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18 September 2007 9,365 views 24 Comments


Overman, Becker, Chua, Downham, Douglas, Garg, Hiebert, Jaroch, Matsuoka, Middleton and Ng. JACS, 2007, ASAP. DOI: 10.1021/ja074300t.

This is one mammoth piece of work. And that was the understatement of the week (which for me is saying something…). Loads of research groups have been working on this beast, including Weinreb, Heathcock, Cha, and Marazano. And to the uninitiated, it might look like a relatively simple target… However, this nice, fat 16 page JACS article shows how difficult it can be. Anyway, retro time:


As you can see, this retro is a bit more complex than the average retro I draw. Also, the structure I’ve taken it back to still has four stereocentres, and isn’t exactly a trivial synthesis itself. I should also point out that this retro is based on the forward synthesis that worked, not the groups original plan. Plans evolve…

It’s interesting that in all this work, there aren’t any particularly standout steps (other than one specific example I will highlight). Rather, the synthesis is full of logical and reasonable transformations; no funky catalysts or weird reagents have been shoe-horned in – this is what worked. So what I’ll focus on in this post is the reactions that built the complexity.

The synthesis really kicks-off with a tasty Michael addition to an unsaturated ester. The stereochemistry of the oxazoline SM was sufficient to direct the addition in great d.r. The Boc group was nuked by heating the crap out the substrate, and then a bit of Me3Al to induce amidation. They were then able to alkylate the lactam with 3-bromo-2-methylpropene with good control of stereochemistry. Then a little bit of acid did quite a lot…

Taking this rather complex lactam, a reduction took care of that carbonyl, and forming the spiro-fused lactone was relatively straight forward. Reducing this lactone to the lactol promoted a cyclisation of the tosyl amine, completing the six-member ring, and producing something reminiscent of the natural product core.

Formation of a carbamate with the free hydroxyl was simple, and tied up the core nicely. They then cleaved the double bond with ozone to give a handle for a olefination with a one-carbon substrate that allowed for aldehyde formation. The silyl enol-ether was formed and a bit (of rather hindered) base promoted an iminium ion cyclization – and my favourite piece of chemistry in this paper.

With four rings intact, and functional groups-a-plenty for functionalisation, I’ll quit discussing the forward here. The macrocycle construction gave the group quite a head-ache, but the results and methodology used is self-evident from the retro. However, they go into quite some detail about what didn’t work, and why it didn’t work, which makes this paper more than just a great synthesis, and more than a great read.

InChi data:

/h6-20,25-26H,5,21H2,1-4H3/t25-,26-/m0/s1 InChI=1/C18H25NO6S/c1-14-9-11-15(12-10-14)26(22,23)19(17(21)25-18(2,3)4)13-7-6-8-16(20)24-5/h6,8-12H,7,13H2,1-5H3/b8-6- InChI=1/C47H58N2O10SSi/c1-10-56-43(51)47(36(32-41(50)55-9)30-31-49(44(52)59-45(3,4)5)60(53,54)37-28-26-34(2)27-29-37)40

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  • milkshake says:

    just nitpicking: the one stucture before the last depicting the iminium putative intermediate in BCl3-promited cyclization has extra O-C bond between the liberated OH and the iminium carbon; it should not be there. (I would write it with the O-C disconected, as -OBXn).

    Nice work – it must have been quite something to wad through this goddamned synthesis.

  • tom says:

    As an undergrad I liked this synth quite a bit as most of the reagents were definitely within my synthetic vocab. I couldn’t believe there were 149 structure references in the paper.

  • HPCC says:

    Congrats, Paul you did it! :-) Now may you get a night of rest…

  • Liquidcarbon says:

    I was contemplating on blogging this one…

    This kinda of makes me fall out of love with TotSyn. Has the world become better after showing an example of sulfonyliminium-silyl enolate reaction? It took about TEN years! For no particular activity! Look at the authors’ affiliations…

    though I agree that this is a very interesting read…

  • ZAL says:

    Sorry if this is a stupid question, but could someone explain to me how the last transformation works? I don’t see how a base can generate an iminium ion from the structure on the left (which is what it does, if I got Paul’s description right), and what’s exactly the role of BCl3? Thanks!

  • milkshake says:

    Paul has one extra bond written there incorrectly. BCl3 is super-strong Lewis acid. It ripps away the ROH from the tosylated aminal, producing tosyl iminium which then does electrophilic substitution on vinyl silyl ether (has to be bulky and stable TIPS silyl enol ether or you get desilylation instead). So it is iminium version of Mukayama.

    You need a very hindered (poorly Lewis-basic) base that would soak up protons from H[ROBCl3] (which is very acidic and would therefore mess up the silyl enol ether if no base was present.)

  • Liquidcarbon says:

    BCl3 binds to N,O-acetal oxygen and generates N-sulfonyliminium which reacts with silyl enolate. Pyridine base is just an acid scavenger. Lewis acid strength of BCl3 was found to be optimal — stronger reagents cleave silyl ether first and/or simply destroy the molecule.

    Paul just forgot to cleave C-O bond in the iminium structure, it should be [-CH2OBCl2, or [-CH2OBCl3]-, whichever you prefer.

  • ZAL says:

    Thank you guys, very quick and clear answers!

  • willyoubemine says:

    man, talk about an impressive piece of work. Kudos to those Overman students who thugged this out.

  • gilgerto says:

    This is a SI compared to previous KCN synthesis in ACIEE. Very detailed exp for every compound and 1H NMR as clean Mr. Clean cap. Great job.

  • nido says:

    this is a full paper in JACS where full experimental and a full account of the work are both requisites. The former was a communication in ACIE in which the authors are not actually
    required by the journal to send SI at all. If you look at all the NMRs here you will see that not all are 100% clean. Probably becuase, as every chemist know, somtimes its impossible to shift that trace amount of minor diastereomer or the compound starts to die a bit on the column/prep plate.
    Isnt it better just to show the whole thing with a few impurities and still provide SI rather than just provide none?

  • nido says:

    although I geuss then you wouldnt have anything to bitch about.

  • gilgerto says:

    To #11 and 12: It’s not my pleasure to bitch about SI, I just feel that when you provide a SI without experimental procedure as KCN does oftenly, there’s clearly some information lost during the publication process. For exemple if you want to make a compound reported in last KCN pub, you will need to make some optimisation since you don’t have full exp details, and I really think that you should’nt have to do this. Concerning NMRs, I’m not perfect so I understand that some minor impurities might be present since sometime it’s a real pain in the ass to get clean compound, but in the KCN case we’re not talking about minor impurities… Anyway I think we already had this discussion, did’nt we?

  • HPCC says:

    Overman is notorious for having the highest standards from his group when it comes to publication – including reproducibility. I’d bet my house on the fact that I could reproduce every single reaction in there. But don’t tell my wife I wanna bet the house… ;-)

  • NCSUchem says:

    Im a grad student at NC State and saw Overman present this work at GSK in the RTP for a distinguished lecturer seminar. It was quite impressive and a lot of steps for a molecule without that much functionality

  • Anonymosity says:

    Paul, gonna blog this?:
    J. Am. Chem. Soc., ASAP Article 10.1021/ja0744448 S0002-7863(07)04444-7

  • Tot. Syn. says:

    Anonymosity: You’re never as anonymous as you think you are. Your IP address (which is logged every time you visit) can be traced back to the domain you are on. So in your case, it leads back to UT-Austin. Interesting…
    Anyway, it’s a neat synthesis, so probably. I’m kinda busy just now, but it should be blogged in the coming days. And congrats if your were one of the investigators!

  • Anonymosity says:

    I am not one of the investigators (I wish I could claim so), though i know them and know the work. And I agree, they should be congratulated with or without a solicited blog recognition.

  • milkshake says:

    I also track the IP addresses of all commenters at Org Prep Daily. It’s only done for the eventuality that someone writes objectionable comments. That way I can allert their school or employer or government authorities. (The problem usually stops right after that. Hah.)
    I am not a grass – but there are some things that we have to report

  • kiwi says:

    Freedom is the freedom to say that two plus two make four. If that is granted, all else follows

  • carbazole says:

    I’ve met Neil Garg, the post-doc (current asst. prof at UCLA) who finished this beast. Great guy, and he definitely has earned a rep as a finisher of molecules. It says something to be able to come in and finish something like this in under a year that’s been ongoing for that long.

  • Rof5 says:

    #19: Wow, a tracker. That reminds me of the movie Rabbit-Proof Fence.

  • gilgerto says:

    #19: thanks Big Bro!!!

  • milkshake says:

    “We are slowly turning into a fascist state. But it’s taking forever!”