Bioinspired Total Synthesis of Brevianamide

Although already isolated by Birch et al. in 1969, it took 50 years for the first total synthesis of brevianamide A (1). Published in Nature Chemistry from the research group of Andrew Lawrence (University of Edingburgh, UK), the authors not only present a synthetic access, they also make a new proposal for the biosynthetic origin of this complex alkaloide. They envisioned that the oxidation of the natural occuring dehydroxydeoxy-brevianamide E (4) could deliver 3. This intermediate then should undergo a retro 5-exo-trig cyclixation and a [1,2] alkyl shift yielding in Diels Alder precursor 2.

To test their hypothesis they started to synthesize 4 out of commercially available tryptophan methyl ester 5. After protection of the primary amine with 6, indole 7 was subjected to reverse prenylation conditions with 8 yielding in 9 in 69% yield over 2 steps. The following unusual saponification prevents the partial deprotection of the amine and delivers 10 which was directly transformed into the acid chloride and afterwards coupled with amine 11.  Finally 12 was deprotected to 4. Note that the authors were able to synthesize this precursor in only 5 steps (34% yield.)