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Vinigrol   

31 October 2009 49,269 views 105 Comments

vinigrol

Baran, Maimone, Shi, Ashida. JACS, 2009, ASAP. DOI: 10.1021/ja908194b. Article PDF Supporting Information Group Website

Yep, it’s done.  Surprised?  You shouldn’t be, not after the Angewandte published last year, which was tantalisingly close to the natural product.  For the uninitiated, this target has been on grant-proposals world-wide for the last twenty years, subsequent to it’s isolation in 1987, culminating in nearly twenty ‘syntheses towards’ type papers, but no cigar until now.  And don’t think that those incomplete approaches were by the Bionic Bros – were talking big names like Paquette.  So what did Baran do to triumph?  Let’s start back in that Angewandte.

vinigrol_1

The key reaction at the beginning of this terpene synthesis is a Diels-Alder between a not-particularly-commercially-available diene and (E)-methyl 4-methyl-2-pentenoate installed the initial bycycle in a reasonable yield and diastereomeric excess.  Baran states that this result is unoptimised, but one would hope that a more exotic Lewis acid might a) confer a higher yield / diastereoselectivity, and b) induce a spot of enantioselectivity.  But not in these papers.  A Stille coupling installed the vinyl side-chain, whilst an oxidation state adjustment gave an aldehyde.  Addition of allyl magnesium chloride caused formation of a triene intermediate, which under heating did the Diels-Alder thing again, providing a further two rings.  That’s a cracking yield for that process, providing much of the vinigrol core in a few untraumatic steps.

vinigrol_2

Barring a slight modification of conditions and substrate, the chemistry in the new JACS paper follows that of the earlier paper for a few steps here.  There’s a slight disconnect (which may just be me, bleary eyed on the weekend), but presumably an oxidation occurs, allowing regioselective enolate formation and alkylation.  A reduction returns the alcohol with opposed stereochemistry this time, and mesylation sets us up for the centre-piece of this route – a Grob fragmentation, followed by addition of bromonitrile oxide.

vinigrol_3

Breaking the Grob fragmentation down, it can easier to see what’s going on, and why this is such a smart route.  Y’see, the problem Baran is surrmounting here is an extranious carbon-carbon bond.  By deprotonating the alcohol, the hydroxide can shut, forming a ketone, and kicking out the mesylate.  A not-entirely dissimilar Grob fragmentation was used by Steve Ley in his syntheses of the Thapsigargins.

vinigrol_41

Now, the addition of bromonitrile oxide might look a bit bizzare, but this is effectively a masked hydroxy-methylation.  A more familiar method of installing a hydroxyl and a methyl group over a double bond might be epoxidation, followed by addition of methyl-metalate.  However, this approach was unsuccessful, as can be seen at the end of the Angewandte.  So to the addition of a nitrone – which was easily reduced to the analogous amino alcohol.  It’s all good, except for an unwanted primary amine.  Perhaps I would have tried chemistry analogous to reductive removal of an alcohol, such as tosylation and then treatment with super-hydride.  However, tosylamides are far more resilient, so I was intregued to see Baran’s approach – a Saegusa deamination sequence.

This seems quite akin to a Barton-McCombie deoxygenation – turning the heteroatom functionalisation into something that can be radically reduced.  In this case, the key functional group is a isonitrile.  Treatment of this with AIBN and tributyl-tinhydride resulted in a decent-enough yield of the desired LHS.

vinigrol_5

I’ve deliberately ignore the functionalisation of the RHS, because that would have left me transcribing both papers.  However, one reaction is definately of note, as this sets-up the whole affair.  It’s a simple, but amazingly selective dihydroxylation / oxidation sequence which confers the correct diastereoselectivity, and ultimately forms the desired ketone only.  To summarise the rest of the route, a Shapiro reaction with trisylhydrazone provided a vinyl anion, which added to formaldehyde to provide the methanol sidechain.  Damn – I did rewrite it all…

vinigrol_6

Awesome.  Just awesome.  Hopefully, a bit of tinkering with that first DA will give us an enantioselective route soon…

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105 Comments

  • LiqC says:

    Now all the non-Bionic Bros are gonna be quite upset…

    • L J P says:

      I am totally cracking up over the Bionic Bros. comment right now. Does everyone get that reference? LaClair’s Hexacyclinol…?

  • earth23 says:

    In the final scheme, should the olefin in the 8-membered ring be absent? Or am I missing something…

  • ,,, says:

    Paul, regarding that ketone they alkylate… There is no disconnect, they make it in Angew Chem paper on the way from cmpnd 14 to 15. Just to let you know…

  • The Next Phil Baran says:

    This is nice! The Grob is particularily good at forming the large ring. I just hope that Phil is trying to teach his students to do the same.

    • milkshake says:

      I am afraid only to his inner circle; Grob fragmentation is revealed only to selected initiates after they take the Oath… The others have to get by with mere metathesis and oxy-Cope

  • Gui says:

    In the 1,3 dipolar addition of the bromonitrile oxide, Why did it have that regioselectivity? What is the yield for that reaction? I would imagine the other isoxazoline would also form (the one with the nitrogen on the tertiary carbon)

    • RikeB says:

      Yield is 88% on a large scale according to SI. Maybe steric hinderance reason? Really incredible.

    • Anonymous says:

      alkene attacks at the imine carbon to give carbocation in two possible ways. In this example, it will give a tertiary carbocation which is more stable than a secondary one. How do u think?

      • Gui says:

        I work in 1,3 dipolar additions a lot and they are concerted. Maybe this reaction in particular has an ionic mechanism? What solvent did they use? Protic? I would imagine it has something to do with orbital coefficient sizes(as most pericyclic reactions do) I don´t know. Anyone??

  • Tickle MY Nancy says:

    Woo Who yeah Baran! Kick ass takes names later.

  • Ni-lithium says:

    Baran, what a man! Great synthesis, and such incredible transformations. Next up on the Baran menu, Palau’amine?

  • Jose says:

    Wow, stunning. He makes it look so damn straightforward, after decades of messing about! I, too, would be shocked if Palau’amine didn’t appear sometime in the very near future.

    • aa says:

      “after decades of messing about”

      this is definitely a landmark synthesis, so i don’t mean to detract from it. but it should be kept in mind that the decades of messing about on the ‘more obvious’ routes meant Baran et al had a much easier time of it… imagine if no one had published the “routes toward” papers and each lab was completely in the dark of every others for how to go about making this molecule.

      especially considering the efforts of paquette, and corey’s contribution of the grob fragmentation idea, this is a real case of standing on the shoulders of giants.

      • Jose says:

        Agreed for sure, but everyone else working on it also had access to all the same knowledge, eh?

        • BU breath says:

          Jose is right. The ultimate judge of ability is doing what others tried and could not do. Every other measure is subjective in my opinion.

        • aa says:

          very true. just pointing out that vinigrol has more “progess toward” papers pre-total synthesis than any other current target (probably excepting palau of course). in that sense, its a little different than your normal everyday molecule.

          clearly, baran and coworkers deserve immense credit and kudos for finishing this off. at the same time, the overall fact that the molecule was made at all is due to the combined efforts of the groups cited in ref 2. in that regard, i hope the other groups working on this are not overly dejected to have been beaten to the finish line. any predictions on who will publish version #2?

          oh, yes. considering the ester from the DA adducts is converted to aldehyde before allylation, anyone know how well this DA reaction would work under organocatalysis? seems as though if that step is feasible, a simple reorder of the vinylation/allylation sequence would have this enantioselective in no time.

  • Gui says:

    What is the mechanism for the CDMT reaction? Why did they use that base in particular?

    • ABC says:

      it is not a base

    • Johnny Bravo says:

      … and not all 1,3-dipolar cycloadditions are concerted.

      • milkshake says:

        BrCNO is gotta be pretty hot. (Even very hindered el rich nitrile oxides like mesityl-CNO do unactivated trisubst C=C well below the room temp)

        • InfMP says:

          what is the mechanism though? I looked up the Saegusa paper and they already have the isocyanide. I can’t find anywhere that explain the formic acid/CMDT, Phosgene NEt3 step!

          I hope there is a full article. it will be a treat.

          • happychemist says:

            InfMP, it looks like CMDT acts as a traditional coupling reagent. NMM deprotonates formic acid to produce formate, which undergoes nucleophilic aromatic substitution at the chloride position of CMDT. The substrate amine is free to attack the activated ester now, to produce an amide. O-alkylation of the amide by phosgene, followed by deprotonation by TEA to eliminate CO2 and chloride, followed by another deprotonation will produce the isonitrile. This is a very interesting transformation!

          • Martyn says:

            See Tetrahedron, 1999, 55, 13159 for DMTMM, the cationic coupling agent you get from CDMT + N-methyl morpholine. I’ve had a lot of success with this in amide couplings in the past, though I’ve never formed it in situ as seems to be the case here.

            Anyone know how Njardarson’s route is coming along? He can’t be far behind Baran.

          • bitterbeerface says:

            you must be joking

          • happychemist says:

            Martyn, I think you’re absolutely right that a cationic coupling agent is formed in situ. However, I believe that the N-methyl morpholine simply deprotonates formic acid. If you look at the conditions presented in the paper, Baran uses 0.1 equiv DMAP. I think the pyridine catalyzes this reaction by displacing the chloride in CDMT. The resulting pyridinium is then displaced by formate. It sounds like you have more experience than I do using this coupling reagent, though. How does this sound?

          • bitterbeerface says:

            i meant joking about njardson being close behind

          • Martyn says:

            Happychemist – that seems very reasonable; NMM certainly mops up HCl somewhere along the way. I guess DMAP could also get involved a second time, reacting with the activated ester to give the acylpyridinium.

            Re. Njardarson, he seemed to be tantalisingly close a year ago, when I saw him talk about it. Was that just good salesmanship?

          • InfMP says:

            thanks, that must be it

  • hello says:

    formylation and dehydration InfMP

  • ben says:

    what is the B(O-pr)3 for in the carbtree Hydrogenation? never done that before…

    • Beef Supeme says:

      It is the terminal reducing agent.

      • BLUE says:

        What does the B(Oi-Pr)3 change finally ?

        • Beef Supeme says:

          I didn’t notice that they used H2 in addition to the borate. I guess I’m not sure why they needed the borate.

          • Mike Rudd says:

            B(OiPr)3 has been used before as Lewis acid additive to increase rate of reaction/turnover in a hydroxyl directed reduction of a sterically hindered tetrasubstituted olefin (Trost, Org. Lett. 2003, 5, 1467.)
            The thinking in this case was that the presence of a Lewis basic group other than the hydroxyl was binding the Lewis acidic Ir catalyst and reducing reaction rate; therefore adding another Lewis acid (boron) might be able to help the Ir equilibrate to the desired hydroxyl group.
            Baran may be using it in the same way to potentially prevent the isoxazole from binding to the Ir catalyst.

  • Gui says:

    How is the hydroxiimidic bromide made? Can you buy it?

    • PC says:

      SciFinder

      • milkshake says:

        these “phosgene-oximes” vith various halogens (Cl, F, Br) are great for making Novitchok class of organophosphate active ester agents that are an order of magnitude more potent than VX gas – and the added bonus is that sub-lethally poisoned subjects suffer a horrendous neurological damage from which they don’t recover

        • Gui says:

          HCO3 is enough to make the nitrile oxide? That´s very impressive. I was expenting to see chloramine T somewhere

  • industrialguy says:

    The dibromoxime is very easily made on hundred gram scale as a crystalline solid stable in the fridge. it slowly looses bromine over several months but can be recrystallized if needed. And it is safe to work with.

  • BU breath says:

    Wonder where UBChem is now? Ha ha ha

    • milkshake says:

      “Put yourself in mind every morning that before that night you will meet some meddlesome ungrateful and abusive fellow, some envious or unsociable churl. Remember that their perversity proceeds from ignorance of good and evil – and that since it has fallen to my share to understand the natural beauty of a good action and the deformity of an ill one and since I am satisfied that the disobliging person is of kin to me, our minds being both extracted from the Deity – and since no man can do me a real injury because no man can force me to misbehave myself I cannot therefore hate or be angry with one of my own nature and family”

      • bandit says:

        millkshake, dont you have anything better to do?

      • USC says:

        If both minds are extracted from the deity, then it speaks volumes about the malevolence of the Diety.

        • milkshake says:

          Our good Deity has its own mysterious agendas in which even churls have their place; and it will be all good in the end.

          I do comment banditry for recreation: bludgeoning obnoxious strangers with Marcus Aurelius is a lot funnier than calling them the names they deserve. (This was a copy-paste from ‘Squashed Philosophers’ – free and online, check it out.)

          • USC says:

            Nothing about being a Deity implies that it must be good.

            “Our good Deity has its own mysterious agendas in which even churls have their place; and it will be all good in the end.”

            Except for the churls I’m sure

  • UBChem says:

    For the record. This is a fantastic synthesis. The Baran lab has worked very hard to achieve something of great importance and has deserved the respect and positive comments that have been written here. to BU breath…Go Fuck Yourself.

    • The Next Phil McGroin says:

      I agree that this is a fantastic synthesis. Can someone enlighten an admittedly “uninitiated” why they have achieved “something of great importance.” I like this paper a lot, but why is it important?

      • BOttoms up says:

        Here we go again!

        • The Next Phil McGroin says:

          No, we dont. I am not questioning the JACS worthiness (It is) or the quality of the work (its clearly great), merely the assertion that it is important.

          • The Next Phil Baran says:

            I guess the question is what’s next? The enantioselective synthesis should come pretty quickly, but then what will stimulate the minds of synthetic chemists? It’s all kind of anti-climactic, makes the discussion of “hot” molecules redundant. On with the science!

        • stop says:

          Phil McGroin – the “something of great importance” comes from the fact that people have been trying to make this molecule for >20 years. it was simply an outstanding challenge. see ref. 1 & 2 in the paper for all the previous work.

          a very nice synthesis as far as i’m concerned.

          • Dean McToste says:

            Agreed. McGroin’s innocent question is basically a slap in the face to everyone in the field of synthesis – methodology and total syn. Aside from the whole “nobody could do it for 20 years” issue, the strategies developed in this route are extremely important to synthesis design in general, the lack of PG manipulations, and the fact that they could make gram quantities of the intermediate 2 steps from the end is amazing given the taxol-like complexity of the target. You are free to ask “is this important”, but you look like either an uninformed grade-school student or simply an idiot.

            This synthesis raises the bar yet again for the field. McGroin should be asking the “is it important question” to the piles and piles of nano and supra and DNA stuff and conjugate additions to nitro olefins that are published daily in JACS.

          • PC says:

            simply an idiot!

          • Skeptic says:

            I fail to see the “great importance” of a synthesis in which over half of the steps are redox reactions and in which five heteroatoms are installed only to be removed in later steps. Although Baran’s approach to the core of vinigrol is nice (albeit not entirely original) a lack of novel chemistry renders this synthesis pedestrian. Being first simply is not good enough. Baran has left a lot of room for improvement with this one.

          • Tot. Syn. says:

            @Skeptic:
            If it’s so easy, why did this take twenty years to complete? Some really top minds applied themselves to this synthesis, but failed. The obvious reactions didn’t work. For instance, epoxiation / methylation as I suggested. So a more laborious route was required, but it did work. You’re in the fourth year of your PhD – surely you realise that some substrates are just a bastard to make. When thermodynamic and kinetics stand side-by-side against you, it’s time to get creative.

      • Skeptic says:

        I think that people too often forget that there is a big difference between an accomplishment being impressive and and accomplishment actually being important.

        • BOttoms up says:

          If this synthesis is not important than to hell with the field. Nothing on this blog or any method except for metathesis and palladium chemistry qualify for important.

          My bet is skeptic belongs to a method group or is one of the people that could not finish. What a joke you are!

          • Redman says:

            Lets not forget that despite all its Glory, metathesis CANNOT make vinigrol, just ask paquette.

        • PC2 says:

          let’s ask this : Is woodward’s strychnine impressive or important?

          • BOttoms up says:

            For the field of chemistry very important. For a geologist or your mother, obviously not. But consider how many chemists were inspired by this and went on to do amazing things like invent medicines.

            In essense, mcgroin and skeptic and people like him are anti-fundamental science. I would argue that the things which are most instantly “important”, are many times in the long run less important than fundamental breakthroughs.

          • The Next Phil McGroin says:

            For the record, no one has given a direct answer as to this work’s import. Because people have tried to due something for 20 yrs does not mean that thing was worth doing, or that its completion important.

            I am not a Baran basher as I have repeatedly praised this work on this blog, or “anti-fundamental science.” I asked a simple question which, no one has answered directly, and judging by the apparently contentious debate I think I have a valid point.

            Feel free to disagree, that is why I love this blog.

          • Dean McToste says:

            I did already. Read my previous post.

          • stop says:

            phil mcgroin – i did answer your question.

            consider: in a field where you make things, making something no one else can make is important. or impressive. thats semantics in my opinion.

  • LiqC says:

    Suggestion:
    There was this paper on rubromycin, full of bizarre and instructive transformations.
    http://doi.wiley.com/10.1002/anie.200903316

  • Chembotitron says:

    To McToste:
    Two weeks ago I would have agreed with you on the “…and conjugate additions to nitro olefins that are published daily in JACS”
    I was very skeptical of the utility of that reaction, but then I saw this excellent application.

    Darren Dixon’s Nakadomarin synthesis
    http://pubs.acs.org/doi/pdf/10.1021/ja908399s

    Worth a look.
    That molecule has garnered a lot of attention as well, (not as much as vinigrol) but some big names for sure.
    Cheers

    • anon says:

      Eh, a better example of the utility of asymmetric Michael addition to nitroalkenes would be this: 10.1021/ja026788y

      Development of a Catalytic Enantioselective Conjugate Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes for the Synthesis of Endothelin-A Antagonist ABT-546. Scope, Mechanism, and Further Application to the Synthesis of the Antidepressant Rolipram

      Process group invents Michael addition of beta-ketoester to nitroalkene, does a bunch of neat mechanistic work, runs the reaction on multi-kilo scale for production of a backup compound. Sounds useful enough, no?

  • asscheeks says:

    Its pointless arguing over what is important here, since that is often judged over time. I bet if most of us bookmark this page and look at it in 15 years we will be surprised how easily we confused “hot” science with important science.

    • The Next Phil McGroin says:

      That is exactly the point I was raising when I posed the question. This is clearly a notable and impressive accomplishment. There were some amazing transformations and disconnections that led to the completion of this work, but import is something that does no come across, to me at least.

      15 years from now, how will the scientific community be enriched, or the general public even remotely effected but this work? I am NOT suggesting that it will or wont be, or that it is possible to answer that now, merely that the assertion that this work is IMPORTANT premature.

      In the last few months, Kishi published an improved route to Halichlorins, Magnus Galanthamine, Corey’s Omuralide, Wenders Prostratin work, etc. These are potentially important papers, as they could lead to improved medicines for people.

      And lets not forget the most important work performed in the last 20 years, the discovery of NaH as an Oxidant!!!

      • PC2 says:

        What an argument! I guess in a geologic time scale, even the existence of human being is not important…

      • Piss and Vinigrol says:

        15 years from now the scientific community will be enriched because Baran will be able to look back at his trophy.

        It’s pretty much the same theory his mentor has. Make it because you can, make it because you’re first.

        • Recalled says:

          The only time these comments get sick and ugly is when Baran publishes a paper.

          Just an observation.

        • Piss on Piss and Vinigrol says:

          Speaking of theories, here is mine: You are pissed because you tried to make it and could not or knew you never could from the start so never tried. Pretty good right?

  • ... says:

    Anyone know whats up with the NaH thing? Its still listed as an ASAP on JACS website, yet it was published online 7/21/09. Shouldn’t it have had a page number by now?

    • PC2 says:

      As it’s reported on C&EN, it will not go to hard copy until the authors corrected their bugs

  • WillisWill says:

    I think it is an unfortunate consequence of the development of chemistry that people might not view this synthesis as “important.” After all, does anyone actually believe that palau’amine (or any other compound du jour) CAN’T be made? With enough people/funds/time, the compound can be cracked (it may not be pretty, but it can be made)

    In Woodward’s time, there were real questions as to whether complex compounds could in fact be made. That’s a real difference from where we are now. I see total synthesis as more of an engineering field (akin to architecture) than necessarily a discovery field. Structures can be made, and the compound/route can be appreciated for its elegance, economy, etc.. Not to say discovery won’t/can’t be made in the context of total synthesis, history is littered with such examples (Woodward-Hoffman rules, etc)

    I also believe there is no better training to be an organic chemist than total synthesis

  • hawkeyechemist says:

    what is the difference between science and engineering? there are none when you are considering the frontiers of that discpline. Yes anyone can build a building or for that matter a simple molecule with enough time. But can you make a building 5 miles tall even with unlimited man-power? Science and engineering are the same damn thing when applied to most cutting edge problems of the day, because quite simply, you dont know the outcome. Total synthesis is not simply architecture, architects have at hand a series of tools that they know are reliable, total synthesis chemists also have tools, but they are often NOT reliable in a complex setting. Its funny because i have worked in both methodology and total synthesis labs in my lifetime and methodology sure felt a lot more like engineering. LEts be honest, 99%+ of the methodology’s out there, the student knows in his heart that if he runs enough reactions, and tries enough catalysts, solvents, temperatures and additives he will eventually get what he is looking for. This surely cant compare to the thrill of “discovery” woodward must’ve felt back in the day.

  • TWYI says:

    ‘Lets be honest, 99%+ of the methodology’s out there, the student knows in his heart that if he runs enough reactions, and tries enough catalysts, solvents, temperatures and additives he will eventually get what he is looking for. This surely cant compare to the thrill of “discovery” woodward must’ve felt back in the day.’

    I think this is a decent description regarding the evolution of our subject. Although I would go with a number way lower than 99% in the opening sentence.

    90% of the total synthesis papers nowadays just go through the motions – literature methods. Nothing new, but merely a training ground for students who’ll eventually end up handle turning R groups day in, day out in industry.

    • milkshake says:

      “turning R groups day in, day out in industry” – don’t worry, not too many people end up employed in pharma these days (or in synthetic chemistry jobs anywhere else) so the problem obviously will stop being relevant

      • John Wood says:

        What the hell is everyone in Grad school going to do?

        • InfMP says:

          copy/paste from “in the pipeline”:
          InfMP on November 9, 2009 9:51 PM writes…

          I just got a job offer this week from a small company. The pay is lower than big pharma. And they may close up shop if their first few compounds fail clinical. you never know. But these days it seems like there is less risk with the small guys since they aren’t public.

          Ive had several interviews in big pharma as well. I studied interview strategy hard and also solved every at-the-board problem, but terrible layoffs and mergers occurring between interview and offer prevented them from commiting….not a good sign.

          As a freshly graduating person, I was scared for many months about no longer even having a lab to go to….it’s been a pretty scary ride. I was lucky that my chemistry worked and i got publications. There are numerous other people in my dept who are just as qualified as me, but are trying to find jobs at the mall because there is just no hope anymore….I have no experience outside of academics and ill tell you competing against hundreds of layoff people with tons of industry experience is NOT fun.

          • InfMP says:

            I hope to be doing more than turning R groups (that comment is really witty, by the way). If I can keep new ideas coming and I am at the right company, then more than 9am-5pm suzukis will hopefully be possible.

            I love doing chemistry, and I don’t think that will change (unless I stop reading the ASAPs, as Derek Lowe has noted).

            While I may be heading to Med Chem and have never worked in a total syn lab, I remain fascinated by it. And for the people who doubt whether it is “important,” it was my key to a successful interview. If you know your total synthesis, then you know a lot more retrosynthetic disconnects than the next candidate.

  • PB convert says:

    To McGroin:

    This beautiful synthesis is VERY IMPORTANT. It is an inspiration. A learning tool. These spooky compounds create great chemists. You might as well question the importance of ‘all synthetic chemistry’… or try living in a world without it. Just by choosing to read this blog you have already answered your own question.

    PB is growing on me more and more with each ridiculous synthesis. I’ll take a pass on his ‘economy’ reviews – but I love it when he cranks out these sweet targets.

    But two authors on a total synthesis – now that’s special.

  • Truth Squad says:

    I’ve heard plenty of BS from those that are scared by total synthesis and its endless challenges. Why not invent a new buzzword instead, probably starting with”nano”, or “bio”, do a couple of textbook reactions and sell the “work” to Angew or JACS? Or substitute chiral ligand X for Y, and and run this hot textbook reaction again, and again, and again… Even with unlimited funds, manpower and time, who else could possibly do that?

  • LW says:

    Ok, so I guess there is a bit of a gripe as to whether total synthesis is relevant or not. It is….to an extent. I believe that the training given to a total synthetic chemist, the exposure to different experimental techniques and reactions, puts them in a good position to go forward and delve into other areas of chemistry, and use their synthetic knowledge somewhere else………if they want to and have the intellectual ability, and if they can actually think independently without constant prompting by their supervisor. In other words, just carrying out operations like a robot. Unfortunately, there’s probably more of these types of people than not. I’m not a total synthetic chemist (as such), but it does have it’s place. The only problem is that there’s too many crap ones out there. Baran and his students are not in that category. He’s still young, and has published an astounding number of total syntheses. Furthermore, it’s not like these papers have numerous authors either, a testament to the students aswell.

    I’d be really intrigued as to how he would make Taxol, and how short and efficient his synthesis would be.

    The ‘relevance’ argument. Man, this is a tough one. One of the biggest ‘relevant’ discoveries that went completely unnoticed was the Eder-Sauer-Wiechert Robinson annulation with Proline in the 1970′s. There will most surely be other notable examples.

    Also, whoever mentioned the Nakadomarin synthesis. Yeah that is pretty good. Very short, and quite a bit of material synthesised to boot!

  • Blindman says:

    I hate to tell you, but Methodology is the breading ground for robots, not total synthesis

  • Cascade says:

    I agree with TWYI. Total synthesis is merely a training ground for new chemists. I dont think that many would disagree if I say that you cannot win a Nobel prize even if you make all of the toughest molecules. However, if you can develop a methodology that will help the “real time” synthesis…then the case may be different. Look at SAE, NHK and so on. I think thats way more creative than making molecules, infact, I beleive the both should not even be compared. I have talked to several tot. syn chemists and it seems they beleive more in labour chemistry than in rational thinking. But, having said this, the field has to go on. How else would a trained labour loving organic chemists for the industry!

    • John Wood says:

      Well Cascade, I think its these complex molecules that provide the schema to contemplate such creative thinking. That is what synthetic chemists pursue.

    • ,,, says:

      It’s unbelievable how confused some people are about synthesis! Hey, Confused Cascade, it’s kind of funny that you’re actually blogging at Tot Synth dot com

  • Cascade says:

    To John Wood;
    I know what synthetic organic chemists do and I totally appreciate their work. Infact, I think that the amount of hard work, patience and endurance that has to be put in this line of work is unmatched and that not all chemists can master this art succesfully. As far as the synthesis at hand goes, I think it demostrates one of the highest standards in tot. syn. In my above comment all I wanted to say is that contemplation of a discovery can seldom match the merits of the later.

    To ,,, says;
    “It’s unbelievable how confused some people are about synthesis!”
    Exactly my point! Thank you.

  • milkshake says:

    With regards to the argument that methodology projects breed robots I have only one thing to say to my total synthesis colleagues:

    http://abstrusegoose.com/204

  • ,,, says:

    Nobody “breeds robots”. Whoever says that either methodology or synthesis does must be missing something in his own research. Now if someone feels like he’s becoming a robot he shouldn’t be generalizing everyone else’s situation.

  • achiral says:

    hello!

    This is a really clever synthesis. Following the Grob fragmentation, I believe the olefin is hydrogenated… Otherwise great!

  • Masa says:

    What is the mechanism for the TEMPO oxidation? Why did not formate diketone?

    • achiral says:

      It’s a selective oxidation. It goes through a radical intermediate. I think sterics may have something to do with it. but that’s just hand waving! You can check it out here:

      Burns, N. Z.; P.S. Angew. Chem., Int. Ed. 2007, 46, 205-208.

  • patrick says:

    December 22, 2009

    VIP: Total Synthesis of Palau’amine
    Ian B. Seiple, Shun Su, Ian S. Young, Chad A. Lewis, Junichiro Yamaguchi, and Phil S. Baran*

    The long-anticipated total synthesis of palau’amine has been accomplished by a route featuring highly chemoselective transformations, cascade reactions, and a remarkable transannular cyclization to secure the unprecedented trans-5,5 ring junction.

    Coming soon.

  • samir says:

    well done phil keep it up

  • Steve says:

    Back to somebody’s original question… “I agree that this is a fantastic synthesis. Can someone enlighten an admittedly “uninitiated” why they have achieved “something of great importance.” I like this paper a lot, but why is it important?”

    I agree, its some beautiful chemistry, but people seem to get mixed up between interest and importance.

    Personally I’m in med chem so I’m biased, but most of this total synthetic work seems to try to make complicated natural products, JUST for the sake of making them. Is there any real life application to this work? Considering that morphine is still produced entirely naturally, are were really going to be synthesising vinigrol when fungus can do it for us?

    For example we recently had Gary Molander visit our university, who gave a great talk on several projects of his. However on the last one he spoke of, he said he had been trying for XX years with his grad students, and they were 1 methyl group off a compound which surely weighed >2000 g/mol. From a pharmacologist’s point of view, this will probably make sh*t all difference to the biological properties – why not aim for a feasible synthesis of a similar compound?

    Now I know that Gary Molander has his name to several reactions. My question is, is it this quest for exact synthesis which develops new reactions which go on to be used in other fields of chemistry?

    I don’t mean to offend anybody, but personally I think it is interesting work, but unless it has yielded new reactions or better understanding of existing mechanisms, I fail to see the importance.

    Please generate some decent discussion instead of yelling at me :)