A range of tertiary amines was constructed using a “traceless” linker on a polystyrene resin (REM resin), starting from secondary amines, primary amines, and resin-bound “ammonia”. The methodology is characterized by three essential steps conducted under ambient conditions:  (1) coupling of the starting amine (Michael addition) to the resin, (2) activation (quaternization), and (3) cleavage of the product amine (Hofmann elimination). The linker is compatible with both acid and base sensitive protecting group strategies. The nature of the chemistry ensures that the tertiary amine products are obtained in consistently high purity (95% or greater). After cleavage of the product, REM resin is regenerated and can be reused for repeat syntheses. The yield and purity of repeat batches is maintained over 5 cycles, allowing the automated synthesis of >0.5 g quantities of pure tertiary amine.

The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.

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