A Versatile Method for Solid-Phase Synthesis of Polyamines: Neuroactive Polyamine Toxins as Example

Abstract A general method for sequential synthesis of polyamines on solid-phase is described. Each polyamine chain elongation step is based on alkylation under Mitsunobu conditions of resin-bound amine, activated with a 2-nitrobenzenesulfonyl group. The Mitsunobu reaction was accomplished with 1,1’-(azadicarbonyl)dipiperidine and tributylphosphine, using 2-(trimethylsilyl)ethoxy-carbonyl-protected amino alcohols as the chain extension elements. The yield of the Mitsunobu reaction was optimized with respect to reaction time, reagent ratio and concentration, order of addition of the reagents, and temperature; the optimized yield approached 100%. The method was used for synthesis of philanthotoxin-433, a natural polyamine wasp toxin, and of its seven analogs, with all possible combinations of trimethylene and tetramethylene units separating the nitrogen atoms of the polyamine chain. The yields of purified end products were 23-40%.