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28 January 2009 10,514 views 25 Comments

Kerr and Carson. Org. Lett., 2009, ASAP. DOI: 10.1021/ol802870c. Article PDF Supporting Information Group Website

After the ChemDraw marathon that was helicterin B, I was bloody glad to move on to a smaller target (even if the configurations are tightly packed…). This one has a pretty decent biological profile, and with a phosphate group hanging off it, no surprises that it interacts with the DNA machinary. I’m not going to blab on about it, but it’s certainly a worthy target; this’ll be why syntheses by Snider, Sorensen and Fukuyama (amongst others) are already out there.

So it’s going to take quite a bit of work to bring something new to the table, but Kerr makes a pretty good start with this enantioselective deprotonation. Again, it’s worth checking out Peter O’Brien’s work in this area, and probably this Tet. Lett. by EJ (back in the days when TL was worth reading). This proceedure established asymmetry at a quaternary centre with apparent ease.

The silyl-enol ether was then quenched with NIS to give the ?-iodo ketone (as a mixture of diastereomers, but this isn’t relevent), which participated in a pretty complex Reformatsky coupling. I say this as there are several factors – the aldehyde partner is chiral, so has a bearing, the iodide is also chiral, and the conformation of the cyclohexanone is going to muddy waters too. Kerr doesn’t try to rationalise the reaction too much – he was just happy to get a 4:1 mixture of diasteroisomers, which I reckon’s pretty good too.

A few more steps – a substrate controlled reduction and protecting group manipulations – and it was time to crack that cyclopropane open. Kerr’s been doing work on this kind of chemistry for years, with several publicaion on it, so there’s no real surprise that this goes like a charm. A bit of formaldehyde gives the N-methylene intermediate, which does a stepwise opening of the cyclopropane (nice, stablised malonate helping out a bit here). The malonyl anion then shuts down on the imine, building that pyrolidine nicely.

Seven(ish) more steps took the synthesis to fruition, but there were a few issues along the way. Mono-decarboxylation of malonate was a bit dissapointing, as no asymmetry could be induced at the common centre. This was saponified, Curtiused (protection with a Boc group in-situ), and methylated, giving them an intermediate that was close enough to those previously prepared that ‘formal’ methods were use to complete the synthesis. I would note though that the references for these steps are jumbled-up a bit – I think that 2f should read 2g.

Nice work on a compact target.

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  • UBChem says:

    G. R. Pettit deserves to be forgotten. Arizona State sucks ass.

  • about some old post says:

    UBChem, Why are you so angry?

  • Gilgerto says:

    I’ve seen Carson presenting this synthesis last year. She completed the target in less than a year… Pretty amazing, and it shows that Kerr’s chemistry is pretty efficient!

  • ZZZZZ says:


    …interesting that a malonate anion is proposed to do a 5-endo-trig closure in the final step of the cascade. Not a facile event…


  • UBChem says:

    You have to remember that Baldwin’s rules are empirical and when cations are involved than the rules kind of go out the window, ie acetonide formation from ketones.

  • ZZZZZ says:


    …ketal formation from ethylene glycol and a ketone is more the exception than the norm (for 5-endo-trig). In general, it’s a tough orbital overlap for such ring closures, so this reaction caught my eye. Not to say that it’s impossible of course…


  • earth23 says:


    And here I am thinking that all the professors at Stanford liked each other…..

  • Ondrugs says:

    On a different subject, check this little merger:

  • Tot. Syn. says:

    I think I should probably leave the commercial / business side of Pharma (as well as the Pfizer-baiting) to Derek, but this one’s got me riled.

    Twenty-Six Thousand Layoffs

    I don’t really have to add much to that statement. How the fuck to do they really think that products will appear if there aren’t any staff to make them? Sure, Pfizer can do what it’s good at, and repeat this whole thing with another company in a few years, but it’s not driving innovation.

    But it’s making the City bods really happy, so they’re chopping at the bit for the next merger, regardless to the actual pragmatics of it. You don’t want to know the rumours I’ve been hearing (really, you don’t – it’s all BS…).


  • Keith says:

    UBChem. Baldwin’s Rules???? If Sir Jack heard you use the term “rules” I think you could expect some of his famous temper to be directed toward you. Baldwin’s Guidelines was how he preferred to view them…

  • Mike says:

    It’s often said that Baldwin wants them to be referred to as “guidelines”, rather than “rules”… but if that’s the case, why did he call his paper “Rules for Ring Closure”?

  • Keith says:

    So does that mean at group meetings that JEB never ranted at you or somebody else when they referred to them as rules? You make a fair point, but I doubt anybody would have the guts to mention the naming of his paper to him. Certainly not when got into one of his “redhead” moods. ;-)

  • Mike says:

    Damn you Keith, you’ve seen through my cunning pseudonym and identified me as an ex Baldwin-group member! You’re absolutely right that JEB prefers the term “guidelines”, and even more right that one wouldn’t want to argue with him. But I’m afraid that, whether it’s the most appropriate or not, the term “rules” is the one in the literature, and the one that most people will continue to use.

  • Next Phil Baran says:

    UBCchem: All theories are empirical man. Watchu talkin’ bout? Mike: Game, set, match. They can’t be called rules if they are broken. Guidelines is a good way of describing them. Maybe ” Baldwin’s suggestions for ring-closure based on observed experiments” would be better.

  • Heiko says:

    hey paul,
    i just published this one a few days ago on my own blog ;)
    maybe you could link my one? it’s a cool reaction but to the end they wasted lots of material.
    I just found another interesting one in the same paper where they built up a pyrrolizidine but I disagree with the proposed mechanism. Maybe one of you find some answers?

    have a look: Synthetic Nature

  • InfMP says:

    Nova Scotia represent!!!! what up Cheryl

  • Ed says:

    Tot. Syn. I guess those rumours you were hearing were about the extra 6,000-7,000 job cuts at AZ then?

  • Tot. Syn. says:

    Actually, it was something else – involving another big(ger) British pharma company and AZ. However, that particular rumour seems to have been squashed, but this isn’t brilliant news either. However, those 6000 job losses are reported to be over 4 years, so shouldn’t be too harsh. Fun game, this pharma business…

  • Liquidcarbon says:

    ZZZZZZ is right at pointing out the Baldwin… thing. However, this case, where planar iminium is attacked by a planar malonate anion, is different from dioxolane closure, in which sp3-oxygen attacks intermediate carbocation. With both reacting species flat, separated only by one sp3-carbon, the ring closure is very disfavoured. I wouldn’t even draw this mechanism so confidently as stepwise.

    Paul, tell us the truth, do you look at the picture of the featured grad student before posting? :)

    Also, they call Sorensen “Sorenson”.

  • cc says:

    i am sorry that my arrows are upsetting people. i admit that i have not studied the mechanism of the reaction of imines with 1,1-cyclopropanediesters. we have done some work regarding the reaction of nitrones with cyclopropanes and believe it proceeds in a stepwise manner. i know this makes six-membered rings, not five. the Johnson group has reported on the reaction of aldehydes and cyclopropanes, and also suggest a stepwise mechanism (JACS, 2008, 130, 8642). the reaction of tethered oxime ethers with cyclopropanes is another example (JACS, 2008, 130, 4196). take that for what it’s worth. frankly, i was just relieved the reaction worked. yes, that typo is very embarrassing on several levels. i’m not really sure what the comment on my personal appearance is supposed to mean.

  • Liquidcarbon says:

    Thanks for the reply!

    I guess the stepwise mechanism indeed makes sense, in line with the competition experiment in Johnson’s paper (good paper!). Aldehydes or imines then should be considered nucleophiles, which is a bit unusual, but cyclopropanedicarboxylate is could be called a stong “homo-Michael” acceptor, further activated by a Lewis acid.

    I had my hands on cis-diaziridines + ketenes reaction, where we had occasionally observed pyrazolinones arising from 5-endo-trig enolate + iminium reaction. Most of the times it didn’t get to this point, especially with more basic enolates (i. e. not from diphenylketene). Since ketenes were generated from acyl chlorides and Et3N, we couldn’t be sure that the formed (more basic!) enolate would not be protonated by triethylammonium. So, after aqueous workup the iminium would fall off, giving a hydrazide.

    My dubious comment means that I’m abusing the anonymity of the internet to state that “it’s nice to have pretty AND smart girls in the lab” and should not be viewed as anything but a compliment.

  • Jose says:

    “back in the days when TL was worth reading”

    It is staggering how true this is. About 4yrs ago I stopped reading every issue. I keep skimming a new issue every 6 months or so to see if there is anything… Damn, it is truly a wasteland!

    • Tot. Syn. says:

      It’s a real shame, ’cause (at least in my mind) it starts to undervalue the journal as a whole, rather than just the recent issues. The old stuff, tellingly published prior to Org. Lett., was frequently awesome. Many an important Corey paper went in there.

      • Martyn says:

        About 50 % of the papers in Tet Lett so far this year have some supplementary data – that’s certainly the right way to go about reclaiming some credibility, just ten years too late.