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15 December 2008 14,018 views 43 Comments

Kobayashi, Yamashita, Murata, Hikage, Takao, Nakazaki, and Kitahara. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200804544. Article PDF Supporting Information, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200804546. Article PDF Supporting Information

When the synthesis is spaced over two papers, you know it’s a biggie; a true beast of a natural product, Norzoanthamine made the gloried pages of Science when it was first completed by Miyashita back in 2004. Bulging with interesting biological activity (the headline being prevention of decrease in bone weight in osteoporotic mice), med-chem work is apparently under way. Coupled with a lack of comments about ‘scarcity’ or ‘low isolation yield’, I’d guess that it’s relatively easy to get hold of (though perhaps not is kilo-quantities), but that shouldn’t stop work on it’s synthesis.

Kobayashi’s approach is surprisingly linear, starting with the now rather familiar Hajos-Parrish ketone (discussed here a few months back); the easily installed asymmetry in this starting material is used to control the bulk of the synthesis. However, it has to be said that elaboration of the 6,5-fused system took quite a bit of effort; eighteen steps took them to a tightly functionalised, but still small core. In a few more steps, though, this was to change, as a rather nice alkylation bolted on a diene (nice stereocontrol, but this centre is perhaps irrelevent). This allowed a powerful IMDA reaction to occur, creating a further pair of stereocenters, and completing the A,B,C fragment. A hard slog, but with nine stereocenters, it was never going to be easy.

Next up was the fragmentation of the original penanone moiety found in the SM, now revealed. This was intended to become the D ring, a lactone, and thus an oxidative fragmentation was intended. However, things didn’t go as planned (which I’m sure involved a Baeyer Villiger oxidation), but the job was done using a pretty interesting series of reactions. Formation of a silyl enol ether using base and silyl chloride went as expected, but treatment of the enol ether with oxone ozone didn’t result in cleavage as expected, but as a single diastereomer of the α-hydroxy ketone. When this was treated with lead acetate, cleavage of the carbon-carbon bond was this time evident, but again the result was not quite as expected – rather than delivering homolytic oxidation, it appears that the hydroxy center is the focus of the oxidation action. The group postulate a mechanism for this chemistry, including a 1,2-hydride shift of the intermediate lead complex – worth a look…

Formation of the desired D ring was simplicity itself – treatment of the SM with unbuffered TBAF resulted in selective deprotection of the C-ring TBS ether and cyclisation in the basic environment. The last of the carbon skeleton was appended using a Horner-Wadsworth-Emmons olefination, and the group were soon ready to build the distictive bicyclic O,N-acetal. This went in reasonable yield, generating the desired stereocenter; the group must have been confident on this success, though, through model studies.

The D-ring, which had only been in place for a few steps, was then broken apart to allow oxidation of the C-ring centre. Then a final cyclisation, building two rings, completed the synthesis by formation of the second N,O-acetal. This is certainly tidier than the end-game employed by Miyashita, but a similar strategy.

Hmm. There are certainly some nice reactions used in this synthesis, but I feel somewhat underwhelmed. Don’t get me wrong – a synthesis on this scale is an extraordinary acheivement – but I don’t think I learned a lot along the way. Tell me what I missed!

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  • Gilgerto says:

    The silyl enol ether was not treated with oxone but with ozone as depicted in scheme 3.
    This is a strange way to perform a Rubottom oxidation. Any comments on that?
    By the way the alkylation using the bis allylic silyl ether to form a silyl enol ether is quite nice. I wonder if it is possible to use allylic silyl ether instead?

  • chinstrap says:

    @ Tot. Syn.
    Kobayashi came a couple of months back and presented this work at our institute. Claimed that it took about 10 years from start to finish. Wonder how many hours and underlings bringing up advanced material it took to complete. He had alot of slides of stuff that they tried but didn’t work out that weren’t shown in the communiation. If they get around to a full paper some of the blanks might be filled in.

  • BOB says:

    @ Tot. Syn.

    There are a few steps that stick out… Cuprate addition near the beginning to install the vicinal quat centers w/o protection of the ketone (I would have thought 1,2 addition would be more of a problem). The [3.3] to install the enone from an allylic alcohol with PDC is also a nice disconnection and I enjoyed the endgame of the synthesis with formation of the hemianimal.

    That being said, I have the same general feeling about the route. Too long, too many protecting group swaps that shouldn’t be needed. A colleague once told me that good science is about asking the right questions, and the problem synthesis often encounters is that the questions we are asking are really narrow. So I can’t help thinking that we (org chemists) get so fixated on relatively unimportant problems and over 10 years (and how many chemists?) there should be more to show for the effort.

    But Kobayashi should still be commended for his determination, I think I would have giving the whole thing up after 4 years or so…

  • Liquidcarbon says:

    With this endgame it should generate quite a few partial synthesis — you only need to make this ester-aldehyde now. And I’m quite convinced it could be accessed more effeciently.

    The five-membered ring from Wieland-Mischer-Hajos-Parrish was essentially a waste…

    I have on my mind a Diels-Alder between a AB-ring silyl enolate with dimethylpentenedicarboxylic acid anhydride. You would then oxidize it back to enone, and make quat. stereocenter with Me cuprate. This AB-ring silyl enolate comes from a decalinone with just (well, just) 5 stereocenters.

  • chinachem says:

    Nice work!

  • o-QM says:

    good one

  • npsynthesis says:

    Never heard of oxidizing a silyl enol ether with ozone..i have heard of enolates reacting with oxygen to give diketones…first done by Corey in the 70s.

  • ... says:

    Rubottom oxidations with ozone are a rarity. Sterically hindered alkenes get epoxidized by ozone rather than cleaved.

  • BOB says:

    My guess is that this is what is happening here…
    Epoxidation of the silyl enol ether would give the hydroxyketone after the TMS grp falls off in the workup.

  • q says:

    In your second scheme, what you show as a TES group is supposed to be a TBS. At this point, all three groups are TBS’s, they selectively deprotect the one they want (I noticed this because I had a difficult time rationalizing the chemoselectivity), cyclize, then switch the remaining two to TES’s. So, in your third scheme, the TBS should be a TES.

  • Tom says:

    Mulzer synthesis in jacs ASAP is pretty damn nice. Love the creation of the quat. stereocenter with the photocyclization between diene and arene

  • BOB says:

    And if you are really daring brevetoxin A was just published by Crimmins in Org Lett. You know the era of the long synthesis is over when a molecule like that can’t even get into JACS.

  • person says:

    mulzer’s synthesis is nice since it’s efficient, but almost identical to Wender’s work on silphinene (hydroxymethyl vs. methyl in the meta cycloaddition). it’s funny that penifulvin is in JACS and brevetoxin isn’t.

  • ,,, says:

    It reminds me how Mulzer approached platencin… (no offence though, he is a great chemist).

  • keenbeibei says:

    it seems there is gona be a lot more total syn starting with Hajos’ ketone

  • ZG says:

    They propose a hydride shift for the selectivity during the oxidative Pd(OAc)4 opening of the Hajos ketone. However, it seems that it is also possible to have an equilibrium of oxocarbeniums through an ene-diol where again one oxocarbenium is favored to be attacked by methanol. This would, of course, be very fast since proton transer is diffusion limited.

  • BOB says:

    The alpha hydroxyketone would exist as two possible tautomers and they would interconvert via enolization and protonation (I don’t think this is diffusion limited, although its a mute point anyway because enolization would be rate limiting). So long as this interconversion is faster than the oxidative cleavage (which is almost certainly true) you would have a Curtin-Hammett situation, where the ratio of the tautomers has little to do with the ratio of products observed.

    So the minor tautomer (that you don’t see by NMR) is attacked by methanol. This makes sense b/c you have a sterically less hindered ketone and the resulting hemi-ketal will not have gauche interactions with the quat. carbon center. Exchange with lead acetate, ox. cleavage and you have the product.

    The part about this that is a little strange is that you would have 4 possible hydroxyketone tautomers (b/c protonation can occur from either side). My feeling is that if you looked at the data for this compound it would probably be a mess – they just pushed it forward and eventually got to a single product after the stereochem has been erased.

  • vik says:

    Wonder if those types of hydride shifts are known ? The proton transfer makes more sense..dosent it ?

  • milkshake says:

    Have you seen the tasty Penifulvin A synthesis from Mulzer group, in JACS ASAP?

  • Johnny says:

    Anyone else notice the most recent synthesis of Zaragozic Acid C in the latest JACS issue?

    There have been a lot of nice syntheses lately. The photocyclization in Mulzer’s synthesis of penifulvin is pretty slick.

  • crab says:


    I see that there is a crab again…..pulling the ts crabs again

  • ,,, says:

    To milkshake

    It is in fact quite tasty but suffers from the same thing his (Mulzer’s) approach to platencin did (see discussion above regarding its relation to Wender’s work)…

  • steve says:

    to ,,,

    what’s the “same thing” about his approach to platencin?

  • person says:

    penifulvin was made in 6 steps, and you can’t really beat that, so in terms of efficiency this synthesis is fantastic.

    The rearrangement was nice, but the most difficult part is making the angular triquinane, no? Wender made silphinene in 3 steps (the triquinane minus the oxidation) and pioneered the meta cycloaddition while doing this.

    Wender and Ternansky, TL, 1985, 26, 2625.

    So in terms of novelty, they’ve made a molecule, they’ve done a neat rearrangement, and modified a known arene cycloaddition. That’s 3 new steps. Is it wrong to be critical about this point? I think it’s justified. But with that said, it’s still probably the most efficient synthesis to this molecule, but with that said I think Wender’s approach to silphinene was the most concise as well.

    So here’s an interesting question. I think there is a particular aversion in synthesis to use someone else’s chemistry, even though it may be the most efficient way to construct the molecule. If Wender had made penifulvin using this approach, I have to admit that I wouldn’t have felt the same way, and thinking about it now, it’s pretty ridiculous. Is this aversion justified at all or just a remnant of the big egos of the past?

  • ,,, says:

    Uups, I certainly ment platensimycin, not platencin. He (Mulzer) references Manders work, which is pretty much the key in the synthesis.

  • cjdquest says:


    You make an excellent point regarding the ‘aversion’ to use someone else’s chemistry. Is it justified? Is it appropriate? Think on this – why would anyone bother to develop a reaction if not to someday have others use it? Isn’t that somewhat in opposition to the whole endeavor of science and technology?

    In the old days of gentleman-scientists, some papers would end with a line about how the author wishes to “reserve the field for himself” or some such statement. I believe some of the first papers on carbon-centered radicals and the Diels-Alder reaction contained such statements. Is that the best way to do things?

    Its perhaps important to realize that Wender himself did not ‘discover’ the meta-photo cycloaddition of arenes, but he was instrumental in developing it as a synthetic method. An old review on arene photochemistry makes reference to the discovery of meta-photo adduct of a benzene and alkene in a PhD thesis from Reading in 1969 – the year Wender earned his BS… I’m not sure if this is even the first report. What if these people had put a “reserve for myself” type statement, but then never developed all the creative approaches and applications Wender did? I think the field would be worse off for it.

    Bryce-Smith Tetrahedron 1977, 33, 2459, refs 31 and 32 therein.

    Perhaps it is also important to note that Wender has been less active (do not read as inactive) in the photochemical cycloaddition area in the last decade or so. Its “heyday” in his group appears to be the late 1980’s – early 90’s or so.

    I don’t know Wender, or his opinions in this matter, but most chemists are usually happy when they see someone is using a method or strategy they were integral in developing – so long as its not in a way that they were directly competing on. As you point out, MuIzer adds a ‘neat rearrangement’ and ‘modified a known cycloaddition’, but as I’ve pointed out, although it would be incorrect and overly cynical, one could say that all Wender did in the 80’s was modify a “known cycloaddition”. My feeling is this type of reductionism isn’t that helpful, at least in this case.

    I would hazard a guess that Wender might have even been a reviewer for the Mulzer paper. If I were an editor, I probably would have sent it to him.

    Is it more appropriate now that Wender is less active in the area? – there is little chance he was actually in direct competition on that target. How would one feel about using an Aza-Cope Mannich approach to a target? Or a Trost-Tsuji allylation? Both of these are more “mature” synthetic strategies. How do you feel about Stoltz’s recent work with Trost-Tsuji allylation using Pfaltz-type ligands- genius or inappropriate? Some of this work got into Nature – I think the work was elegant. How about using a Buchwald-Hartwig reaction or a hydroamination- the groups working on these reactions don’t do as much total synthesis – does that somehow make using their chemistry more acceptable?

  • ZG says:

    I don’t think you would see 4 isomers for the hydroxy ketone since the rearrangement would not take place under the ozone treatment of the silyl enol ether. Only under the acidic condition of the Pb(OAc), should this take place and at that point oxidative cleavage takes place so the isomers are not observed.

  • ZG says:

    and of course enolization is rate limiting for the equilibrium, so the rate of proton transfer is a mute point

  • person says:


    I appreciate your points. Here are some thoughts.

    Corey wasn’t the first to reduce ketones with proline-derived boranes. Evans didn’t invent the aldol reaction. Hartwig/Buchwald weren’t the first to cross couple an amine with an aryl halide. But they certainly made huge contributions to these reactions that nobody would ever refute, even if they were “modifications.”

    Stoltz didn’t invent the tsuji-trost allylation nor the tBu-Phox ligand, but he improved upon it rendering it an enantioselective process that constructs quaternary centers. He was certainly very creative in applying it to total synthesis, and i think his work was very elegant. So i agree, reductionism as you labelled it is greatly oversimplified.

    Likewise, Wender didn’t discover arene cycloadditions, but was one of the first to apply it to natural product total synthesis. he made many triquinane structures while he was at Harvard. i thought his brilliance was the recognition that these reactions could be applied to rapidly assemble these popular targets of the time. While it’s not his reaction, i would contend that he is one of its pioneers as in its application to total synthesis, even though now he is less active in this field.

    I realize that we are all standing on the shoulders of giants. I agree that reactions are developed for a purpose, and that there shouldn’t be any aversion to applying these in later cases and by other people. i can’t think of a better way to make penifulvin than through what has been demonstrated. nonetheless, the key intermediate is one of Wender’s with different oxidation at one carbon. does this make it less efficient? no, but i do contend that it isn’t very novel.

  • milkshake says:

    What I liked about Mulzer’s paper is that it is a complicated natural compound that can be assembled fast, by one pair of hands (and it even has some useful bioactivity). It avoids drudgery so in this sense it is a great tot synth project for a student; and it does not bother me that they used Wender’s methodology as long as they gave the due credit in the references. Whether it is “groundbreaking” enough: there is plenty of pretentious material-science filler in JACS so I was delighted to see this clever piece of synthesis there.

  • cjdquest says:

    milkshake & person,

    I think I’m in agreement with your opinions on Mulzer’s penifulvin synthesis. Although the impact in the science of meta-photocycloaddition is not so high – the importance of the paper is in the disconnections and implementation, allowing the complicated target to be assembled really quickly. I can’t think of a better way to tackle penifulvin either.

  • ,,, says:

    It doesn’t feel right when we talk about something like “pretentious material-science filler in JACS”. Unless you, guys, have expertise in this area, we better discuss synthesis, not that stuff. Mulzer’s work is great, I agree that its hard to think about a better and more efficient way to built that molecule. Its just, well… like utilizing Overman’s aza-cope for certain indole alkaloid synthesis and not being Overman. Something like that…

  • Swapna says:

    Anyone see the Nature website?


    Nature Chemistry, how about that?

  • orgchem says:

    Hey guys, did you notice that Keck has published a more complicated bryostatin analogue in the Org Letter. So it seems that the publishing journal depends not on what you do but who you are.


  • Ian says:

    I would worry about this more to be honest. The same week a total synthesis of Brevetoxin A appears in Org. Lett., we get this ‘beauty’ in Angewandte

    Total Syntheses of Cytotoxic, Naturally Occurring Kalasinamide, Geovanine, and Marcanine A
    DOI: 10.1002/anie.200804388

    :| Sigh

  • ,,, says:

    Scary!.. Its the first synthesis, compounds are bioactive, but still… its just tricyclic aromatics. Please tell me I’m missing something!

  • Ian says:

    you are not missing anything other than the author knows all of his buddies on the Angewandte board of referees?

    this paper is an absolute joke

  • John Wood says:

    @ Ian: I figured that was coming! Anyways – fuck the Impact factor! If your chemistry is exciting or worthwhile then publish it anywhere, the people who really care will know the difference.

  • BOB says:

    I read the paper above and its pretty scary. I usually don’t believe that authors can get papers accepted by having friends review them. Either my faith in the peer review system is misplaced or o-chem is in worse shape than I would have thought.

  • BOB says:

    @ Tot Syn

    Take a look at ACIEE they just published a 3 pot synthesis of Tamiflu, really impressive stuff!

  • LW says:

    @ BOB.

    Yeah I just read that paper now. That really is a good succint paper. Is this the best yield on Tamiflu so far? I remember it was 57%.

  • LW says:

    My bad, it was better than previous syntheses.

  • LW says:

    @ John Wood

    I agree. However you have to admit, when you have papers bounced back because your supervisor doesn’t kiss arse and suck up to people (which is the way it should be) and you KNOW that it should have got into the journal it was first meant to go into, it really does make your balls ache after a while.

    Too many arsekissers out there now.