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Aburatubolactam A   

7 October 2008 9,724 views 28 Comments

Phillips and Henderson. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200803593. Article PDF Supporting Information Group Website

Look familiar at all?  If you’ve seen Phillips’ synthesis of cylindramide A (back in 2005), you might have a strong feeling of déjà vu, but I didn’t cover it, so this is a good opportunity to look at Phillips’ work on this intreuguing class of natural products (termed the ‘tetramic acid containing macrolactams’).  Again, we’re short on biological data; just a quick mention of ‘cytotoxicity, antimicrobial activity, and the inhibition of superoxide
generation’, but not specifically for this molecule.  However, we’re not short on chemistry.

Although it’s got more than a little conjugation, the macrocycle (at least to my eye) is the least challenging portion of the target, with the 5,5-fused LHS looking far more problematic. If you’ve read the cylindramide A paper, then  you’ve got a pretty good idea as to how Phillips makes the octahydropentalene system, but it’s such a sweet method, I drew it out in full:

So what’s going on?  A MacMillan-catalyst directed Diels Alder between the enone and cyclopentadiene gives the bicyclic product, generating a 93% e.e., and setting a quartet of stereocentres.  A bit of base, followed by TMSCl and then (stoichiometric) palladaium acetate oxidises this ketone to the enone (a Saegusa oxidation), which isomerises when treated with Grubbs 1.  Presumably, the driving-force for the isomerisation (RORCM) is strain-release.  Either way, it’s a nice way to get that system…

A few steps down the line, and they did a rather tasty Sakurai allylation, using a mild prep developed by Majetich.  Using fluroide (rather than, say, tickle-four), the silyl group is attacked creating an enhanced leaving group, faster.  Unfortunately, though, the stereochemistry went in favour of the undesired isomer with a 1:4 ratio.  This was improved to 2:1 by forming the silyl ketene acetal and hydrolysing it with HCl, but they had to do the next step (an iodolactonisation) before they could separate the isomers.

The last few steps of the synthesis were a really nice sequence of events (which Phillips describes as requiring a few different strategies before succeeding).  The two main fragments were coupled by heating together in toluene, giving a β-ketoamide.  A Stille coupling then bolted on the acrylate unit, and was followed by a intramolecular (Lacey) Dieckmann cyclisation, giving the five-membered ring product.  It’s a very useful reaction for this system, and not the first implementation; Ley’s synthesis of physarorubinic acid is another that comes to mind.

Deprotection of both protecting groups in TFA, and amide coupling completed a rather nice synthesis.

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  • gilgerto says:

    Holy sh… That is a bad looking guy (my opinion, of course)

    ASAP in JACS, Charette described a similar RC-ROM strategy to build a quinolizidine skeleton. Interesting to see this powerfull method in action.

    Also, I would’nt say that the TMS group is becoming an enhanced LEAVING GROUP upon fluoride addition…

  • mevans says:

    Why didn’t they use a chiral activator for the Sakurai reaction? Seems like that would’ve improved their dr’s more than fooling around with silyl ketene acetals and such…perhaps I’m missing something. Looking at the o-c.org page, I don’t actually see any stereoselective allylations of enones…

  • Tot. Syn. says:

    Hmm. A group that leaves = leaving group? A trimethyl silyl cation isn’t going to leave, but TMSF is…

  • conte says:

    congratz to furrowstatin: the Nobel Prize went to Tsien, as he/she guessed some days ago!

  • gilgerto says:

    To me, a leaving group is leaving with his electrons, which is not happening in the case of the pentacoordinated fluorosilicate group. But of course TMSF is ”leaving” here.

  • milkshake says:

    called “nucleophilic activation”, the penta- or hexacoordinate Si- forming agent does not have to be fluoride (a somewhat problematic in total synthesis because of silyl protective groups). When you use allyl-SiCl3 it works with HMPA or even pyridine N-oxide as a catalyst. We just had Kocovsky visiting recently at institute and he gave a nice seminar on his asymmetric catalytic version of these allylations.

  • gilgerto says:

    Yeah! the Lewis base activation of Lewis acid has really nice applications. S. denmark’s chemistry in that field is of mention.

  • bad wolf says:

    “A group that leaves = leaving group?” I for one support this controversial definition.

  • milkshake says:

    leaving group, in pharma industry – updating the CVs and packing boxes The last man turns the lights off

  • gilgerto says:


  • pdf says:

    Talking about leaving… one more Nobel Prize in Chemistry “leaving” from chemistry to biology. Three guys this time. I quit.

  • Giagan says:

    I too take issue with the reference to the silyl group as a “leaving group”.

    In nucleophilic substitution reactions, the leaving group is typically attached to the atom being attacked, not being attacked itself. Take, for example, the displacement of mesylate by chloride; chloride attacks the adjacent carbon atom, and mesylate is the leaving group.

    In this case, the silyl group itself is directly attacked by fluoride (by analogy to the Hosomi-Sakurai allylation reaction that Tot. Syn. linked). If anything, the substrate itself, the intermediate cationic bicyclo[3.3.0]octane, is the leaving group is this displacement reaction.

    I do agree that the synthetic approach to that fused bicycle is pretty sweet.

  • q says:

    I have a couple minor questions about this synthesis, if anyone can help me out:

    1. Why stoichiometric Pd in the Saegusa oxidation? I thought you could do that with catalytic quantities. Especially at such an early stage in the synthesis where they are blowing through a lot of pricey Pd.

    2. Is Lacey-Dieckmann a special kind of Dieckmann, or is it just a normal Dieckmann with an extra name?

    3. As a general question, I know that conjugated polyenes tend to be unstable. I don’t imagine that this one has enough olefins to be too problematic, but is there a general rule about how much conjugation you need before you really have to worry about it?

  • gilgerto says:

    In a deprotonation, is the proton a leaving group??? :)

  • anonymous says:

    No, it is being taken up a base; leaving group some thing that leaves when something kicks it out…..specially from behind. ….):

    I like Milkshake analogy……the old guys in pharma is kicked out by the younger ones!

  • gilgerto says:

    Nice definition

  • Liquidcarbon says:

    Oh, semantics. I’m gonna call it ‘electofuge’.

    Paul, check my recent comment on azadirachtin…

  • Liquidcarbon says:

    i mean ‘electrofuge’

  • KCN says:

    We have discovered a very interesting substance which has a lethal dose in rats as low as 0,2 micrograms/kg. It has a very unusual structure and contains 3 Se atoms. We aren’t very certain wheter the structure we determined is right so we have to do more research. I’ll give more information later…however it has a continuous 145 C chain, 3 Se, 22 O, 8 N and 3 Br…It will be imposible to synthesise it in the 21 century due to it’s complicated policycles which will be publised as soon as possible. Any comments? anestezin@yahoo.com
    I am so praid I know so much chemistry….I expect to receive the Nobel prize very soon.

  • Tot. Syn. says:

    Look you Romanian cock, using different email addresses does not hide your identity. Why bother? A quick look on RIPE server returns: “Organizatia Studentilor Medicinisti Cluj”, which sure as hell ain’t KCN. Plus, I’ve heard he can speak English. I normally delete your comments out-of-hand, but for once I’ll leave your mouth-breathing idiocy for posterity. Feeling embarrassed and ashamed of your inadequacy yet? You should be.

  • KCN says:

    Well, Tot. Syn., it is quite obvious that when you’re IQ reaches 50, you should sell. Of course dear I didn’t expect you to believe I am the real KCN. However, I admire him very much. Moreover, I am sure I know more organic chemistry than you…you??? Ha. I don’t think you’re even a chemist so please, don’t comment. Tot. Syn…..Who are you? An administrator :)))

  • KCN says:

    Moreover baby, I don’t fell embarased !!! But you should. Because you hate romanians. I hate you

  • Undergrad senior says:

    Hey, I am trynna go to grad school for synthetic chem but I don’t which schools fit me, and which are sort of safety schools, would anyone here know where I should look? Or know from personal experience?

  • Tot. Syn. says:

    Let’s start with you telling us which country you’re in / interested in moving to ?!

  • TWYI says:

    I would use English in any applications

    ‘Trynna’ is a definite no no

  • undergrad Senior says:

    Thanks TWYI,

    However, I am planning on applying in the united states, and I currently am a Pharmacology major at Stony Brook University. I am ending up with the issue of not having enough safety schools because I do not really know what a safety school is for me.

  • Tok says:

    undergrad senior,
    If you’re looking for a job in industry, I wouldn’t go synthesis. Get out while you can! It’s a sinking ship!

  • % says:

    agreed with Tok.

    Some experts guess that within the next 15 yrs we’ll see an 80% decrease in state-side employment for medicinal chemists…