Synthesis of Naamidine A and Selective Access to N2-Acyl-2-aminoimidazole Analogues

A short and scalable synthesis of naamidine A, a marine alkaloid with a selective ability to inhibit epidermal growth factor receptor (EGFR)-dependent cellular proliferation, has been achieved. A key achievement in this synthesis was the development of a regioselective hydroamination of a monoprotected propargylguanidine to deliver N-3-protected cyclic ene-guanidines. This permits the extension of this methodology to prepare N-2-acyl analogues in a fashion that obviates the troublesome acylation of the free 2-aminoimidazoles, which typically yields mixtures of N-2- and N-2,N-2-diacylated products.