Baran and Newhouse. JACS, 2008, ASAP. DOI: 10.1021/ja8042307.

This was one of the final presentations at the BOSS conference (which I’ve still not finished blogging), discussed as part of Baran’s impressive talk.  We can leap into the chemistry pretty quickly, as Baran pointed out in his lecture that there’s no biological activity. (However, I bet it does something.  Give it a go, Tim – you’ve got 2.5g going spare – try some in a nice strawberry and banana smoothie and get back to us…)¹

So for the first time in quite a while, I’m able to draw a convincing retrosynthesis.  The indole on the bottom was added in a Buchwald (Goldberg-Ullmann) copper mediated amination, using trans-1,2-diaminocyclohexane as the ligand, and achieving a cracking yield.  Also high-yielding was the Larock indole synthesis for the top indole, using a TMS acetalyene (as terminal alkynes don’t work well).  This takes us back to a highly substituted octahydropyrrolopyrrole (I didn’t even make that up…).  It’s work pausing for a second to consider the chemoselectivity of those events – the Larock synthesis is completely selective for the aryl iodide, leaving the aryl bromide intact for aminiation.

And that’s the key to this work – chemoselectivity.  Their key reaction for the synthesis of the above intermediate involved an oxidative coupling of an indole with an aniline, and then cyclisation of the resulting imine with a pendant amide to form the aminal centre.  If one considers the vast array of competing reactions possible, the chemistry looks kinda daunting; indeed, Baran’s literature search only showed hits for the competing processes – there was no precidence for his desired chemistry.

Sure enough, the first few attempts were met with little or no product, but shifting to NIS as the oxidant did the business in a more than reasonable yield.  Baran suggests that the mechanism initiates with N-haloaniline formation, but further work is apparently proceeding to confirm the full process.

So that’s it – all over in five steps (seven if you include preparation of the bromoindole) – with nary a protectiong group in sight.²

1. It should be noted that Tot. Syn. does not endorse the consumption of lab chemicals by mouth.  However, I was always tempted to try some dimethyl malonate.

2. I don’t count the methyl carbamates as protecting groups as such, as they are not removed – rather, they are transformed into methyl amines.

Newhouse, T., Baran, P.S. (2008). Total Synthesis of (±)-Psychotrimine. Journal of the American Chemical Society DOI: 10.1021/ja8042307