishly water soluble) without having to use HPLC can be such a downer.
I look forward to see what else he does in the future. Perhaps his expertise could be offered towards work in non-total synthesis related (long standing) problems that exist. I think Baran is proving quite rapidly that no molecule will be resistant to the endeavours of total synthetic chemists if carefully planned and executed…..except for maitotoxin (I just wouldn’t bother with it).
The purification of highly polar compounds just requires a different skill set than ~typical~ organics. Instead of silica, use ion-exchange and size exclusion chromatography using methanol/ethanol/water (with perhaps a drop of apolar solvent) mixtures, following by lyophilization of the solvents – major downside is that columns need to be long (6+ feet sometimes for ~500 mg product) and you can’t exert downward pressure via forced air or gas, and sometimes need to be run multiple times. A robot that automatically moves the receiving flasks is a must.
Take it from a guy who spent his senior undergraduate year isolating palau’amine from the sponge. I wonder how many of the folks who tried to make it reached out to Kinnel/Scheuer for their accumulated expertise on the behavior of the compound. When I was in grad school I had lunch with a very well known synthesis guy who had come for a lecture, he said his lab was working on palau’amine. I mentioned my undergrad work; he was openly dismissive of Kinnel as someone who was “only at a undergrad college” and couldn’t possibly contribute. Needless to say, I’ve not seen any publications from him on the compound…
Ha ha! It’s been my experience that total synthetic people and natural products people often clash, despite the seemingly obvious fact that they can form productive collaborations if they would just put their respective egos aside. God forbid an organic chemist should do that though, right?
Well, now I kinda want them to do the cisoid version of it. Since it took everyone so much and ruined so many postgrad student´s lives!!
Unlike Baran and his coworkers, I wasn’t brilliant nor careful enough to catch the errors made in the original structure assignment and was part of a team that went after the “cis-oid” version of Palau’amine. Although those years were difficult and all the approaches we tried ultimately ended in tears, I still wouldn’t say it ruined my life. As long as one does not define one’s self-worth strictly on the successes (or failures) in the lab, a doomed route (or many doomed routes) can still be a good learning experience. Of course it did help that my supervisor at the time did not needlessly abuse me because we failed to make Palau’amine. That said, I too would love to see a synthesis of the original assigned structure of Palau’amine
I don’t see how a total synthesis chemist could ever win the Nobel Price. From a state of the art organic synthesis point of view Baran’s stuff is amazing but sadly, unless they solve any serious medical problem or unless he develops a general synthetic method he will never shake the hand of the Swedish King…
See: Robert Woodward, Nobel 1965.
but , that was 1965…the field was vastly different then, agreed?
Yes. I was pointing out that it’s not unheard of. Just extremely rare. I also doubt that Phil will ever win it for the reasons everyone else has stated, doing total synthesis doesn’t necessarily revolutionize the chemical landscape (although discoveries in the course of total synthesis can lead to that). He does have some great ideas like the paper he wrote about minimizing redox operations throughout a total synthesis, but who knows how much that will alter the landscape.
I’m on board the Evans bandwagon. Mainly, I’ll be happy if biochemists/biologists don’t get the chemistry Nobel next year.
thats the prize you pay
Yes Wooward obtained it in 1965. That’s quite long ago. Phil Baran’s parents weren’t even born then. Even so, the compunds Woodward synthesized in the 40′s-50′s were (amongst others) Quinine, Cortisone, Reserpine, Cholesterol. Compounds which made a huge medicinal impact in those days. And still do.
Nevertheless, Baran has obviously great skills in synthetic organic chemistry and if he in future uses his chemistry skills to build something humanity can benefit from, then sure he would and should be a Nobel Prize candidate.
/start rant/
That’s nonsense – none of the compounds RBW made were ever put into a human or likely even subjected to a biological test – all of them were available in large quantity from natural sources. The medicinal use of the actual compounds he made had no impact on the prize
RBW won the prize, imo, because he showed that humans could in fact produce the same complex compounds as nature, a triumph, so to speak, of man over nature
EJC won the prize, in addition to his numerous contributions to methodology, for making total synthesis a more rational discipline, wherein retrosynthetic analysis could replace the flashes of brillance that previously characterized total synthesis. (whether ejc invented retrosynthesis is up for debate, he certainly popularized it)
The reason KCN will never win the prize, imo, is because while he has made amazingly complex compounds, he has not really precipitated a sea-change in the way people perform and perceive organic chemistry. If a total synthesis guy is going to win anytime soon, my bet would be dave evans, not only for his total synthesis work, but also for his chiral auxiliary and later py-box work. (sadly he missed the train on the sharpless/knowles/noyori prize)
In order for Baran to win, simply on virtue of total synthesis, he would have to devise general ways to make complex compounds in large scale economically – not unlike what amos smith is trying. but instead of simply picking a target and optimizing the hell out the route, baran would need to develop a technique which could be applied across a large landscape of compounds.
of course, the end result (large quantity of compound in economical manner), is also possible via synthetic biology and genetically engineered organisms. I’d put my money on that horse.
/end rant/
in the end, this is all trite – baran doesn’t need a nobel prize to validate the fact that he is doing amazing work.
Agreed with the above
Nobel prizes are not going to get given for throwing 98 postdocs at a project just to finish a compound first
… Phil Baran’s parents were less than 12 when he was born?
I guess it could be physiologically possible, but I’m skeptical.
@ TotSyn:
I guess I could be confused but when you say “this reaction was selective for the trans-configured 5,5?-fused system”, what exactly do you mean? For me, I fail to see how this reaction has anything to do with controlling the configuration of the 5,5′-fused system. The trans-stereochemistry was set long before any ring closures (i.e. in cmpd 7). Indeed, the macrocycle is a trans-9,5 system, and during ring closure, the stereochemistry at that particular juncture cannot be altered.
I think what is most intriguing about this macrocycle strategy in general is that imo it seems to be a more plausible biosynthetically. If you consider that in the vast majority of X,5-fused ring systems, the trans isomer is generally favored, it doesn’t seem all that far-fetched that nature may be starting from a macrolactam.
The man deserves all the accolades that he’ll have coming his way…
And I, for one, think that he has already developed a strong enough methodology to warrant consideration for a future Nobel Prize…
He’s picking out the toughest molecules to synthesize using standard syn. org. based on their inherent “naked”/unprotected reactivity. After all, these molecules have to come together somehow in nature! And granted, the protein environment has the ability to activate/protect functional groups much the same way as traditional synthetic chemistry – but this is not always the case. As Baran is showing, the retrosynthetic strategy using theorized biosynthetic pathways is now “Baran Chemistry”.
You know you are badass when that alone is sufficient to let people know what you’re talking about.
KCN has not changed the subject at all IMO. Organic chemistry would get by perfectly without his efforts.
We’d only lose the synthesis of a few compounds, 99% of which sit in his fridge. Never see any biology papers from him
Making compounds for the sake of it is just a training ground for his students,
Dave Evans, revolutionising stereochemistry all the way
One more vote for Evans: clear and educational, useful methodology – and very thorough too. The trouble is that everything that matters to Tot Synth people is completely obscure to the Nobel committee.
My boss described Evans as clear, rational development of useful techniques and Sharpless as taking random things off the shelf until he hit on something.
KCN does do testing sometimes, but i know what you mean.
See 10.1021/ja902939t for example.
Baran knows that making compounds is not about the prestige. It is not 1970 anymore
http://pubs.acs.org/doi/abs/10.1021/np9006876
test these compounds for God’s sake, why spend a billion dollars to have them sitting in the fridge gathering dust?
[...] in Nature, C&EN, Health Candal.com, Chemistry World Blog(RSC), Tot. Syn. Dot Com, Chem-Station, C2W – [...]
When will he move to Harvard?
@GHB Maybe Never. Baran has a good thing going at Scripps, and the Harvard chemistry department seems to be kind of dysfunctional as of late (low student morale and professor apathy). With Harvard in a downward spiral, Baran can still be king of synthetic chemistry from the west coast
Harvard is a far better place than Scripps. Better students for starters and with Jacobsen he would be able to call the synthesis shots there as Liu, Kahne, Schreiber aren’t really synthesis and Evans et al are on their way out. PB = EJC replacement…unlike DuBois, I bet he wouldn’t turn them down.
Baran hated Boston during his stay in EJ’s lab. At Scripps, his students don’t have to TA = more time in lab. I don’t catch your meaning about calling the synthesis shots – no one is preventing him from doing the research he wants to do or forcing him to take on projects. As far as students, there really isn’t much difference between the top level schools. I’ve know and worked with great chemists as well far less than great ones from both institutions.
Princeton will buy him, same deal as with D-Mac.
[...] Palau’amine. I am not going to recount the paper here, since Tot. Syn. has already posted a nice summary (as an aside, the comments to that post are simply embarrassing, so many ass kissers…). I [...]
seriously? why would anybody go to princeton?
Evans should get the Nobel Prize, but it seems unlikely at this point, for the following reason: The historical context of Evans’ discoveries is lost. The “done” was introduced at a time when asymmetric synthesis was still in its infancy, and he moved into asymmetric catalysis at a time when most people believed it simply wouldn’t ever be possible. He was not alone: Sharpless, Noyori, Jacobsen and many others have made similar game-changing contributions. These guys created the FIELD of asymmetric catalysis.
Got to talk to a professor who is in the Nobel Committee. He told me that many were against that Corey got the prize, and he said many still think he should not have gotten one even today. Why? Because The Nobel prize is awarded for an Invention! You might publish a small paper with some brilliant idea in TL, your successor might develop this idea and publish 100 Angewandtes, still the man who deserves the prize is the one who Invented the thing. That is the major difference between an award and the Nobel prize. It does not matter how brilliant you are in the field – you must be the first one and an inventor, not just an implementer. According to him, it is absolutely unlikely that another guy gets the prize for just total synthesis. If he (Baran) is so good and hopes to get Nobel prize soon, he better shift his huge total-synth resources to methodology and reaction developement.
Exactly. Which is why KCN will never get anywhere near a Nobel.
You need to change the subject, something he has not come close to doing and never will – as proven that he is trying to make maitotoxin. Jesus Christ what a waste of money.
What Dave Evans has done for our subject makes him the stand out candidate in our field – you only have to compare the azaspiacid syntheses to see the enormous gulf in class between him and KCN
he throws books out promoting his work, when it is all pretty incremental, boring and has done nothing for our field
He published an organocatalysis paper a while back, suggesting he is at least trying to contribute/improve methodology…nothing since though
when he retires put someone in his job that is going to contribute
this is totally not true…. just look at a recent GFP and Dr. Tsien! He didn’t invent it… he implemented it!
Well, usually, if three guys get the prize, at least one is the developer etc. But still, this sort of degrades the Nobel prize. The idea still is to award it to inventors or discoverers. One of the “best” winners was 1993 K. B. Mullis for the PCR invention. This is probably one of the best prizes in Chemistry in the last 20 years. He really invented the technique and it is used worldwide nowadays. This is the basic idea of the prize, unfortunately, there are not enough real discoveries nowadays in chemistry.
Spot on, agree with all your posts. I have a feeling that people behind CO2-capturing chemistry or general Green Chemistry could be candidates for Nobel Prizes this decade. There was an interesting paper last spring on a reaction where CO2 was turned into Methanol in a heterocyclic carbene catalyzed hydrosilane reduction sequence. That kind of chemistry will be the shit that will gain much attention.
This also made it to Wired.com
http://www.wired.com/wiredscience/2010/01/palauamine-synthesized