A novel diterpenoid lactone-based scaffold for the generation of combinatorial libraries

A novel labdane diterpenoid-based scaffold: 14-deoxyandrographolide has been identified for the generation of combinatorial libraries using solid-phase methods. To allow access to a larger pool of building blocks with wide structural diversity, 14-deoxy andrographolide has been linked to 2-chlorotrityl chloride resin. This was followed by a series of solid-phase reactions carried out on the C-3 hydroxyl and the C-8(17) double bond. The details of our synthetic strategies involving coupling of the resin, solid-phase acetylation under neutral conditions, esterification, oxidation, epoxidation reactions and formation of oxime esters from oximes are presented here. The utility of the scaffold has been demonstrated by synthesizing a small, 20 member, library of 14-deoxyandrographolide derivatives via esterification and oxime ester formation using five alkyl and five aryl carboxylic acids.