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Totally Synthetic by Paul H. Docherty, 1 August 2008

Total Synthesis of Psychotrimine


T. Newhouse, P. S. Baran, J. Am. Chem. Soc. 2008, 130, 10886-10887.

DOI: 10.1021/ja8042307

Baran pointed out that there’s no biological activity, so we can focus on the total synthesis:

The indole on the bottom was added in a Goldberg-Ullmann amination modified by Buchwald, using trans-1,2-diaminocyclohexane as the ligand, and achieving a high yield. Also high-yielding was the Larock indole synthesis for the top indole, using trimethylsilylacetylene, as terminal alkynes don’t work well. Fortunately, 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 highly substituted octahydropyrrolopyrrole 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 somewhat 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 - the total synthesis needed five steps (seven if you include preparation of the bromoindole) - with nary a protectiong group in sight. (I don’t count the methyl carbamates as protecting groups as such, as they are not removed - rather, they are transformed into methyl amines).