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N-Methylwelwitindolinone C   

14 August 2011 18,110 views 19 Comments

Garg, Huters, Quasdorf, Styduhar. JACS2011, ASAP. DOI: 10.1021/ja206538k Article PDF Supporting Information Group Website

Technically beaten to the finish-line by Rawal (JACS in March), but still the first asymmetric synthesis of the Welwitindolinone family, this synthesis is one of many contributing to a hell of a year for Neil Garg.  I think the key to the synthesis was picking the perfect starting point – and dealing with poor yields that get you seriously further forwards.

That critical starting point is  fantastically smelling (S)-Carvone.  Not only does this make the lab (and presumably the chemist, his notebook, laptop, wallet…) smell great, but it also gives an asymmetric entry into the synthetic campaign.  Working from a previous synthesis of Hapalindole O (by Natsume in 1994 – PDF), a referenced synthesis appends a vinyl group and adds a stereocenter.  This was neatly done over five step (but tracing the yields was an exercise in exasperation, so I apologise!)

Cleavage of the pivolate group with a little base set them up for a major fragment coupling – appending that indole group.  The team did this using an iodine promoted alkylation, presumably by formation of the halonium ion followed by attack by the bromo-indole.  The yield might not be great, but this is a fantasticly succinct coupling strategy.

TBS protection (why didn’t they just keep the pivolate?  Did it prevent the coupling reaction from going well?) then set them up for the next critical coupling.  The medium ring was installed using the surprisingly simple approach of an indolyne cyclisation (have a look here to read more about indolyne, but think of it as a benzyne derivative), using just a little sodium amide.  So the base does two things – it forms the reactive aryne intermediate, and it forms the proximal enolate by deprotonation.  However, this kind of reaction always works better on paper than in practice, as the two different processes probably have different thermal requirements.  Attack of the O-enolate to form an ether was a competing reaction in what wasn’t the highest yielding process, limiting the team to a 33% overall yield – but yet again, this a was an impressive step-forward.

The latter intermediate is now looking pretty much like the target, but two key features are missing – the vinyl-chloride group, and the bridgehead nitrogen.  Let’s start with the earlier and easier transformation, the chlorination.  Taking the protected alcohol, deprotecting and oxidising with DMP took them to the corresponding cyclohexanone, which was deprotonated and treated with Comins’ reagent.  This generated a vinyl triflate, which was then converted to a vinyl stannane via some palladium catalysis.  Lastly, treatment with copper chloride (as below), gave them there vinyl chloride.  Nice.

Now for what looked like the more challanging move – converting the bridgehead methine into an amine.  Reduction of the ketone with DiBAL-H and formation of a carbamate was the easy bit, but necessary, as intermolecular amidation was impossible.  The group then intended to cyclise onto bridgehead, but of course, there are two bridgeheads, both neopentyl, so a selectivity issue appears to beckon. Looking at the (ultimately successful) reaction conditions shows a real witches brew of stuff – but we’re definately heading in an oxidation direction.  What acually happens under these conditions is formation of a nitrene, followed by C-H insertion – smart.

Quite a tour-de-force of chemistry here, using an impressive manner of techniques.  Congrats to the group!



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  • gippgig says:

    Pure speculation – perhaps it was necessary to deprotect the OH to get the correct stereochemistry at C-15. The extremely bulky indole side chain would be equatorial so the OH is axial. If the bulky pivaloyl was still attached it might favor the opposite configuration at C-15 so both substituents could be equatorial.
    Speaking of that oxygen, why would the ether side product (but not the main product) have lost the TBS?

    • Tot. Syn. says:

      Yeah, that oxygen is a typo…

      Good thoughts on the conformation of the cyclohexenone, though. I might try modelling that this evening.

      • gippgig says:

        Why would the indole attachment be stereospecific? I’d expect (in the absence of significant steric effects) a pretty random mixture of diastereomers at C-15.

      • gippgig says:

        A reaction (17 to 18) in the hapalindole O synthesis you link to yielded a very similar product with the pivaloyl attached which is strong evidence that my suggestion is wrong.

  • Hadriel says:

    The yield part, I can understand your feeling. I’m giving a presentation tomorrow on this paper (along with Rawal’s 2 syntheses and a bit of Baran’s 2 works and Wood’s), and doing the numbers for ANY of them is quite a pain. You certainly saved my life for that Natsume et al. paper, because I couldn’t get access to it.

    I can appreciate the amount of effort that all of these groups put in, but the yield side is quite… sad… Rawal’s work took 7 steps to reach the starting ketone at 15.8%, while Garg’s took 5 steps at about 10%… and his 17 steps took him till 0.78% before considering the carvone steps, whereas Rawal had 3% (0.45%) and 5.9% (0.88%) for Wel. D and dihydro-Wel. B before (and after) considering his 7 step synthesis of the ketone [from quinic acid…] Baran’s words in his first Wel. A paper on similar issues indeed made some sense now.

    But no I guess we shouldn’t be too critical on yield. It’s almost as if they’re at war here – you go this way, I go that way. This idea is original and fairly creative imo, but at a rather heavy price. That CHO-functionality in Rawal’s work certainly helped them a great deal, since nitrene insertion by Garg would theoretically be at a maximum of 40% (if you recycle). They certainly exhausted all the methods I (as a 1st year undergrad) can think of to install that group.

    Things I liked: vinyl chloride installation, iodine-catalysed michael-type addition (anyone has any idea on the mechanism? Loh’s paper doesn’t look terribly convincing to me, and I don’t thing the I would drop out just like that if via the usual halonium mechanism), and “indolyne” cyclisation.

    Things I didn’t like: the difficulty in trying to trace yields (dotz), and the low yields (not that they can do much about it. It feels like such a bad blemish, despite the nice reactions here.

    I note they tried to use the OTBS epimer to do the “indolyne” cyclisation, but it didn’t work. Modelling required.

    In all, I really appreciate all the effort they put in, and the nice ideas and chemistry behind it. Seems kind of overshadowed by the previous syntheses of the Wel. family. Still, not a bad first! (spare a thought for Rawal’s synthesis of dihydro-Wel. B…)


    • Hadriel says:

      Sorry I’d like to correct myself for the yield check for the 1st 5 steps in this synthesis from the carvone:

      71% * 91% * 35% * 95% * 80%(this one from Garg) = 17.2%

      So TS you can use these numbers – I did the math from all the papers.


      • Tot. Syn. says:

        Thanks – going to add them later today! Sometimes those journeys into the (metaphorical) dusty end of the library can be facinating – other time just a bore. I guess this was the later!

  • Vedran Hasimbegovic says:

    Hey, thanks for posting this synthesis! It’s a nice synthesis and good that they refer to Marc Julia and colleagues who pioneered this method during their Lysergic acid efforts. Julia’s is in my opinion the most creative route to Lysergic acid so far.

    However, it’s a bit surprising that they didn’t try to improve upon Julia’s original concept. As it happens, the 5-bromo-indole substrate should give rise to two isomeric aryne intermediates – one productive (triple bond between positions 5 and 4) and one useless (triple bond between positions 6 and 5). Placing the halide on position 4 instead of 5 should solve the problem as only the productive aryne intermediate would be able to form. I guess that would improve the yield substantially. Of course, a less nucleophilic base than sodium amide, say LiTMP, wouldn’t hurt either.


    • SH says:

      Check out their initial publication (Org. Lett, 2009, 11, 2349) – 4-bromo and 5-bromo react similarly, but the 5-bromo is easier to synthesize.

  • retro-Claisen says:

    Not a bad synthesis… i have to say i prefer rawal’s ring closing step- the pd-cat. enolate arylation was more effective. Unfortunatly, the synthesis of said precursor was a battle. Garg would get better selectivity if he could convince the negative charge to sit more on the carbon of the enolate rather than the oxygen… thats how rawal gets his selectivity.

  • VB says:

    Congratulations to the Garg lab for the wonderful synthesis. I don’t want to hijack the discussion away from welwit C, but would like to clarify a few things.
    In Rawal’s welwit D synthesis, the TBS enone was synthesized from 3-Me anisole via a four step sequence (Birch, hyrolysis, epoxidation, base/TBSCl) and not from quinic acid (which is a seven step sequence). The refs cited for the enone in the manuscript did not explicitly state this which led to this confusion. Moreover, the quinic acid route would have been asymmetric while the welwit D synthesis was racemic. About the Pd enolate arylation, its not a Heck cyclization as mentioned on Njardarson’s site.

  • gippgig says:

    According to the SI cupric rather than cuprous chloride was used to introduce the Cl.

  • J.J.L.C. says:

    Garg pounds his way through another beast of a molecule, wow. Looks like he knows a thing or two about bending molecules to his will.

    Garg always celebrates with his students to show them he is humbled by their efforts, and he always makes sure the party matches the magnitude of the synthesis. This was taken just minutes afterwards. Look closely at 1:42, I’m very impressed.


  • Purple says:

    A question on nomenclature – TotSyn. calls the nitrogen a bridgehead nitrogen. Is this accurate? For example, tropane, DABCO and quinuclidine have a bridgehead nitrogen, where the nitrogen is actually at the bridgehead. However in this synthesis the nitrogen is only attached to the bridgehead carbon. How do you distinguish between the two via nomenclature? Better to call the above example a tertiary amine/isothiocyanate attached to a bridgehead?

  • Jostein says:

    “The team did this using an iodine promoted alkylation, presumably by formation of the halonium ion followed by attack by the bromo-indole.”

    You are probably right. I, however, thought of I2 as Lewis-acid promoting the Michael-addition.

    • Tot. Syn. says:

      The more I think about it, the less convinced I am that this reaction involved a halonium ion pathway. Must be Lewis-acid mediated as you and most other right-thinking chemists have suggested!

  • IITK chemist says:

    Iodine is indeed a mild Lewis-acid which promotes the conjugate addition. I fail to understand the iodonium ion pathway. What is the fate of iodo-compound generated in that pathway? I presume Iodine is catalytic.