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4 May 2009 19,279 views 58 Comments


Castle, Li, Tartakoff. JACS, 2009, ASAP. DOI: 10.1021/ja9024403. Article PDF Supporting Information Group Website

First-time out for this complex little target – not big, but with five contiguous stereocenters, including a neopentylic chlorine and two quat-carb centers.  Enough to get busy with, then.  Biology-wise, Castle doen’t exactly wax-lyrical – he mentions selective T-cell cytotoxicty, and “antiamnesic-effects” (sounds good for a Saturday night-out), but that can’t have taken up much space in the grant application.

Let’s move on to the chemistry – stepping in at a rather advanced step in this Org. Lett., published in 2007 and detailing much of the initial chemistry (DOI: 10.1021/ol701757f. Article PDF Supporting Information).  (The two rings seen in the SM were unified by a Grignard coupling, BTW).  One reaction that struck me as interesting in this paper is the chlorination of the allylic alcohol.  Using conditions identical to those I’ve used myself to form a mesylate, Castle performs an invertive displacement, citing Robert Williams; cleary the allylic nature of the alcohol makes all the difference.


Ah, radical time. :-) I love a good 5-exo-trig, especially when that adduct radical does it’s polar crossover… Ahem.  Anyway, I spent three years making cyclopentanes using radical chemistry, so I’m not surprised to see them in action here.  It’s that radical/polar crossover thats the key to this chemistry, as rather than terminating via hydrogen atom abstraction or elimination, the use of an oxaziridine results in oxidaiton and with fantastic control of stereochemistry.  A sixty-percent yield is pretty decent in this case, but this was actually improved by oxidation of a biproduct, giving an overall 66%.


Moving on to the JACS paper, a few futher steps brought them to creaction of the final ring, requiring firstly an allylation.  Substrate control was unfortunately unsuccessful, resulting at best in a 7:3 d.r.  However, moving to Nakamura’s chiral allylzinc reagent gave them a far better yield (but had to be used in quite an excess).  (I presume that the meso oxazole can be recovered, so the reagent should be ‘recyclable’ in a fashion.)  A nice result, but a glance at the target quickly suggests that the new allyl group is in the wrong position.  However, a bit of base and an oxy-Cope rearrangement lead to a cracking yield of the desired target, creating the second quat. center very neatly.  That’s the way to do it – install the asymmetry in an easy-to-impart center, and then rearrange into your desired product.


So how does that final ring go in?  A bit of Lewis acid is all that is required, once a pendant methylamine in in place.  An addition into that rather conspicuous looking (and remarkably stable) dimethyl ketal did exactly what they wanted (in a moderate yield), installing the final stereocenter in predictably cis manner.


Nice work from a group I was unaware of.  I’m looking forward to more from the Castle group!

1 Star2 Stars3 Stars4 Stars5 Stars (5 votes, average: 3.80 out of 5)


  • GYA says:

    leaves room for improvement

    • milkshake says:

      No i think this is most impressive work, given that the actual lab work was all done by just two people, and considering all the possible complications that could have happened late in the synthetic scheme

      • The Next Phil Baran says:

        This is a rather complex molecule: lots of functional groups, stereochemistry, etc. Its synthesis will be difficult for most groups. I think you are right on this one Milkshake, it is pretty impressive as a synthetic endeavour. I guess GYA is remarking on the difficulty of getting the advanced precursors. Once they have the proper substrates for some of the big transformation (radical, etc) then it is beautiful. Unfortunately, the number of reactions to make these precursors is lacking. If the precursors could be made in less steps then it would definetly add to it, but their major synthetic cuts and execution are rather nice. I also like the implementation of the cyclic amine starting from the aromatic.

        • HPCC says:

          I really loved that synthesis, and may I disagree with GYA: if you’ve ever tried to build ADJACENT quaternary ALL-CARBON stereocentres, of course WITH control of the stereochemistry… you’d appreciate the feat. :)

          My apologies for yelling in CAPS, but I have no clue about html tricks to use bold or underline…

          • GYA says:

            I HAVE built quaternary all-carbon stereocenters. Not adjacent one’s, but I understand the difficulty. I just feel the entire synthesis could have been executed in a far more concise manner. The elaboration of the spirocycle is lengthy. Case in point: one carbonyl is reduced, protected, carried through some steps, deprotected, oxidized, and methylated. Come on! The entire synthesis is also quite lengthy and it doesn’t even trace all the way back to commercially available SM’s in the OL paper. I almost guarantee someone will tackle this challenge in a more concise manner. Once again some of the reactivity is interesting and creative, but there is room for improvement.

      • Fil Barn says:

        Terrible, absolutely terrible, and I use those words without exaggeration or hyperbole.

        After reading some of the other comments, it seems others are impressed by how many “cool” transformations are involved (perhaps some of that is ignorance on their part). It’s far better to have a good, short strategy that doesn’t require fancy footwork. Synthesis is not “let’s see how complicated of a methodology or convoluted a cascade I can work into this molecule.”

        Room for improvement? Definitely. It’s going on my potential target list.

  • Potstirrer says:

    I like this synthesis a lot. A very creative solution to a beautiful little molecule. Anyone else wonder why they used the zinc allylation procedure as opposed to some other more well-known asymmetric allylation conditions?

    • Rico says:

      If you look up the allylation reference, it points back to an earlier Castle paper in JOC:


      It looks as though they screened a lot of different allylation conditions on the hasubanan alkaloids and Nakamura’s chiral allylzinc reagent was the only one that gave good yields and high ee. The structural similarity between those alkaloids and acutumine probably led them to believe that other allylation techniques would yield poor results.

    • aa says:

      i don’t have access to the paper right now to check references (and no updated publications list on his webpage), but could swear this group published an earlier paper describing the use of the chiral allyl zinc as the only one that gave good selectivity for these ortho-quinone monoketals…. anyone have that reference (if i’m not crazy and it really exists)

  • Pete says:

    Very nice work. The radical cyclization/polar crossover (in the Org Lett) is very nice. The [3,3] is beautiful. Maybe steppy in spots, but no doubt one of my favorite syntheses this year thus far.

  • UBChem says:

    Pete, you also liked (+)-Peloruside A so what do you know.

    • asdf says:

      what’s wrong with evans’ peloruside?

      • UBChem says:

        Nothing. I thought it was a long standing problem that got solved nicely. I just know Pete and was just having a little fun. No offense meant.

  • Anonymous says:

    It would be good if a list of all such little cuties could be pooled here.

  • PotStirrer says:

    So Paul, you did a lot of radical chemistry. I’m trying a 6-exo-dig radical cyclization onto an internal alkyne (Bu3SnH, AIBN, PhH, 0.1 M, rflx.) and only got VERY slow reduction of my heteroaryliodide. Do you have recommendations on what would be obvious to try next?

    • Tot. Syn. says:

      In my limited experience with reductive radical reactions (I did my DPhil on oxidative), this smells like bad news. It’s far easier to tweak a reaction that is giving undesired biproducts than force a radical reaction to go. Quite often the limiting factor is an unfavourable geometry, which requires a scaffold-redesign – a nightmare. The other common problem is insufficient stabilisation of the adduct radical. If the edduct radical is more stable, no cyclisation will occur, so ask yourself if there’s any scope for temporary functional group transformation.

      Okay, that’s all the bad news. There are other reagents you could try with the current system, though – and as reduction of your iodide is the only product so far, perhaps non-reductive tin propigators could do the trick. Something like hexabutylditin. It’s pretty nasty stuff, and needs photolysis to initiate, but it seems effective. Have a look at this JOC note.

      There’s not much scope for changing solvent, as far too many can donate hydrogen atoms to boost your reduction. Perhaps acetonitrile is worth a go – always did the job for me.

      Let me know what you think / what happens!

    • atomic.snow says:

      I did some reductive free radical fragmentation with (TMS)3SiH and cat. BEt3 in toluene at O°C. It went faster than Bu3SnH and cat. AIBN at 80 °C and gave better selectivity. Don’t know if this helps in your case.

    • Fil Barn says:

      Depending on your specific substrate, why not try a reductive Heck reaction (i.e. run a Heck reaction with a reducing agent such as formic acid present)?

      • PotStirrer says:

        @Fil Barn–Another good idea…that’s next on the list. Thanks for your suggestions guys!

    • Mike says:

      I’m with Paul on this one – if trapping of your initial radical with Bu3SnH is faster than cyclisation, then atom-transfer cyclisation could be the way to go as it makes the initial trapping degenerate and hence not a problem. As well as Bu3SnSnBu3, you can sometimes get these to go with Et3B/O2 – see this Tet Lett. Of course – as Paul says – if the product radical is less stable than the aryl radical, then you’re probably screwed whatever reagents you use.

      What’s peculiar is that you’re getting “very slow” reduction, which perhaps suggests that formation of the radical is not happening for some reason. Have you tried making fresh Bu3SnH?

  • Org Lett Reader says:

    I have to agree with GYA. No one can argue that 14 steps to install the last ring leaves no room for improvement.

    Still a nice accomplishment considering that BYU is not a graduate institution. I would not be surprised if the Professor carried out a reaction or two himself.

  • GYA says:

    Glad you agree, but BYU actually does have a graduate program and the individuals on the paper were almost certainly grad. students or post-docs.

    • Org Lett Reader says:

      Oops, you’re absolutely right about the graduate program at BYU, GYA. Not sure why I thought they didn’t have one.

      What does GYA stand for anyway?

  • Joe Oakwood says:

    So it seems that many of you who love this work have no problem with the fact that the only synthetic scheme presented in this paper details 14 steps to introduce one ring, with half of those steps being either oxidation state or protecting group manipulations. I appreciate the completion of a synthesis of this challenging target, but I must say that all of the interesting chemistry is presented in the Castle group’s earlier papers. Ask yourselves this: If this were not the first synthesis, would this paper be (or deserve to be) in JACS? I feel that the impact of this paper would have been greater had it described for the first time their radical-polar crossover work, but I understand that Castle is up for tenure and needs to publish as much as possible.

  • Cat Herder says:

    WTF… can we PLEASE stop discussing whether every synthesis belongs in JACS or not? Who cares? Does it affect you personally? If not, can we just move on and discuss the science in the paper?

    This happens with literally EVERY JACS synthesis that gets posted here. If this is all we are concerned with in the synthetic community, maybe its time we hung it up…

  • GYA says:

    if we don’t hold ourselves to a higher standard, what are we doing? do you want to see every synthesis in JACS where someone has used RCM to close a large ring or aldol methodology to make a polypropionate. its poor representatives of total synthesis that give us a bad rep. and lead many to feel the field is dead.

    • The Next Phil Baran says:

      Welcome GYA. Your words will fall on deaf ears, but the juice is worth the squeeze.

  • John Wood says:

    @ GYA:

    Tartakoff was an undergrAD

  • Dazed and Confused says:

    I think people want to get into discussions about JACS worthiness because in a way it is a measure of the quality of the science. JACS is a good journal and therefore they should be publishing good science. But since some people don’t want to talk about this, I’ll talk about the paper directly. Personally I don’t like this synthesis much at all. It is very steppy and lacking elegance. I agree that its a challenging structure and that again this proves that we as synthetic chemists can prepare just about anything with enough time and experimentation, but other than the radical cyclization worked out in the OL paper, the rest of the synthesis is pretty unremarkable. The anionic oxy-cope has already been shown to be an excellent method for making adjacent quat. centers, and it is exploited here well, but all the protecting group manipulations and oxidation state changes seem to make this synthesis long and cumbersome.

    Also the allylation using another chiral auxiliary is unfortunate. We all know how inefficient auxiliaries are; there as bad as protecting groups! I really don’t see any reason why we should continue to develop auxiliary based methods in this day and age. Auxiliaries had there day, but we should be striving to develop more efficient processes rather than continuing to develop such auxiliary based methods just in order to get publications. Can I challenge the chemical community to strive to try and solve difficult problems using new ideas in order to get around the efficiency problems associated with current methods rather than sticking with standby ideas just because it is easier?

    Overall, I think the impact of the earlier radical cyclization, and this synthesis would be greater if a more insightful route to the natural product had been developed.

    • milkshake says:

      Auxiliary methods: they can be quite lovely and save time to a medicinal chemist in hurry (no need to develop a chiral HPLC assay, or to do much optimization on the chiral catalysts, etc). My faves are Oppolzer sultam and Ellman’s tBu-sulfinimines.

      But what you are talkuing about in this case is not actually an auxiliray but a chiral-ligand-based stoechiometric reagent. I am not against them either (especially if they are bottle-stable) but they lack the charm of auxiliaries – producing the diastereomeric compounds when the induction does not work as intended

      • Dazed and Confused says:

        Ah, milkshake you do bring up a valid argument that sometimes auxiliaries can be very valuable since a catalytic asymmetic variant may not be available or practical. And indeed because of the low cost associated with some of the auxiliaries you mention in addition to Leighton’s work and others these methods can still be cost effective. However, lets not get bogged down in semantics. Using stoichiometric amounts of chiral material that is not incorporated into the final product is unattractive. I just want to urge people to try and think of ways to solve this problem by coming up with new solutions that use catalytic amounts of chiral material rather than just sticking with any inefficient technology. Personally, I don’t think auxiliaries or “chiral-ligand-based stoichiometric rgts” have much charm, but I realize that sometimes their use is unavoidable.

        • milkshake says:

          Rochelle tartrate salt that one uses to work up Al reductions is a single enantiomer. So is the cellulose in your filter paper. Regarding the atom economy – its not like we are getting rid of ethyl acetate and hexane, or trityl and TBDPS and Fmoc protecting group in the synthesis any time soon.

          • Dazed and Confused says:

            Don’t quite get your point. While I agree its not happening anytime soon, that doesn’t mean we shouldn’t be striving to get there. Do you think people living during the days of the roman empire would have ever thought that someday there would be electricity, cars, the internet, etc.??

  • Cat Herder says:

    Dazed and Confused,

    Thank you. That is the sort of discourse I hope for when I come to this site.

    GYA and TNPB, we *should* hold ourselves and the community to a higher standard, I just get tired of having every synthesis not being worthy. Clearly we can’t make brevetoxin in three steps in a bathtub, but I get the feeling that if someone did that, there would be posts here that it shouldn’t have gotten into JACS.

    As has been previously discussed, the fact that there is such a high standard for TS in the major journals while nanocrap and chemical biology can do anything they want and get these types of papers. It seems to me that since we referee our own community, this result is symptomatic of a rather dysfunctional scientific culture.

    The fact that many groups are working on this molecule and Castle finished it with a relatively straightforward approach is worthy of a major publication. Hopefully its appearance in such a forum will spark ideas and discussions that lead to solutions to some of the problems that make the synthesis less than spectacular.

    In other words, I agree that we should be critical, but not to the point where we just tear each other down to the detriment of the field. I fear we are dangerously close to that point already. After all, why do you think there are so few TS papers in JACS? probably because they all got rejected by other TSers.

    • HPCC says:

      Sometimes, just because it is the first, and still showcases a few interesting methods (the 3,3 rearrangement and the oxidative radical crossover), although it contains too many non-C-C bond building redox steps, it will get in JACS. Why? Because it was a ‘well-sold paper’.

      Think of the CP molecules. KCN made them first. With Phil Baran’s help (LOL). It contained a lot of useless redox steps. The next-generation syntheses were nicer.

      My point is, this publication will stimulate the other research groups working on it to avoid these loopholes thrive to publish a JACS-worthy piece of work.

    • European Chemist says:

      Dear Cat Herder

      Let’s not forget the “fashion” aspect of science. In the good old days of Organic Chemistry (up to the 1980’s) you’d see a lot of it get into JACS and Angewandte. Nowadays, let’s face it: Org Chem is a more mature field than Nano or Biotech-shit-whatever. It hurts because we synthetic chemists KNOW that there’s still heaps of stuff to be discovered – but it’s the truth.

      On the other hand, I think you totally hit the spot. The synthesis community has grown WAY out of proportion – look at the number of research groups worldwide working on Synthetic Organic Chemistry or related fields. And think for a second – if ALL these people were brilliant scientists, doing risky and truely innovative chemistry, shouldn’t we have progressed MUCH MORE in the past, say, 10 years? The fact is that 80% of the groups end up doing what’s fashionable – be it Gold catalysis, Organocatalysis or C-H activation and just spend every possible second trying to get publishable material; and that’s it. I mean, look at all the nice reactions people are discovering and publishing on these fields and to 1) how few Full Papers are published with detailed studies (mentioning e.g. that for every table of 10 >90% yield, >90% e.e. examples, there are 30 others that DID NOT WORK WELL at all) 2) How little effort is devoted to mechanistic understanding; people draw whatever they want as “mechanistic rationale”, with very little evidence or even desire to acquire such evidence – because it doesn’t pay out in terms of publications!

      And then comes the peer-reviewing issue. I don’t think that the environment is more hostile in TS or Org Chem in general – but the proportion of people working on those fields is huge! Students know they will be judged by the amount of publications, tenure-track faculty know it even better and everyone just dances to this tune. Bottom line is, there is no incentive whatsoever to take risks or do far-reaching, deep-understanding chemistry. I talk very often to Inorganic Chemists and they are always appaled at the way things function in the Organic Community. For them,
      a) it makes no sense to publish a new reaction and then have to report 10-15 different examples of the same process
      b) it is completely ludicrous to test 60 different chiral ligands for an asymmetric reaction rather than to understand the kinetics and mechanism so you can UNDERSTAND which ligand or small family of ligands will work best. I open this for discussion…

  • The Next Phil Baran says:

    I think we have consensus on our non-consensus.

  • resonance says:

    Prof. Sorensen group is also working on this nice molecule. he gave a talk on the Last ACS meeting.

  • Gilgerto says:

    Anybody knows what’s going on with Sorensen? This guys has like 15 postdocs in his group and can barely publish 2 synletts per year (for exemple in 2008)


    • Aurora Borealis says:

      Ai caramba!

    • T says:

      I was out Sorensen’s talk at ACS as well. Ironically, he gave shout-out to Steve Castle who was in the audience! Those two must have been racing on this molecule to the very end – as it looked that Sorensen was quite close to finishing as well.

      I don’t think Sorensen’s publishing situation is all that odd – MacMillian has a huge group as well, but does not publish as much as one would think for such a huge group.

      I think some of this is due to the fact that these folks only want to submit papers to JACS/ACIEE and similar quality journals. But, that’s just my opinion. I could be wrong.

    • bad wolf says:

      Unmotivated grad students? Geez, a Sames post-doc and a C&E News editor.

  • Kenny says:

    I would challenge anyone who is critical to come up with a shorter or more elegant synthesis. This is a deceptively difficult target! Congratulations to Prof. Castle!

  • Anonymous says:

    why did he give shout-out?

    • T says:

      He was telling how some graduate students at Princeton who were undergrads at BYU were some of the best students currently at Princeton, and this was a testament to the quality of BYU.

      I’ve never met him personally, but Sorensen seems like a genuinely nice person.

  • Gilgerto says:

    I personally met Pr. Sorenson and I can tell that he is a really nice person. I understand that quality is probably better than quantity, but at some extend, something has to get out of your lab when your group is 30 with many post-doc.

    If you look at his list of publication, his group published only 7 papers between 2006 and today, and only one of these publications turns out to in a top quality journal (as some might say)…

    • BT says:

      Sorensen has always taken a “High Risk, High Reward” approach to designing his syntheses, often employing late-stage cascade sequences [e.g. FR182877, hirsutellone B,(+)-harziphilone etc…]. Gutsy– but when successful, it’s damn impressive.

      That being said, I think his approach to synthesis makes for a very slow pipeline of publications. Much of the work likely involves model studies and re-working of entire syntheses to fine-tune a late-stage cascade sequences. Not the type of stuff you see in JACS or Angewandte *too* often.

      In any event, his papers are almost always top notch, even if they fall into Synlett/Org Lett. I hope to hear more from this group soon…

      • chinstrap says:

        Whats wrong with Org. Lett?

        • Gilgerto says:

          Nothing is wrong with Org. Lett.

          • milkshake says:

            The funniest snobs are anxious students who parrot their snotty advisor. Arrogance is their antidote to insecurity.

          • BT says:

            There definitely isn’t anything at all wrong with either Org Lett or Synlett! I simply meant that seeing Sorensen as a co-author is enough enticement for me to read the communication, regardless of the journal.

            Quite a defensive group of readers you have here, Tot Syn…

      • Ian says:

        Idiotic last paragraph

  • xyz says:


    You sound like UncleAl!

  • Ian says:

    This synthesis is pumping Fe!!

  • John Wood says:

    Didn’t quite read every comment here, but what happens in the radical tin step?