Home » Still In The RBF


24 June 2010 17,797 views 29 Comments

Shair, Liau, JACS, 2010, ASAP DOI: 10.1021/ja104575h. Article PDF Supporting Information Group Website

After wading through the Heathcock paper last week, I’m glad that today’s topic of discussion is a little shorter and easier to read.  (Seriously, part of me hates reading paper older that the 90’s as the style used in the schemes and figures is so difficult to follow.  Some of those 1960’s JACS papers are a real slog to get through – but worth it, normally….)

The target of choice today is Fastigiatine, a member of the Lycopodium alkaloid family, a popular target these days.  Two reason for that – 1. tasty biological activity checks the right boxes on the grant applications and 2. a complex, strained ringsystem makes for high impact publications.  What’s not to like?  Fastigiatine in particular is a tough cookie to crack, as additional complexity has resulted in a tightly-packed pentacyclic ring-system – something Matt Shair hoped to crack with a biosynthetically inspired synthesis.

The first reaction to catch my eye is the rather busy mixed cuperate addition into a malonyl cyclopropane.  I haven’t checked, but you can be fairly sure that Aldrich don’t carry these particular species, so it’s a good thing that their syntheses are fairly short.  The cyclopropane takes four steps from epi-chlorohydrin, so isn’t too bad, whilst the masked cyclohexenone was produced from the corresponding vinyl iodide (itself a five-step procedure).  See the SI for full details on these.  Combination of the two resulted (unsurpisingly) in opening of the cyclopropane to generate bulk of the substrate for the next important step.

The substrate in question certainly looks reactive enough, with two olefins along with that rather sensitive looking ketal.  Surprise (!) – a bit of acid unmasks the ketone, promoting a formal [3 + 3] cyclisation.  I’ll leave it to Matt to explain their thoughts: “…7-endo-trig intramolecular conjugate addition to form the C6-C7 bond, tautomerization to secure the C12 stereocenter, and finally a transannular aldol reaction to form the C4-C13 bond.”  Damn neat work.

Impressive as this was, the group actually targeted an even shorter route – one in which the nosyl protecting group was removed prior to cyclisation.  They hoped that this would be free to react with the ketone, resulting in an initial iminium ion formation, completing the whole ring system in one cascade.  However, the free amine was a reactive little beastie, preventing them from following this plan.  This left then with the final pyrollidine ring to install before retiring to the pub – a plan dispatched by firstly methylating the now-free amine, the using the tried-and-tested method of heating the crap out of it.

The group speculate that this process occurs firstly by retro-aldol to cleave the C4-C13 bond, then iminium ion formation and transannular Mannich reaction, using much of their original ideas.  To complete the target, the group were left with just a carboxylation of the tert-butyl ester and an acetylation to finish a really sweet synthesis and a fine read.

1 Star2 Stars3 Stars4 Stars5 Stars (11 votes, average: 4.36 out of 5)


  • James says:

    Awesome synthesis! They beat out several groups to the finish line… 30% overall yield! I’m only 10 steps into my synthesis and my yield is already half of that… Job well done!

  • A stickler says:

    While the Lycopodium family does have some members with interesting biological activity, fastigiatine does not.

    I do like the disconnection strategy, but am disappointed that they did not include the 4 steps it took to make the starting material (not to mention the mixed cuprate, neither of which are commercially available) in their overall tally of steps and % yield. Even though such practices are not uncommon throughout tot. syn. papers, it is disingenous.

    • organic chemist says:

      No matter how elegant the syntesis is, people always find a way to criticize. This is one of my most favourite synthesis.

      • diyne says:

        organic chemist: The tone of your post is anti-scientific. It’s beautiful work, I agree. It’s also not immune to scientific critique. I think stickler’s analysis was spot on.

        • PC says:

          it’s great work!really can’t see your critique is that “scientific”. Just forget about the stupid bioactivity and talk about chemistry…

          • A stickler says:

            There are a multitude of justifiable reasons to pursue a total synthesis. Here are the main ones:

            1) Interesting bioactivity (you need to make >5 mg. of product to justify any rudimentry biological studies, however)
            2) Highlight a new methodology by its application to kung fu a complex molecule in half.
            3) Highlight a strategy that enables access to an *entire class* of natural products, and not a shoehorned approach.
            4) Confirmation of structural analysis.

            The disconnection approach for this target is not new, and very Heathcock-ian (which isn’t bad, mind you). I applaud their use of simple reagents (except that mixed cuprate) and transformations throughout the synthesis, including the use of the cyclopropane in the first step to address that extra carbon, but beyond that, this contributes nothing novel except it is the first synthesis of this natural product. A very well executed synthesis, but neither is it ground breaking.

            The only other reason I can think of climbing such mountains (pardon the analogy) is the challenge to innovation. Sometimes you hit a brick wall, and need to come up with a completely new and useful solution to circumvent it. Other times, entirely unexpected results can present unique opportunities for new methods, disconnections, etc. In academia, we’re engaged in basic science. We’re tasked with charting undiscovered country, boldly going where no one has gone before (pardon the Star Trek analogy). This paper illustrates what can be done with tried and true 1970’s & 80’s era disconnections and simple transformations, but not what *could* be done. I expect more from a setting as exalted as Harvard.

          • European Chemist says:

            To “A stickler”

            You forgot to add

            5) To reach the target in fewer steps/higher efficiency than previous syntheses
            6) For sheer intelectual stimulation! Who can tell what will come out of ANY research project? It’s this disturbing tendency to ditch out work which presumably “brings nothing new to the field” that causes Organic synthesis to have stagnated as it has. If the big dogs of the 1950-60’s and 1970’s had to justify every single research project they got into under the umbrella of “is this groundbreaking? does it use fancy chemistry? will it make it to JACS?” our field would never have advanced the way it did. Because you never know where truly unexpected and sound discoveries are going to be made – it can be while trying the fanciest C-H oxidation with gold or in the first steps of a “not innovative” total synthesis.

          • PotStirrer says:

            I propose the use of Heathcocky as opposed to Heathcockian. :)

  • ch3mical says:

    pants on the ground

  • European Chemist says:

    This one really is a gem. Quite honestly, would anyone care if the overall yield was 20 or even 15% instead of the 30%? And if instead of 15 it should be 19 steps?

    The monocylic precursor is assembled in a clever manner (additions to activated cyclopropanes are quite underappreciated in total synthesis), and the way in which that vinylogous amide snaps shut, using only aqueous HCl, is impressive. Plus the cyclisation of the nitrogen onto the angular alcohol, just by heating in trifluoroetanol… this looks like one of the top total syntheses of 2010 to me, from the standpoint of design and innovation.

  • head scratch says:

    What exactly is the innovation here? A mannich reaction? opening of an activated cyclopropane? another lycopodine-family synthesis? Read Heathcock’s syntheses of these types of molecules – also high overall yields and low step count. These types of mannich methods to put together alkaloids are decades old and obvious.

    its a solid synthesis of a 1970’s era target with similar era chemistry.

    • Ian says:

      Agreed 110%

      This synthesis is great if it is 1985

      • Starvinmarvin says:

        Does an elegant synthesis need to include fancy reagents or gold catalysis for some people to find it admirable? Even if the chemistry is solid and old, it’s the retrosynthetic thought that counts. If you are able to pull off a molecule like this using good old cheap chemistry, it’s even better.

        But I guess some chemists are disgusted when they don’t see reagent-controlled stereoselectivity, fancy catalysts or exotic cascades.

        Anyway though, I found this particular paper worth reading and I think Shair did a good job on that molecule. Shame though he failed to include initial steps in the step count, but I guess more and more groups tend to do that like it really mattered if you finish the molecule in 19 or 34 steps. It’s the idea that matters. An idea that either uses some new fancy chemistry, or (at least I admire such syntheses) syntheses that show that you can create complexity with tools from 1950’s R.B. Woodward style.

        • European Chemist says:

          That’s already two of us, Starvinmarvin. It seems that more and more of the “new generation” of chemists tend to despise simple but efficient synthetic tools, if they were not published in some JACS communication post-2000 under a fancy name.

          • The Next Phil McGroin says:


          • LUMO says:

            I agree with Starvinmarvin, the simpler the reagents are (combined with smart retrosynthetic analysis), the more elegant the synthetic approach is. In my experience, when you try to apply fancy methodology to your substrate, it usually fail. However, old school reactions and reagents use to work properly.

            PS: Thanks Paul for your nice and interesting blogging, I’m waiting for the next post!!

        • A stickler says:

          (5. To reach the target in fewer steps/higher efficiency than previous syntheses)
          This is not a reason to embark on a total syntheis, but is a result of the #2 reason that I mentioned above. I should note that being the first is not always the best. The synthesis itself should impact the field rather than just those working on the natural product/class, and I think subsequent syntheses of natural products which highlight new and powerful methodologies are just as valid.

          (6. For sheer intelectual stimulation!)
          I agree, within reason. Read my last paragraph in the above post. Curiosity and the ability to pursue it is the underlying attraction to academia, and I don’t think anybody should discard a good idea if it doesn’t fit into one’s conception about what is ‘JACS-worthy’ or not. Sometimes a new methodology would make a better JOC note than a JACS communication, but that shouldn’t stop someone from pursuing that initial line of insight. Its always better to prove a new methodology with a simpler system before its application to a total synthesis. If it’s a key step, most funding agencies won’t fund a proposal if there isn’t a valid reason for it to work in a more complex system.

        • Stef says:

          v true – there is no “old” chemistry, if it is good chemistry and working properly it is timeless good chemistry. I prefer it to a fancy new method that only works on a v limited scope. Not saying that every “new” chemistry is like that though. But there is certainly nothing wrong in using a Mannich reaction as it is as an aldol-type reaction one of the best methods to do a carbon-carbon coupling and even chemists that do fancy gold-stuff still say that the Aldol-reaction is probably the most important reaction in organic chemistry!
          I absolutely like this synthesis!

    • chemist_in_the_making says:

      Yeah I agree. Heathcock used a almost similar Mannich protocol to assemble the backbone of another lycopodium alkaloid – Lycopodine. But atleast Shair didn’t reproduce the Heathcock synthesis. I would like to give him the benefit of the doubt. And also, that address of MIT helps in getting the work known to broad audience and getting the article published in well known journals. This synthesis is not really that concise either (19 steps). The best synthesis, in my opinion, of the lycopodium alkaloids published over last two years is the Dake synthesis of Fawcettidine (ACIEE) and Johnston’s synhesis of Serratezomine A. Very original methods and strategies were utilized to finish the syntheses of these two highly oxygenated lycopodium alkaloids in 15 steps each.

      And then, there has been atleast 4 syntheses of lycopodium alkaloids (15-17 steps) reported in Eur. J. Chem and org lett (mostly Takayama and Mukai) in the last few months. They all have really good strategy and planning-not inspired by any previous work. I really considered them JACS/ACIEE worthy but I am not the one reviewing them.

  • Canadian Organicker says:

    In my opinion, getting bogged down in step count detracts from the beauty of a key step. The transamination, followed by tandem bond formation to form the tetracyclic core shown in the second scheme is quite stunning. Arguing if the synthesis of a known but not commercially available compound (that according to the SI can be prepared rapidly on a multigram scale) should be in the sequence or not is sort of beside the point.

    @chemist in the making, The Dake synthesis of Fawcettidine is indeed a fine read, but I do not believe that the “original” yet sequential assembly of the rings over 16 steps has the same aestheic appeal as the approach employed here. To finally beat a dead horse, I will point out that the Dake work starts from Pulegone, a chiral pool material of considerable complexity and a known compound. It is simply an accident of nature that a terpene (or any chiral poool material) provides an appropriate starting point for someone’s strategy toward an alkaloid(or any other target). If that compound was not available to him, he might have required more steps up front too, which he also would not have counted if they were previously known materials.

    PS, last time I checked, Matt Shair is at Harvard, not MIT, though that obviously does not change the implication of your argument.

  • chemist_in_the_making says:

    Canadian Organicker quotes:
    To finally beat a dead horse, I will point out that the Dake work starts from Pulegone, a chiral pool material of considerable complexity and a known compound. It is simply an accident of nature that a terpene (or any chiral poool material) provides an appropriate starting point for someone’s strategy toward an alkaloid(or any other target). If that compound was not available to him, he might have required more steps up front too, which he also would not have counted if they were previously known materials.

    Clarification: That interemediate 10 in Shair’s synthesis comes from R-pulegone!!

    Canadian Organicker quotes: Its not. The transamination, followed by tandem bond formation to form the tetracyclic core shown in the second scheme is quite stunning

    Clarification (repeat): Its not. This strategy has earlier been used by Heathcock.

    P.S – My bad on confusing MIT with Harvard.:)

    • HeathCocky says:

      You know, Heathcock added to an iminium ion to make lycopodine, not fastigiatine (which makes it transannular for fastigiatine). Stork also added to an acyl iminium ion, forming the same C-N bond, also to make lycopodine. Does this mean that Heathcock ripped off Stork? The formal [3+3], although sharing the same iminium ion disconnection, is unique in it’s own way.

  • AIK Stockholm says:

    I’m a “new generation” chemist but personally I’m driven and fascinated by simplifying syntheses, as this one for example. The beauty of it is mainly the nice disconnection strategy which gave a really elegant way of forming the main C-C bonds. How cares if it would have been possible to do in the 1980’s? Apparently it wasn’t since this is the most effective way to synthesize it. It’s quite obvious that critics of this kind of simple, biomimetic synthesis are people in the fields of fancy transition metal chemistry. Loosen up people and be humble enough to give cred to nice scientific work!

  • Matt's Chair says:

    Another really nice synthesis from the Shair group. You may only get one or two a year but when they do come along they are worth the wait.
    With the ‘is it worthy?’ comments in early what do you think of Shair’s tactic of only publishing few but strong papers as opposed to the opposite thought of quantity over quality (already having tenure of course helps)?

  • InfMP says:

    I agree with your comments.
    That’s what makes Classics such a good book. I don’t have a chance in hell of being able to actually read those manuscripts!!
    I hate the roman numeral figures. Just compounds with no arrows or conditions

  • rs says:

    How is the C6-C7 bond formation an “7-endo-trig” intramolecular
    conjugate addition?

    Will some one be kind enough to explain?

  • Thomas says:

    “7”: the shortes C-atom count from C-6 (nucleophile) to C-7 (electrophile) is 7.
    “endo”: the attacked C(7)=C double bond is inside the formed ring.
    “trig”: C-7 is sp2

  • rs says:

    Thank You. I appreciate it. I was misled by the dotted lines forming the 6-membered ring.

  • Ph.D. quitter says:

    Looking slick, but once u get into the pharma those fancy transformations are kinda useless, problematic to reproduce and don’t work as well as it’s written in the article…& after a while you look at those articles and say ‘ok, again the 253 synthesis of strychnine, taxol or whatever’….