Synthesis of Skeletally Diverse Alkaloid-Like Small Molecules

A synthetic approach to skeletally diverse alkaloid-like compounds, involving two consecutive three-component reactions, was developed. First, reaction between a range of secondary amines, carbonyl compounds and triazines yielded cyclic imines. Crucially, the identity of the substituents in the amine and carbonyl compound components determined through a folding pathway - the alkaloid-like scaffold that was prepared. The cyclic imine products were substrates for a second reaction, most usually a Joullie-Ugi reaction with an isocyanide and a carboxylic acid. Thus, the final products were, in general, ultimately derived from five separate components, and wide and independent variation of the substitution of each scaffold was possible. The 43 products were based on 28 distinct graph-node level frameworks. The high skeletal diversity of the products stemmed both from the folding pathway used to define the scaffolds of the cyclic imines, and from cyclic substituents used in each of the components.