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Hedychilactone B   

26 January 2007 4,585 views 14 Comments

Jung and Murakami. JACS, 2007, 9, 461. DOI: 10.1021/ol062811z.

Just a quickie for the weekend; a nice Org Lett by Jung, published at the start of the year. The target has an interesting biological profile, with anti-inflammatory activity and inhibition of nitric oxide production. The potency of the latter is also impressive interesting (see comments), with an IC50 of 28μM. The isolation was published back in 2002, so I’m slightly surprised that this is the first synthesis of such an attractive target, but this is a great approach to a congested decalin system.

I’ve not provided a retro for this synthesis, as the construction of much of the structure originates with one reaction; the [4+2] cycloaddition of a diene with allene carboxylate. This initially generated a cyclobutane via a [2+2], which then rearranged via a [4+2] to leave a pair of diastereomeric cycloadducts, with a 23% yield of the desired product. Although this is a relatively poor yield, this is still an amazing transformation on such a hindered diene. However, check the conditions; fourteen days at reflux in what is presumably toluene!! I wonder if they tried using a microwave…


With this intermediate produced so quickly (seven steps), the overall synthesis was complete in 18 steps; somewhat linear, but a very interesting paper.

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  • WillisWill says:

    I was never one for knowing the names, but isn’t that second pericylcic reaction a cope rearrangement?

  • rb says:

    Yeah, I would agree that the second step is a [3,3] sigmatropic rearrangement. See their earlier paper (Org. Lett. 2006, p 5857). It is interesting that the initial 2+2 is not concerted, which would make sense b/c allene-olefin cycloadditions are normally conducted under photochemical conditions.

  • Chemist of Sorts says:

    In an era when many drugs are single digit nM potency, 28 microM stinks. Yes, it does have potency but I sure wouldn’t call it impressive.

  • Tot. Syn. says:

    Depends which kind of treatment you’re examining; also, I’ve not seen that many natural products with that mode of action. I know that 28μM isn’t useful in terms of a marketable pharmaceutical, but it is a good starting point. Disagree?

  • Chemist of Sorts says:

    Not at all. I think those are good points. And I agree that 28 microM is fine for a lead. I would only add that I think academics sometimes tend to oversell potency. I would use the word ‘modest’ over impressive.

  • Tex says:


    You comment that you were surprised that it has taken so long for an approach to appear – I am not. For one the potency is not that great (it’s ok, but not great), but I think the major reason is that there are so many decalin natural products of this type out there, that most groups avoid them. Gets more difficult to be innovative and to get funding – “not another decalin natural product….”. Still, nice approach from Jung.

  • Peregrine Bertie says:

    I always asked myself: Why are there so many decalin natural products? Is Nature just good in making them or is it some kind of privilegded ligand?

  • Jimbo says:

    I’m pretty sure a microwave wouldn’t be that helpful. There have been several examples where the “microwave effect” hasn’t proven to be anything but a superheating of the solvent. My experience tells me that there are some reactions, particularly organometallic couplings that can benefit significantly from a good nuking, but most “all-organic” reactions don’t seen to benefit all that much.

    Re: decalins — they’re mostly steroid derived and it’s a biosynthetic pathway that’s found all over. If Mother Nature were able to make 1,2,3-triazoles easily, I’m sure you’d see a bunch of bioactive molecules containing 1,2,3-triazoles. I don’t know that the scaffold is all that special. I think it’s more likely that Mother Nature’s combinatorial library (like that of any big pharmaceutical company) is biased toward what She can make.

  • Jimbo says:

    also agreed that 28 uM is crap activity. Not sure if the mechanism is novel or not, but in pharma, most assays aren’t even done above 10 uM. You’d have to take a pill the size of a small potato to deliver enough drug with that kind of potency.

  • weirdo says:

    Totally agree that a molecule with that level of potency and that structural complexity would not get a second look in 90+% of drug discovery efforts — the odds are too long, and it’s likely to take too long to optimize.

    Still more proof that “Big Pharma” lacks innovation, is too risk averse, and is just waiting in the tall grass to rip off another tremendously important academic advance, I suppose . . . . .

  • Tot. Syn. says:

    I guess I was just interested in the biological profile, and I thought 28μM was somewhere to start; of course it’s nowhere near good enough for pharma use, but perhaps one of the other members of the class is more efficacious.

    And, yeah, I’ve heard all sorts of arguments about the μwave effect – it’s still pretty inconclusive. Anyone tried one of those biotage cooling μwaves?
    When I was on my industrial placement, some of the med-chem guys explained to me that the process dudes were having even more issues with the med-chem rout than ever – too many of them involve μwave chemistry, so scaling these reactions up is becoming increasingly tricky. Sometimes heating the crap out of them is effective, but other times it just diches…

  • Russ says:

    I have used the Biotage microwave system extensively, and read a fair bit about them. I think most, if not everyone, in the field now believes that there is no special microwave effect. Yet still, the microwave is invaluable for a number of reasons:
    – safe way to heat a reaction up to 250 degrees C or 20 bar
    – exquisite temperature control
    – automation

    Maybe not so practical for process purposes, but a great tool for a research lab

  • Jimbo says:

    Weirdo: I think you’ve been sold a bill of goods. Starting from a crappy lead and forcing it makes no sense when a high-throughput screen (which uses exquisitely beautiful nanotechnology) gets to useful leads much more quickly. Working a natural product into a drug lead isn’t new… that’s how the pharmaceutical industry got started. Innovation is the ability to decide what target you want to hit, then finding a molecule that hits it… not waiting around for mother nature to make a molecule that binds your protein of interest.

    I love academic chemistry, and certainly academic research drives innovation, but how many academic (chemistry) groups are actually inventing anything new? Is there a truly -new- reaction anywhere in the above described synthesis? (I know there isn’t in my own total synthesis work.) How about a new general reaction? My point is that if you’re going to knock pharma for lack of innovation, then you have to knock everyone. Almost all of the great minds that leave grad school ultimately end up at large companies… they don’t suddenly stop liking chemistry and stop thinking when they leave. They apply those skills in the synthesis of druglike molecules, the fine tuning of which is a much, much, much more difficult problem than any total synthesis. Ask someone in pharma! They’ve all done total synthesis AND med chem… almost all will tell you the same thing. On any med chem project there are dozens of parameters that must be fine tuned before a drug could even be considered a candidate for development.

    I’m constantly amazed by the stuff that goes on in pharmaceutical research… not only is the chemistry just as difficult, but all of the technology that has been developed either by them or at their behest is nothing short of phenomenal.