Totally Synthetic by Paul H. Docherty, 24 March 2007
Total Synthesis of Hapuindole U and Ambiguine H
P. S. Baran, T. J. Maimone, J. M. Richter, Nature 2007, 446, 404-408.
It’s not a regular occurrence that synthetic publications have such a high level of anticipation, but the synthesis of Hapalindole U and Ambigune H by Phil Baran and co-workers at the Scripps Institute in California has had the community at fever-pitch. Featuring the trademark Baran-blend of old-school and cutting edge synthetic technology, the total synthesis started with a literature synthesis of a relatively simple terpene, which was directly coupled with a bromoindole.
So on with the synthesis:
Nice. They actually investigated the coupling with plain indole, but even though they got a good yield, the subsequent 6-exo-trig cyclisation went best with the bromide in-place. Interestingly, radical cyclisation conditions went via a 7-endo-trig route, which I wouldn’t have thought to be so facile.
I’ve missed out the next few steps, primarily because they are a little less novel… Anyway, with Hapuindole U done, all that was required was to install the tert-prenyl unit onto C2 of the indole - but direct methods weren’t compatible with the isonitrile group. However, following a protocol developed by Danishefsky, they formed the pentacyclic chloroimidate by addition of prenyl-9-BBN.
A Norrish-type 1 cleavage of the chloroimidate is followed by the usual hydrogen abstraction allowed deborylation and reduction back to the indole with the prenyl group in place - nice!
Sweet total synthesis, over in six steps! I can’t believe how good that last sequence is… Anyway, we’ll look at welwitindolinone A and fischerindole I in subsequent posts…