Reductive alkylation on a solid phase: Synthesis of a piperazinedione combinatorial library

The synthesis of a prototype trisubstituted piperazinedione combinatorial library of 1,000 compounds has been achieved from three precursor sets — two sets of ten α-amino acids and one set of ten aldehydes. A sodium triacetoxyborohydride-mediated reductive alkylation was crucial to the success of the multi-step synthesis on resin. This protocol represents a new method to augment compound files rapidly with novel heterocyclic entities for high-speed screening.