Targeted Exploration of Bio-inspired Cascade Reactions: A One-Step Total Synthesis of Nesteretal A

Nesteretal A was recently isolated from a marine actinomycete. An appealing and challenging cage-structure along with an unusual biosynthetic pathway prompted us to explore an expeditious bio-inspired total synthesis of nesteretal A. An unconventional strategy was chosen and a cascade reaction starting from diacetyl was studied. Under organocatalytic conditions mimicking an aldolase-type sequence with a cyclic secondary amine, nesteretal A was detected and targeted through LC-MS/MS and NMR analyses. Starting from a double aldolization of three units, an intramolecular succession of aldolizations and acetalizations probably drives the highly reproducible formation of nesteretal A. An easy isolation protocol has been devised to overcome a non-surprising low yield but largely counterbalanced by the straightforwardness and cost-effectiveness of this first total synthesis of nesteretal A.