Garg, Huters, Quasdorf, Styduhar. JACS, 2011, ASAP. DOI: 10.1021/ja206538k
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!