We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

In this article the utility of phosphoramidite ligands in enantioselective Au I catalysis was explored in the development of highly diastereo-and enantioselective Au I -catalyzed cycloadditions of allenenes. A Au I -catalyzed synthesis of 3,4-disubstituted pyrrolidines and γ-lactams is described. This reaction proceeds through the enantioselective Au I -catalyzed cyclization of allenenes to form a carbocationic intermediate that is trapped by an exogenous nucleophile, resulting in the highly diastereoselective construction of three contiguous stereogenic centers. A computational study (DFT) was also performed to gain some insight into the underlying mechanisms of these cycloadditions. The utility of this new methodology was demonstrated through the formal synthesis of (-)-isocynometrine.

By adjusting the electronic properties of the ancilliary ligands high selectivity can be achieved for either gold(I)-catalyzed [4+2]- or [4+3]-cycloaddition reactions of diene-allenes. Triarylphosphitegold(I) complexes are employed as catalysts for a [4+2]-cycloaddition reactions leading to alkylidenecyclohexenes. Conversely, di-t-butylbiphenylphosphinegold(I)-catalyzed reactions afford cycloheptadienes via [4+3]-cycloaddition reactions.

It is shown that [4+3] and [4+2] cycloaddition pathways are accessible in the Au(I) catalysis of allene-dienes. Seven-membered ring gold-stabilized carbenes, originating from the [4+3] cycloaddition process, are unstable and can rearrange via a 1,2-H or a 1,2-alkyl shift to yield six- and seven-membered products. Both steric and electronic properties of the AuL+ catalyst affect the electronic structure of the intermediate gold-stabilized carbene and its subsequent reactivity.