Kapakahines B and F
Baran, Newhouse, Lewis. JACS, 2009, ASAP. DOI: 10.1021/ja901573x. 
It’s always nice to be surprised by a synthesis dropping from nowhere… even though the commenting team here at Tot. Syn. mentioned an impeding Baran synthesis of an Indole-containing natural product. And here it is, breaking a unmentioned Tot. Syn. rule – I don’t do peptides. I’ve never mentioned this before, and no one has ever complained, so I guess I’m not the only one! Kapakahine B gets out of this quandry by also featuring a rather tasty tetracyclic indole centered moiety, and a selectivity issue built into the macrocycle.
The synthesis starts with a rather nice bit of Knochel, allowing addition of an alkyne to the primary iodides without disturbing the acidic chiral center. What’s going on here is firstly an insertion of a copper/zinc complex into the alkyliodide, and then attack into the haloacetylene. Nice, as this acetylene leaves them perfectly set for a bit of indole building later.
The next bit of chemistry is distinctly reminiscent of work done by Baran and Newhouse last year, working towards psychotrimine. As I said in that previous post, “their key reaction … involved an oxidative coupling of an indole with an aniline, and then cyclisation of the resulting imine with a pendant amide to form the aminal centre”. And this trick works as well as in the previous synthesis, with a similar yield, and in this case, with impressive induction of stereochemistry.
After doing a Larock indole-formation with both the fragments above, the group had the right-had intermediate shown below. The group’s bet was that under amide-forming conditions, the aminal center will equibrilate between the two forms on the top of the figure. The key point is that one has a free, primary amine, whilst the other has a secondary amide (with the nitrogen lone-pair tied-up into the pi-system). This means that although the 6,5,6 system is less favoured, it reacts in the cyclisation reaction far faster, pulling the equilibrium towards it.
And damn, their bet paid-off. A 70% yield, with the majority in their favour is a fantastic success, using non-too-special reagents. (BTW, HOAt = 1-Hydroxy-7-Azabenzotriazole). What more can be said? The rest of the synthesis is peptide-bashing, allowing completion of two family members in 12 and 14 steps. Top banana.
(12 votes, average: 4.08 out of 5)
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please dont start the jealous baran bashing. im so sick of it
Let’s just all take a moment and enjoy a gorgeous paper…
That’s a rather impressive (and concise) way to get two molecules for the price of one.
wow!
we are in a recession after all cientificorojo
Dear TotSyn
I have the impression that the location of the carboxamide side-chain on each depiction of the 6,5,5-ring system is wrong… Just compare it with the oxidative coupling product.
All of us
Very nice synthesis indeed. No Baran bashing seems justifiable here. Of course, if they had been lucky enough to get this accepted in Science or Nature, THEN the bashing would already be 10-20 comments long.
Though interesting, the acetylene bit presented in the opening paragraph is rather non-atom-economical (do I sound like Trost here? LOL); if to forge a sp-sp3 bond we still need to have a bromine and iodine on each of the starting materials, it’s quite clear that there’s still a lot of work to be done in such methodologies. Any suggestions for a more elegant approach to that building block?
Yes it’s not atom economical to use an iodine atom. And they only made a gram of np.
Imagine if they didn’t need iodine atom! 1 kilo?
Atom economy is nice is principle, but solvent and silica will always dominate a true calculation of the atom efficiency of a process. If you need iodide, triphenylphosphine, trityl, etc. to save steps (or purifications) you end up coming out ahead.
I wonder if they could have used three equivalents of lithium acetylide to deprotonate the carboxylic acid and NH-Boc and then perform the substitution reaction. I don’t think acetylides aren’t so basic as to be able to form the enolate of a carboxylate. Then again, a free acid might not be compatible with the iodination chemistry.
N-protected iodoalanines are known for the ease of elimination… Coupling on copper eliminates the problem.
something along the lines of conjugate addition/enantioselective protonation would seem feasible. darses and genet have used this but not sure if it works for acetylenes (10.1002/anie.200352518)
http://pubs.acs.org/doi/abs/10.1021/ja806955s
this method does not require the use of an iodine atom for a larock type indole
InfMP:
Fagnou’s indole synthesis isn’t applicable in this case. It actually does require pre-activation/substrate modification: an acetyl group on the aniline. Furthermore, that acetyl would block the nitrogen part of the N1-C3 linkage, thus necessitating a deprotection step. Finally, since that paper was submitted in September of last year, it post-dates Baran’s N-iodination methodology reported earlier by him and Newhouse.
As usual the SI is immaculate.
Why the pentavalent carbon in the molecule? I think you added the stereogenic proton?
Yeah… oops. Several stereochemical problems in this post, but hopefully I’ve sorted them now. Still, pentavalent carbon is particularly poor!
ChemSpiderMan: Good eye, gooe eye.
Clearly, there’s something this guys (Baran) get that I will never understand… Impressive piece of work!
Like massadine synthesis in that if the last step doesn’t work it’s over. A fearless way to do synthesis.
JACS worthy? This is as JACS worthy as the last synthesis that was in Science. This is a decent Org. Lett at least. What’s new? Baran even broke his “golden rule” of using protecting groups. I mean one carbon-carbon was formed using ancient technology!
About atom economy: did anyone calculate how many carbon dioxide molecules were produced to make the energy required for reflux? I like the indication of silica gel and solvents being the biggest contributors to poor atom-economy above, at least someone is paying attention.
He never had this “golden rule”. Check out his earlier syntheses. The only work that directly advertised “PG-free” synthesis was the work on fisherindoles etc.
If this isn’t jacs worthy I hereby declare the field of total synthesis dead.
I think you said it all Kellyg ,but i think you meant to include an affirmative on that statement.
Why is it that today’s synthetic chemists seem to go out of their way to protest for just about any NP synthesis paper published in top journals? Assuming that all those vitriolic comments come from future referees in the field, one would be foolish to be doing total synthesis in the first place.
This also answers the question of why an increasing number of JACS-worthy total syntheses end up in OL or even TL.
If people are going to question those who are criticizing synthesis and publications why are they not equally as critical of those who ALWAYS praise these syntheses? And why are some people just critical of the people being critical (tell me what I have said that is wrong without using ad hominem attacks such as: “Well who do you work for?”, “You don’t have any synthesis out there,” etc.)Is it the problem of first year students, with little perspective on the goodness of a synthesis, or is it senior grad students who never actually challenged the established pecking order? I have praised synthesis (including Baran’s) and I have also criticized others. If all of these synthesis are good then none of them are good. Good is a relative term, without bad it doesn’t make sense. If someone can tell me why this synthesis is good without using hyperbole or superlatives that don’t fit the description of this synthesis then do it. How about a challenge instead of expected praise. Even if you are wrong or right at least you challenged something, maybe others will learn from it, including me (maybe I missed a subtlety that I could be enlightened on). Tell those who are critical why their criticism is unnecessary or unfounded and back it up. I gave a reason why I don’t think this synthesis is JACS worthy, not a reason why its not a decent synthesis, because it is. By giving this paper JACS credentials it is putting it on par with some of Woodward’s, Corey’s, Nicolaou’s old stuff and even Baran’s previous work. This is a detriment to the whole idea of progressing in synthesis. These do not belong on the same platform.
Are you being sarcasic again?
rich. your comment on the last synthesis ["that synthesis sucks!"] was such a penetrating insight.
Just trying to poke the bear.
Healthy critique is good but this has turned into something sick… Every paper discussion ends up with who is who and what is what in synthesis. Tot. Syn., what do you think about your blog being a slaughterous arena for current synthetic society?
Ok, I’ll bite. I’d argue that this paper is worthy of being a JACS Comm. because of the key point of the paper – the equilibrium between the 6,5,6 and 6,5,5 ring system under amide-forming conditions. Sure, there may not be any new synthetic technology involved here, but if it works, it works. Those who are criticizing the impact of this finding are missing a bigger picture here – look at how many potential drug targets and natural products have this type of 6,5,6 component. This is a great way to access those types of targets. It’s simple, yet wide-impact. This is the real point of the paper – everything else in there is just gravy.
you are
ben can
Does anybody know if Baran is working on Palau amine itself?
baran cannot, ben can
The indole aniline reaction is new as I am aware.the heterocycles paper people mention is only distantly related. It’s like saying that indole is protonated at the beta position so all reactions at beta position are known! I’m in one of the groups that was scooped by this and we just have to hand it to them. It’s outstanding work.
The reason baran angers so many is because he not only finishes things first but so well that it’s nearly impossible to do better. That’s the truth.
in my opinion this paper is not worth beeing published in jacs. i mean, i like barans syntheses and he is a fantastic chemist but in this case, there are no new features present. the oxidative coupling was known from previous work and the rest is simple peptide chemistry. an unwriten law of jacs is that they, in most cases, just publish syntheses which show new methodology.on the other hand i have the feeling, that jacs very often just publish syntheses because there is a “big name” behind the work (as the recently discussed synthesis from corey).
FFS!
The ‘target the easy to make isomer and equilibriate’ manoeuvre is fantastic! It’s a very old-school idea – reminds me of Woodward’s work – but rarely used these days. I challenge you to find a similar modus operandi in any total synthesis this decade.
Totally Agree! This is the whole point of the paper. I like it.
Mr.Synthesis, simple peptide chemistry? Bet a million half cash if you were to design a synthesis of the kapakahines, you won’t propose a late-stage 5-6 ring equilibrium as an endgame
If any other group makes the molecules Baran does, no one has a problem with them being in JACS. What people dont like is the frequency with which Baran has papers in JACS, but this of course is not a valid concern science wise, and I bet he could care less……
One possible negative – and just a question really:
The title of the paper is Enantiospecific Total Syntheses of Kapakahines B and F. But is the term enantiospecific used correctly here? I know the stereoselective / stereospecific principles for reaction mechanism… how does that relate here?
The Next Phil Baran: I think you have a very good arguement especially about the relative scale of things, If everything is good then nothing is…..very good point. But i have to agree with 2ndyear Dave, the 6,5,6 and the 6,5,5 aminal thing is a pretty important and interesting discovery. Other than that its an extremely concise and seemingly scalable synthesis of a pretty intimidating molecule so i personally think JACS is justified. That doesnt mean he’s automatically as good as Woodward and Corey does it! otherwise you can extend this arguement to all that publish tot.syn. in JACS (although i do think Baran has the potential to be as good as them). Lastly, I think that most of the protecting groups (apart from the TES) are there for the AAcid chemistry, probably one area of chemistry that Baran knows would take something extremely special to circumvent the use of PG’s.
Thanks pilky01. And yes I appreciate the idea of the thermodynamic equilibration of the ring system. It does raise one question: if Baran is after a general methodology for creating these compounds then what effect will small changes (substitutents, functional groups) in the molecule make? Would it require preforming the 6,5,6 or 6,5,5 ring systems first followed by macrolide formation, or is this a one shot deal? I think it requires a few more examples to show the value of this equillibration. I’m also not sure about the use of enantiospecific terminology. To me it appears to be enantioselective because there was two possible products and no specific (geometry wise)reactions were used. 100% enantioselective does not equal enantiospecific. This is just a minor point all the same. I like where this discussion is going!
That’s a really good point actually about what influences the 6,5,6 – 6,5,5 equilibrium. It would be quite interesting to see what types of functional groups can influence 6,5,6 over 6,5,5. Actually, that would make a nice project for a fresh first year grad student.
Actually, it would make a good research project for any graduate student.
enantiospecific must be synonymous with chiral pool, hence correct usage here. hope this helps.
there we have it! Pilky01 made the point!
the total synthesis community is always about who is as good as…. or even better then… or the best there is….
what about just appreciating good work? maybe on the other hand… your only drive is the negative motivation and your jealousy? Grow up and learn to accept that other people are good as well…
scientific input on the synthetic steps and sharing experience would be so much more interesting!
great work by Baran!!! really nice approach and synthesis… NO bashing justifiable!
Im not sure if you were for or against my comment and weather your comments were specifically aimed at me, However i want to add to it. A name doesn’t automatically mean the work is good, each paper has to be judged on its own merit. But if some names have a track record of continually conducting and publishing amazing chemistry (for instance Woodward and Corey) they build a bit of a reputation for themselves and others see this as a benchmark to aim or compare to, I think this is instinctive for most people. But its mostly irrelevant to the actual science, its the current scientific methodology that should be targeted and used as a benchmark to judge a paper. Don’t you agree?
I agree. And exactly this independt judgment is in my eyes missing. I get the feeling many people really dont like Baran… Yet – if you like him or not – you really cant be serious not appreciating this piece of work!
But, dont you think it is ridiculous to compare todays advancements with those of 10, 20, or 30 years ago? So comparing Baran’s work to groundbracking advancements of Corey or Woodward is not legitimate. But, if you compare the here presented work with the fields recent output you have to agree that this work is far above average. Therefore its acceptance in one of the fields top journals is just appropriate! Agree??
(I am referring to:
That doesnt mean he’s automatically as good as Woodward and Corey does it! otherwise you can extend this arguement to all that publish tot.syn. in JACS (although i do think Baran has the potential to be as good as them).)
How do you want to compare???? In analogy, whos better:
Einstein or Newton…?
Michael Jordan or LeBron James?
I agree in pretty much every respect Gauner. My comment was referring to an earlier one made by ‘the next Phil Baran’ maybe i misunderstood his point due to the inherent problems with this type of communication “By giving this paper JACS credentials it is putting it on par with some of Woodward’s, Corey’s, Nicolaou’s old stuff and even Baran’s previous work.” I was merely trying to say that not everything in JACs is equal, some papers have a far bigger impact than others even within a Journal, If the referees for every article said hmmmmm is this as good as what weve seen from Woodward in JACS in the past then i think a lot of things wouldn’t get published. Equally if you publish a JACS you cant expect people to all of a sudden respect you as much as some of these others, even if the chemistry is amazing, it requires consistancy to get the reputation. Personally i think Baran is showing that sort of consistancy.
agreed agreed agreed
Clearly Einstein. Newton stole credit for a lot of stuff from Hooke after he died.
TotSyn
I don’t know if you deliberately ignored my earlier comment (??), but I checked the paper again and the bond connectivity on the 6,5,5-ring system is wrong on your scheme. The amide chain protruding from the final 5-membered ring should be -alpha to nitrogen. Am I the only one seeing this?
To everyone else,
The only really NEW thing in this synthesis is that truly clever thermodynamic equilibration. That, and the fact that these compounds have absolutely HORRIBLE-looking NMR spectra (check the SI).
Making such fairly large compounds on a gram-scale is, on any person’s book, remarkable. Quite honestly? This is definitely JACS material. As pointed out before, Baran’s skill in synthesis renders most of his completed work extremely hard to beat for conciseness, elegance and efficiency.
If, as a referee, you refuse such a paper for JACS, you know what? It’s going to be published in Angewandte Chemie 2 weeks later and highlighted as a VIP-paper. Angewandte actually thanks you Americans for being so foolishly hateful and rejecting the only remaining synthetic work that actually ENHANCES ACS journals…
Ah, I see what you mean now. Finally! Sorry about that – I thought your earlier query was about stereochemistry. I’ll fix it tonight.
So true! I’m an American myself, but I still don’t understand why Angewandte Chemie isn’t appreciated as much as JACS by a wide number of synthetic organic chemists here in the states. As far as impact factor goes, it appears to me that just as many chemists read Angewandte as they do JACS, and all that separates who publishes in which journal is a matter of which continent the PI resides. Same goes for Chem Comm.
Its appreciated but their is still a larger prestige factor of publishing a paper in JACS that can’t be related to impact factor. Also, Angew publishes reviews thus boosting the “realtive impact factor” while the other doesn’t.
You could have a point about prefence realted to the continental divide
My respect for Angew went down a few notches after the JJLC incident, and continues to go down every day I hear nothing from them. Sorry if I’m opening old wounds. That being said, I read Angew just as often as JACS.
Having worked on peptides and mixtures of rotamers I have two hints on how to get nicer looking spectra:
1) Try to record your spectra in the most polar solvent you think you could use (acetonitrile is often a good choice, also has a great 13C window).
2) (even better:) Use (CDCl2)2. Yes, symmetrical tetrachloroethane-d2 and heat the probe to at least 360 K (83 C). – Your NMR lab engineer does not like this temperature? Go kick his/her ***. Most instruments will do this just fine. Oh, you will most likely have to retune/rematch the probe after heating up to this temp (ask your NMR guys for help if you have not done this before). After these adjustments, most Cbz, Boc etc. rotamers will be gone; you will get beautiful, clean spectra.
Thank you for the advice, sir – and I must add:
Congratulations on comment #5000!
Yep, five thousand comments on Tot Syn, picked by my software from 268,300 spam messages over the three years. Wankers…
Really? I had a a series of NBoc protected acetonide protected amino alcohols that coalesce to one isomer at 127 °C in DMSO but not at lower temp. Will try the DCE-d though….
It’s not a thermodynamic equilibration, but a dynamic kinetic resolution, right? The thermodynamic equilibrium favors the wrong isomer, but the kinetics of the coupling reaction allow for trapping of the correct isomer.
First…Great synthesis…Very interesting equilibrium and one that has never been exploited in total synthesis. Very JACS worthy.
Second…I think this shows a bit of versatility in Baran. These peptide-ish natural products are not his ‘standard’ target. He clearly has learned how to put them together nicely.
I don’t think I understand the criteria people are using to determine “JACS-worthiness.” Could someone put together a list so I can understand why a synthesis is or is not worthy? I have a friend who did her Ph.D. in a high-profile physical chemistry lab that works in nano and materials. If they couldn’t properly characterize their materials they would just “dump” the results into JACS instead of putting it in a “proper” journal. To be honest, I find JACS great for new methods, great for interesting total syntheses and horrible for just about everything else. JACS articles describing biology methods, nano work, materials etc, are usually uninteresting from a scientific point of view and usually far from novel. They are only accepted because those fields are “hot.” It is unusual for me to feel a total synthesis doesn’t “belong” in JACS – as they tend to be quite interesting and creative. JACS publishes articles that a lot of people will want to read, whether it is an interesting total synthesis or a very useful biological tagging strategy (even if it’s boring).
A paper is considered “JACS-worthy” if it is deemed something cutting edge by the editor and peer reviewers. At least for a JACS comm… JACS articles are much easier to get published, and for organic synthetic chemists are about on par with a JOC article. Basically, criteria for a JACS comm for a synthetic chemist involves coming up with something that will not only be quite useful but also may have a wider impact application.
It’s tough to get total syntheses in as JACS comms anymore simply because there’s a need for something new with widespread application involved for it to get through. First syntheses of extremely challenging targets also usually end up being JACS comms. For example, if Baran’s grad student who’s on making Vinigrol ends up making it, I’d predict that would end up being a JACS comm. Other than that, it’s rough getting a total synthesis as a JACS comm these days, especially when you have “nano-” this and “bio-orthogonal” that filling up more of JACS’ pages.
If all JACS communications must be cutting edge and groundbreaking there should be much fewer of them – from all fields of chemistry. I personally think synthetic organic chemists have themselves raised the bar higher than, say, physical chemists or computational chemists. It does not improve the status of the field. One might argue that by setting the bar higher the quality will be raised – but this is not necessarily true, people will simply publish their good stuff elsewhere.
Most of the negative posts here come from people who, seemingly, do not appreciate a good synthetic strategy. They demand “new” chemistry, as in new methodology. What do you want, another organocatalysis paper along the lines of “Catalytic, Asymmetric __________” (you can fill in the blank; it’s that boring)? Every new strategy IS new chemistry and in this case it looks to be unbeatable.
@ The Next Phil Baran:
By supporting kellyg’s comment above, you’ve singled yourself out as an opponent of synthesis. If this paper isn’t good synthesis what is? Please tell us what Corey/Woodward/Nicolaou syntheses are good, and we can all decide if YOU have the proper perspective on chemical synthesis.
Not once did I make that assertion. I am a fan of synthesis, it has elegance, efficiency and practical applications. As I have said before I do not agree with a synthesis of this caliber in JACS. A JACS publication is supposed to change the game or blow peoples minds, this publication does not. What novel insight have we gained from this? What’s wrong with this in Org. Lett? There is nothing wrong with Org. Lett. Yes, things equilibrate and we can’t entirely predict the outcome all the time, this is not life altering. Baran’s other synthesis with absolutely no protecting groups is a game changer; he was not the first to propose this idea but he did implement it very well and should be applauded for it.
Baran’s no-protecting groups synthesis also got into Nature.
You’re right, there isn’t anything wrong with Org. Lett., and to be honest I see some stuff in Org. Lett. every now and then that really ought to be in JACS, Angewandte, or Chem. Comm. instead. Not to detract from Org. Lett., but those are just higher impact journals, are they not?
One thing we’re all missing here though, is that the real measure of the success of one’s chemistry isn’t what journal it’s published in or how big of a name that person has already. What matters is if it’s useful or not. Something deemed “hot” right now could be hardly used at all a couple years down the road, and something that is grossly overlooked right now could end up being found to be extremely useful down the road. Take Heck’s chemistry for example. When he was at Hercules and also teaching at UDel, he couldn’t even get funding for his research! It wasn’t until he was about to retire that the widespread utility of his work was finally recognized.
I’m a fan of this work. One thing that I was hoping would get discussed around here is the new reaction arrows used in the paper. What’s with the dot? I’m a big supporter of advancing the style of organic chemistry (I don’t dig Nicolaou’s colored in molecules). I’m not against this dot but what’s it for?
p.s. I am sadly retiring my … handle which I’ve been using since the early TenderButton days. ,,, and new … are welcome to it.
ya for real, what’s with that dot? myself, not in favour of that if it is just “decoration”. it makes the paper look like a circuit diagram. does anyone know what its for?
My best guess is that it’s there to emphasise reactions that have been carried out on more than 1g-scale. In which case we’ll end up seeing a lot of those in the early schemes of Maitotoxin, me thinks…
Very good point. I hadn’t noticed it. It seems irrelevant at first, but a bit annoying when you realise it’s there. I don’t see what it could be for, except to look “better” or “more organised”?
If Baran was attempting to implement some novelty in science dissemination, a footnote, at very very least, would have been enlightening.
Just workin wit the scraps he was given, Baran made miracles every Thanksgivin…
Maybe because the structures are so large it helps to guide the reader from compound to compound?
I personally think this synthesis is JACS worthy since it is the first synthesis of these natural products and it is concise considering the complexity. I do agree though that natural products containing peptides usually make pretty boring total syntheses because of all the aminoacid coupling chemistry, but the ring equilibration rxn is interesting in this synthesis.
Furthermore, as sthm points out enantiospecific refers to the fact that Baran started from the chiral pool. Remember enantiospecific = enantioenriched chiral starting material being converted to chiral product without loss of ee. An enantioselective reaction is one where achiral material is converted into chiral material with enantioenrichment. I don’t really know of any enantioselective syntheses by Baran since he doesn’t have any enantioselective methods. He usually uses the chiral pool or auxillaries which makes these syntheses asymmetric or enantiospecific but not enantioselective.
It is not enantiospecific, it is enantioselective. If there are two products possible by a mechanism and if you get only one then it is still enantioselective. This is a series of enantioselective steps that overall produce an enantioselective synthesis. An Sn2 reaction, or an E2 reaction, is specific, it can only happen one way (backside attack). If it was a series of Sn2 reactions leading to the synthesis it could be called enantiospecific. It doesn’t detract from the result but it is a misuse of the word.
Based on the definitions in Eliel, this synthesis is enantiospecific.
Referring to stereospecific, the glossary (page 1208) states: “The term may be extended to a process involving…a chiral reagent when the configuration of the product of the reaction depends uniquely on the configuration of the catalysts or reagent”
Therefore, the oxidation of the indole is enantiospecific, and diastereoselective.
So we need a new definition of a reaction that is completely dependent on the mechanism for getting one product. What then is the definition of a reaction whose products are dependent on the orientation of the substituents in a molecule, especially if it can only lead to one? Reducing an aldehyde to give only one enantiomer (diastereomer) does not mean that it could not have produced the other, if it can potentially form both then it is still selective. What should we call this unique type of specificity if only one compound is and can be produced? You have to admit they are different so why the same term? If they are not the same then we need to distinguish otherwise it is an equivocation, a fallacy.
An aldehyde reduction that gives only one enantiomer?
You should spend less time trolling on this site and more time in your organic chemistry tutorial sessions.
I think you got it right on the “selective” issue, but wrong on the prefix. Since the starting material for the indole oxidation is already homochiral (enantiomerically enriched), the reaction is “diastereoselective”. The whole synthesis is, therefore, diastereoselective – but definitely NOT enantioselective. Eliel is usually correct on these things…
So, what is an enantioselective synthesis? What’s the difference?
Enantioselective synthesis produces a preference for one enantiomer over the other in the product, regardless of the starting material’s stereochemistry. Enantiospecific synthesis will produce a product from starting material with one set stereochemistry, but not from the enantiomer of that starting material.
Can an ‘enantiospecific’ process even exist – if you started with enantiopure materials (such as amino acids or sugars) and performed only coupling reactions that did not involve the stereocentres then you would get a specific enantiomer of the product, but I don’t see peptide chemists calling all their syntheses enantiospecific.
If you do a stereospecific reaction (i.e. the mechanism dictates the stereochemical outcome, so feeding in one enantiomer/diastereomer gives one product, but feeding in the opposite stereochemistry gives the corresponding opposite result) then you are not guaranteed 100% selectivity, as there can be competing reaction pathways that are not specific (Check out Ian Fleming’s work on silanes – masterful!)
so my question remains – what, if anything, does enantiospecific mean?
As European Chemist rightly this is a diasteroselective synthesis – admittedly a rather impressive one with some interesting observations about equilibria and formation of the heterocycles. It’d be interesting to ask prof Baran (or the relevant student/post-doc) what he meant when he wrote it…
An enantiospecific reaction is one in which the enantiomer of the s.m. determins the product. For example, if you start with R and the product is S, then if it is enantiospecific, S s.m. will give you R product.
An Sn2 reaction is enantiospecific, whereas an Sn1 reaction is not.
Agree with EC, I think the 6,5,5 compounds are drawn wrong above…shouldn’t that chain be coming off the 2-, not 3-position..?
There are (were?) at least 5 groups I know of working on these molecules…..
Eliel? What the hell did that guy know about chirality anyway?
chinese schools have a good way of teaching enantioselectivity using the ‘wang, ba, dan’ principle. i don’t remember the details. can somebody ask a chinese student in their lab about it?
You are a bad, bad man, Guy Knee.
Doesn’t IUPAC have defined definitions for enantiospecific and enantioselective (applied to synthesis)?
I have seen syntheses that have been in Org Lett that should have been in JACS and vice versa. Now that we have such rapid and efficient ways to access journals and skim through abstracts via the internet, not to mention a number of decent blogs, having a paper in a lower impact factor may not necessarily mean it goes unnoticed. An extreme case (I may be wrong because it’s off the top of my head and I can’t log into Scifinder) was the report of a Pd reaction – may have been the Suzuki coupling- I heard a story that it kept getting bounced and ended up in something like Synthesis or Synth Comm….I’ll have to check that though.
I have heard some say that once you’ve got a paper in, let’s say, JACS/Angewandte/Nature, it makes it easier to get papers into the higher impact journals even though it might not be exactly worthy of it’s acceptance. Would anyone agree with that?
Stereospecific reactions are reactions in which a starting material of a certain geometric configuration leads to a product of a certain geometric configuration, while a starting material of the OPPOSITE geometric configuration leads to the OPPOSITE geometric configuration in the product. The simplest example I can think of is an SN2 reaction – the S enantiomer of a compound will react to give an R isomer, while the R isomer of the starting material leads to S in the product (assuming no priority changes, but the R and S are arbitrary). That specific example, where we are dealing with issues of enantiomers, is an enantiospecific reaction.
Stereoselective reactions lead to products in which one geometric isomer (R over S, E over Z, etc.) is formed preferentially over another, regardless of configurations of the starting material (or despite a lack of geometry, i.e. achirality, in the starting materials. Depending on the products, this can be further classified into diastereoselective or enantioselective, and maybe even a few other terms I can’t think of right now. An easy example is asymmetric reduction of a prochiral ketone, and depending on the presence or absence of other stereocenters in the molecule, and whether or not they are homochiral or not, it can be diastereoselective or enantioselective (or both).
By the definitions I gave above, Baran is correct in calling this an enantiospecific synthesis – if he had started with an R amino acid instead of S, he would have ended up with a natural product(s) of the opposite chirality as well.
If some of these anti-Baran people had produced the exact same synthesis themselves, I am quite certain they would have submitted it to JACS, and they would be whinging even more than they are now if it would have been rejected.
Z– they would have submitted to Washington post and called CNN too.
Problem is baran raised the bar too high.
Haha yes that’s true. There’s nothing wrong with raising the bar. The man is just into his early thirties and he’s making molecules at a freakishly fast pace…so what?
I think he should have a shot at Maitotoxin.